Emerging T-Cell Engagers and Novel Immunotargets in Multiple Myeloma

 

 

 

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3. Health Care Data and Analytics

The EMR plays a crucial role in centralizing patient information, making it easily accessible and in a format flexible and optimized for billing. However, since the different EMR systems don’t interact well with others, this dream has not come to fruition—yet. EMRs are certainly a big advancement over paper charts, but improvements in digital interactions to complete connectivity still need further enhancements. The use of big data and analytics can be very powerful with the right data, infrastructure, and analytic tools.

4. Patient Education and Support

This is a powerful tool when used by legitimate health care providers, health care systems, and nonprofit organizations that specialize in disease-specific education and research support. Tools like mobile apps and patient portals allow access to education materials, resources, and communication between patients and the health care system. However, this is also a double-edged sword, as some online educational materials or misconceptions may mislead patients. Pointing out the difference between these educational materials to patients and families is very crucial.

5. Research and Clinical Trial Advancements

Real-world data often informs new directions for future clinical trials with cancer therapeutics. In addition, AI may also help with algorithms to identify eligible patients for specific clinical trials.

All of these digital health care applications have greatly improved clinical care and research in hematology/oncology over the past several decades. The future is bright for the development, testing through clinical trials, and eventual dissemination of novel therapies and treatments to improve the lives of our patients diagnosed with a malignancy.

Digital health care applications have revolutionized oncology over the last decade and are embedded in the daily lives of physicians, health care providers, and patients. Digital applications such as electronic medical records (EMRs), telemedicine, mobile health apps, and artificial intelligence (AI) have greatly enhanced the ability of physicians to provide state-of-the-art health care and translational research to oncology patients. A few examples of areas that have been improved by these technologic advancements include the following:

1. Diagnostics and Screening

a. Genomic sequencing: This technique, instrumental in precision medicine, identifies tumor-specific targets to improve the specificity of cancer treatment on a personalized, individual basis.

b. Liquid biopsies: Using patient specimens, such as plasma, to detect circulating tumor DNA has revolutionized cancer diagnostics, early detection, treatment monitoring, and surveillance. This offers an extremely sensitive and practical way of monitoring for remission and/or early relapse detection in many tumor types.

c. Radiomics: This technology provides an innovative approach to extracting quantitative data from medical imaging, such as CT or PET scans. This may also allow for more personalized data for tumor targeting.

2. Treatment Pathways and Decision Support

AI-driven clinical decision support systems enable hematology/oncology physicians to access patient data, medical literature, and clinical guidelines to create personalized treatment plans. This area has expanded significantly as knowledge and available treatment options for selected tumor types have increased. As new information is published, the modifications can be made quickly to keep the data current.

Revolutionizing Oncology in the Digital Age

Effects on Health Care Providers

Abstract

Background: Bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapies have transformed the management of hematologic malignancies, including relapsed/refractory multiple myeloma (RRMM), lymphomas, and leukemias. These approaches enable targeted cytotoxicity through T-cell redirection and engineered cellular activity, achieving high response rates in heavily pretreated populations. Data presented at the 2025 Immune Cell Effector Therapies (ICE-T) Symposium highlighted expansion beyond B-cell maturation antigen (BCMA) to additional targets such as GPRC5D and FcRH5, alongside emerging multitarget and next-generation constructs aimed at improving durability and overcoming resistance.

Methods: This narrative review summarizes key findings from the 2025 ICE-T Symposium, integrating data from clinical trials, real-world studies, and contemporary guideline-based management, with a focus on efficacy, safety, sequencing, and emerging therapeutic platforms.

Results: Across hematologic malignancies, immune-based therapies demonstrated substantial and clinically meaningful activity, with outcomes varying by disease subtype, target antigen, and therapeutic platform. In multiple myeloma, BCMA-directed bispecific antibodies, including teclistamab and elranatamab, achieved overall response rates (ORRs) of approximately 63% and 61%, respectively, in heavily pretreated populations, with median progression-free survival (PFS) of approximately 11 to 17 months across pivotal studies. Talquetamab demonstrated ORR of approximately 73% to 74% in the MonumenTAL-1 study (NCT03399799), supporting efficacy in post-BCMA settings. Cevostamab has shown promising early-phase activity, with response rates of approximately 55% to 60% at higher dose levels, reflecting the expansion of therapeutic targets beyond BCMA.

In B-cell lymphomas, CD19-directed CAR T-cell therapies, including axicabtagene ciloleucel and lisocabtagene maraleucel, produced high response rates with durable remissions in relapsed/refractory large B-cell lymphoma, with long-term follow-up demonstrating sustained survival in a subset of patients. Among bispecific antibodies, epcoritamab achieved an ORR of approximately 60% to 65%, whereas glofitamab demonstrated an ORR of approximately 45% to 50% in heavily pretreated populations, supporting their role as effective off-the-shelf therapeutic options. In acute lymphoblastic leukemia, CD19-directed CAR T-cell therapies, including tisagenlecleucel and brexucabtagene autoleucel, achieved high rates of remission with deep measurable residual disease negativity, supporting their role as definitive or bridging strategies in relapsed disease.

Beyond hematologic malignancies, early-phase data highlighted the expansion of T cell–redirecting therapies into solid tumors. The DLL3-directed bispecific antibody tarlatamab demonstrated clinically meaningful activity in relapsed small cell lung cancer and has received accelerated regulatory approval based on response rate and durability.

Safety profiles were broadly consistent across platforms. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were frequent but predominantly low grade and manageable with IL-6 blockade and corticosteroids. Infections and prolonged cytopenias represented the principal drivers of morbidity, emphasizing the need for structured supportive care. Contemporary recommendations from the NCCN and International Myeloma Working Group support proactive toxicity mitigation, antimicrobial prophylaxis, and multidisciplinary management.

Emerging strategies, including trispecific antibodies, dual-target CAR T-cell constructs, and allogeneic “off-the-shelf” cellular therapies, demonstrated promising early efficacy and represent key approaches to improving durability, overcoming resistance, and expanding access across hematologic malignancies.

Conclusions: T cell–redirecting therapies represent a central pillar in modern oncology, delivering high response rates across hematologic malignancies with expanding roles in earlier treatment settings. Future progress will depend on improving durability, optimizing sequencing, mitigating toxicity, and enhancing real-world deliverability through next-generation and multitarget platforms.

Introduction

The National ICE-T Symposium is a multidisciplinary forum focused on advancing the clinical implementation of immune-based cancer therapies, particularly cellular therapies and bispecific antibodies. The inaugural National ICE-T Congress was held on July 26, 2025, in Orlando, Florida, bringing together experts from both academic and community oncology settings. Developed through collaborative efforts including the Florida Society of Clinical Oncology and the US Myeloma Innovations Research Collaborative, the symposium aims to bridge the gap between innovation and real-world practice, with a focus on improving access, safety, and delivery of immune effector therapies beyond specialized centers.

The 2025 program highlighted rapidly evolving platforms such as CAR T-cell therapy and bispecific T-cell engagers across multiple hematologic malignancies including multiple myeloma, lymphomas, and leukemias, as well as emerging applications in solid tumors. Key themes included treatment efficacy, toxicity management (notably CRS and neurotoxicity), outpatient implementation, and strategies to expand patient access.

A defining feature of the symposium is its emphasis on academic-community integration and multidisciplinary collaboration, enabling translation of advances into practical, scalable care models. Collectively, the ICE-T Symposium serves as a platform to align innovation with deliverability, supporting broader adoption of immune effector therapies in routine oncology practice.

By Carmel Awadallah, MD, Internal Medicine Resident, St. John Episcopal Hospital, NY;

Anas Zayad, MD, PGY-1, Internal Medicine, Hamad Medical Corporation, Doha, Qatar

Emerging T-Cell Engagers and Novel Immunotargets in Multiple Myeloma

 

Al-Ola Abdallah, MD, spoke about the importance of the ICE-T Congress and emphasized that a major benefit of CAR T-cell therapy is its administration as a single infusion. Unlike traditional maintenance therapies, patients do not need to adhere to a schedule of weekly intravenous infusions or daily pills. Although official confirmation of effectiveness typically happens at the 1-month mark, clinical benefits can often be observed as early as 1 to 2 weeks post infusion.

 

Shebli Atrash, MD, discussed the evolving landscape of multiple myeloma treatment, specifically focusing on the use of bispecific antibodies. He emphasized that the clinical use of these agents is closer than many realize.

From Single Targets to Multiantigen Precision

At the 2025 National ICE-T Congress in Orlando, Florida, Shebli Atrash, MD, associate professor of cancer medicine and myeloma specialist at Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, presented an update on the evolving role of BiTEs in multiple myeloma. His discussion emphasized the transition from early BCMA–focused strategies toward broader antigen targeting, including GPRC5D and FcRH5, with emerging interest in multiantigen constructs.

Rather than positioning bispecific antibodies as isolated late-line therapies, the current paradigm increasingly considers antigen diversity, treatment sequencing, and immune sustainability as central to long-term disease control.

BCMA Bispecifics in Current Practice: Teclistamab and Elranatamab

The discussion opened with a review of the 2 most established BCMA × CD3 bispecific antibodies currently in clinical use, teclistamab and elranatamab. These agents redirect endogenous T cells toward BCMA-expressing plasma cells and have demonstrated reproducible activity in patients who are heavily pretreated. Across pivotal trials such as the phase 1/2 MajesTEC-1 (NCT03145181/NCT04557098) and phase 2 MagnetisMM-3 (NCT04649359), ORRs consistently approach 70% in triple-class–refractory disease, with median durations of response of approximately 12 months. Importantly, emerging real-world data appear largely concordant with these clinical trial results, supporting the feasibility and effectiveness of bispecific antibody therapy outside of controlled research settings.

Earlier Use: Maintenance and Consolidation Strategies

Evidence from studies such as the phase 3 EMN30/MajesTEC-4 trial (NCT05243797) suggests that BCMA-directed bispecific antibodies may induce deep and clinically meaningful responses, including minimal residual disease (MRD) negativity, when deployed in posttransplant consolidation or maintenance settings. Building on these observations, multiple phase 3 trials—MajesTEC-3 (NCT05083169), MajesTEC-7 (NCT05552222), MajesTEC-9 (NCT05572515), and MonumenTAL-6 (NCT06208150)—are actively evaluating teclistamab-based combinations with established agents, including daratumumab, pomalidomide, and carfilzomib. Collectively, these efforts reflect a broader shift toward earlier integration of bispecific antibodies in the multiple myeloma treatment continuum, while recognizing that optimal timing, patient selection, and long-term benefit remain areas of active investigation.

GPRC5D Targeting: Talquetamab as a Post-BCMA Option

Talquetamab, a GPRC5D × CD3 bispecific antibody, has emerged as a clinically important option for patients previously exposed to BCMA-directed therapies. In the phase 2 MonumenTAL-1 study (NCT04634552), talquetamab achieved an ORR of 74%, with a median duration of response of 17.5 months. The toxicity profile, characterized by dysgeusia, cutaneous changes, and nail disorders, is consistent with known GPRC5D expression patterns. Combination regimens explored in trials such as the phase 1 TRIMM-2 (NCT04108195) and phase 1 MonumenTAL-2 (NCT05050097) have reported response rates approaching 90%, although these intensified strategies necessitate vigilant infection monitoring given the cumulative immunosuppressive burden.

Bispecific Antibodies as Bridging Therapy Before CAR T-Cell Therapy

Atrash highlighted increasing real-world experience using talquetamab as a bridging therapy prior to BCMA-directed CAR T-cell infusion, which was previously presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition. In a cohort of 77 patients treated following leukapheresis, 85% successfully proceeded to CAR T-cell infusion, with ORRs during the bridging period approaching 95%. Notably, most treatment-related adverse events resolved before CAR T-cell administration, suggesting that this strategy can provide effective interim disease control without compromising CAR T-cell manufacturing or subsequent therapeutic efficacy.

FcRH5 Targeting: Expanding Antigen Coverage

Cevostamab, an FcRH5 × CD3 bispecific antibody, represents a third immunologic axis in multiple myeloma therapy. Updated findings from the phase 1 GO39775 study (NCT03275103) demonstrated an ORR of approximately 60% and PFS approaching 17 months. Because FcRH5 is expressed across multiple stages of B-cell maturation, targeting this antigen may help mitigate antigen escape mechanisms observed with more narrowly expressed targets such as BCMA.

Trispecific Antibodies: Early Clinical Experience

Advances in trispecific antibody engineering aim to simultaneously engage multiple tumor antigens while activating T cells, thereby addressing resistance driven by antigen loss. Agents such as ISB 2001, which targets BCMA, CD38, and CD3, and JNJ-79635322, which targets BCMA, GPRC5D, and CD3, were discussed as early examples of this strategy. Preliminary clinical data indicate activity in patients who have relapsed after CAR T-cell therapy or prior bispecific antibody exposure. Although these findings remain early, trispecific constructs are being actively explored as a potential means of overcoming treatment resistance in heavily pretreated disease.

Cross-Trial Patterns: Efficacy and Safety

Across trials targeting BCMA, GPRC5D, and FcRH5, bispecific antibodies demonstrate broadly consistent efficacy, with ORRs ranging from 60% to 75% and median PFS spanning approximately 11 to 17 months. CRS is common but is predominantly low-grade. Nevertheless, infections and cytopenias remain frequent and clinically consequential toxicities. As emphasized by Atrash, routine incorporation of immunoglobulin replacement, antimicrobial prophylaxis, and growth-factor support has become essential to the safe and sustainable delivery of bispecific antibody therapy.

 

Shebli Atrash, MD, highlighted
that clinicians are entering a "practical 'aha' moment" in patient care. His primary message is that neurotoxicity management must begin before symptoms even start. This proactive approach is essential
for ensuring patient safety and
treatment efficacy.

Clinical Integration Within the Myeloma Treatment Landscape

Rather than competing with CAR T-cell therapy, bispecific antibodies are increasingly viewed as complementary components of a broader immunotherapeutic strategy. Potential roles include use as bridging therapy prior to CAR T-cell therapy, deployment of alternative antigen targets following CAR T-cell therapy relapse, and incorporation into MRD-positive consolidation or maintenance approaches. Optimal sequencing and long-term positioning continue to evolve as clinical experience and trial data mature.

Take-Home Message

The rapid development of bispecific and multispecific antibodies has fundamentally reshaped the immunotherapeutic landscape of multiple myeloma. Teclistamab and elranatamab remain foundational BCMA-directed agents, while talquetamab firmly establishes GPRC5D as a validated post-BCMA target. Cevostamab expands antigen coverage through FcRH5 targeting, and trispecific antibodies represent a promising emerging strategy for heavily pretreated disease. Importantly, bispecific antibodies function alongside, rather than in place of, CAR T-cell therapy. Ongoing efforts are now focused on refining sequencing, mitigating immune-related toxicity, and improving response durability, positioning bispecific antibodies as a central pillar of contemporary myeloma care.

Charting the Future of Myeloma

Barry Paul, MD, on the Expanding Frontier of CAR T-Cell Therapy

Transforming the Multiple Myeloma Landscape

Over the past 5 years, CAR T-cell therapy has fundamentally reshaped expectations for patients with relapsed/refractory (R/R) multiple myeloma. Once reserved as a last-line salvage approach, BCMA-directed CAR T-cell products are now challenging long-standing treatment paradigms and prompting consideration of earlier integration into disease management.

At the 2025 Orlando Oncology Forum, Barry Paul, MD, assistant professor at the Atrium Health Levine Cancer Institute, Atrium Health Wake Forest University School of Medicine in Charlotte, North Carolina, delivered a comprehensive presentation titled “Advances of CAR T Therapy in Myeloma.” His discussion traced the evolution of BCMA-directed CAR T-cell platforms, reviewed emerging targets such as GPRC5D, examined real-world safety and durability data, and highlighted next-generation strategies to improve persistence, safety, and access.

Throughout the session, Paul emphasized a unifying message: The long-term success of CAR T-cell therapy will be defined not solely by depth of response but also by durability, tolerability, and the systems required to reliably deliver these therapies at scale.

From KarMMa to CARTITUDE: Establishing the BCMA CAR T-Cell Era

Paul began by revisiting the pivotal trials that established BCMA-directed CAR T-cell therapy as a cornerstone of relapsed/refractory multiple myeloma treatment. Idecabtagene vicleucel (ide-cel) first demonstrated meaningful clinical benefit in the phase 2 KarMMa-1 study (NCT03361748), achieving an ORR of 73% and a complete response (CR) rate of 33% in a heavily pretreated population with a median of 6 prior lines of therapy. Median PFS was 8.8 months, representing a substantial advance in an otherwise refractory setting.

The subsequent phase 3 KarMMa-3 trial (NCT03651128) marked a critical inflection point. In patients with triple-class–exposed disease, ide-cel significantly outperformed standard regimens, increasing median PFS from 4.4 months to 13.3 months. As Paul noted, this study signaled a shift from end-stage salvage toward earlier integration, reflecting increasing clinician confidence and expanding adoption beyond highly specialized centers.

Ciltacabtagene autoleucel (cilta-cel) further elevated expectations. In the phase 1/2 CARTITUDE-1 trial (NCT03548207), cilta-cel achieved an ORR of 98%, with stringent CR in 83% of treated patients and a median PFS exceeding 24 months. Notably, a subset of patients remained progression-free beyond 3 years. The phase 3 CARTITUDE-4 trial (NCT04181827) extended these benefits to earlier relapse settings, demonstrating superiority over standard triplet regimens, even among lenalidomide-exposed patients. As Paul emphasized, BCMA-directed CAR T-cell therapy is no longer experimental but has become a therapeutic pillar in myeloma care.

Beyond First-Generation Constructs: Armored and Dual-Target CAR T-Cell Strategies

Building on first-generation successes, Paul highlighted innovations designed to enhance CAR T-cell persistence and mitigate relapse. Armored CAR T-cell constructs, such as anitocabtagene autoleucel, incorporate engineered cytokine signaling elements to improve T-cell fitness, promote sustained expansion, and reduce antigen-escape–driven relapse. Early data from studies such as the phase 3 iMMagine-3 trial (NCT06413498) suggest improved durability, with prolonged remissions linked to enhanced cellular persistence.

Parallel advances in costimulatory domain engineering are refining CAR T-cell activation kinetics. Optimized 4-1BB signaling and modified antigen-binding affinities are being leveraged to smooth T-cell activation, reduce the severity of CRS, and preserve antitumor potency. As Paul explained, the field is increasingly focused on designing CAR T cells not only to eradicate disease but also to endure, recognizing that persistence biology is now as critical as cytotoxic strength.

Beyond BCMA: GPRC5D and Emerging Immunologic Targets

Relapse following BCMA-directed therapy has underscored the need for alternative targets. GPRC5D has emerged as a compelling option, particularly in post-BCMA relapse. Early-phase trials of GPRC5D-directed CAR T-cell therapies, including arlocabtagene autoleucel, have reported ORRs exceeding 70% in heavily pretreated populations, with evidence of durable responses.

Importantly, GPRC5D expression is typically retained after BCMA modulation, supporting its role in sequential therapeutic strategies. However, its expression in keratinized tissues is associated with characteristic on-target toxicities, including skin, nail, and taste disturbances, which are generally low grade and manageable.

Paul also discussed dual-antigen CAR T-cell platforms targeting both BCMA and GPRC5D. These approaches aim to reduce clonal escape and extend response duration, reflecting a broader shift toward multidimensional immunologic platforms capable of sustained immune surveillance rather than transient tumor control.

The Allogeneic Revolution: Off-the-Shelf CAR T for Broader Access

Despite the transformative impact of autologous CAR T-cell therapy, manufacturing delays, logistical complexity, and patient attrition remain significant barriers. These challenges have driven the development of allogeneic, off-the-shelf CAR T-cell products designed for rapid deployment.

P-BCMA-ALLO1 exemplifies this approach. Using CRISPR-based gene editing to eliminate endogenous T-cell receptors and reduce the risk of graft-vs-host disease (GVHD), this allogeneic BCMA CAR T-cell platform offers near-immediate availability, favorable early safety signals, and response rates that, in select cohorts, approach those of autologous products. Paul noted that such therapies may finally provide viable options for patients unable to wait weeks for manufacturing.

Additional allogeneic strategies, including GPRC5D-directed CAR T cells and natural killer (NK) cell–based constructs, are in development and may further reduce cytokine toxicity while simplifying delivery.

Efficacy and Safety: Depth of Response Meets Durability

Cross-trial analyses confirm that both ide-cel and cilta-cel achieve deep and sustained remissions in relapsed/refractory multiple myeloma. Nonetheless, toxicity remains a central consideration. CRS occurs in the majority of BCMA CAR T-cell recipients, typically in the 80% to 90% range, but is most often grade 1 or 2 and manageable with tocilizumab and short courses of corticosteroids. The incidence of ICANS has fallen below 10% with contemporary dosing and monitoring strategies.

Prolonged cytopenias represent an ongoing challenge, affecting up to 40% of patients for months after infusion and contributing to infection risk. Effective management requires proactive growth factor support, antimicrobial prophylaxis, immunoglobulin replacement for hypogammaglobulinemia, and vigilant long-term surveillance. As Paul emphasized, CAR T-cell therapy represents a continuum of care that extends well beyond the infusion itself.

Real-World Outcomes and Evolving Sequencing Strategies

Real-world data from major academic and community centers increasingly mirror clinical trial outcomes, reinforcing the feasibility of broader adoption. Paul highlighted growing interest in deploying CAR T-cell therapy earlier in the disease course, including at second relapse, in high-risk early relapse, and within clinical trials comparing CAR T-cell therapy with autologous stem cell transplantation (ASCT) in frontline settings, such as the phase 3 CARTITUDE-6 (NCT05257083).

Careful patient selection remains essential. Performance status, marrow reserve, infection risk, and organ function all influence outcomes, underscoring the importance of timing and multidisciplinary evaluation. As Paul summarized, selecting the right patient at the right time is critical to maximizing benefit while minimizing harm.

Next-Generation Innovation: Expanding the Pipeline

Paul concluded by surveying the rapidly expanding landscape of next-generation CAR technologies. Emerging targets, including FcRH5, SLAMF7, and integrin β7, are under active investigation. Novel engineering strategies, such as multiplexed CARs capable of sequential antigen engagement and logic-gated CARs requiring dual-antigen recognition, aim to enhance specificity and reduce off-tumor toxicity. Advances in ultrarapid manufacturing, with production timelines under 5 days, may further narrow the gap between diagnosis and treatment.

As the field continues to evolve, Paul predicted that distinctions between autologous and allogeneic platforms will increasingly blur, leading to hybrid approaches that combine durability with accessibility.

Managing the New Toxicity Era in Multiple Myeloma

When Innovation Meets Immune Toxicity

The introduction of CAR T-cell therapy and bispecific antibodies has redefined the therapeutic landscape for patients with relapsed/refractory multiple myeloma. These immune effector therapies, largely directed against BCMA and GPRC5D, have produced unprecedented response rates and depth of remission in heavily pretreated populations. However, this therapeutic success has been accompanied by an expanding spectrum of immune-mediated, hematologic, and neurologic toxicities that require early recognition, structured mitigation strategies, and close multidisciplinary coordination.

At the 2025 Moffitt Scientific Symposium, Syeda Saba Kareem, PharmD, BCOP, a clinical pharmacist supervisor in malignant hematology at Moffitt Cancer Center in Tampa, Florida, delivered a comprehensive presentation examining the evolving toxicity profile associated with immune effector therapies. Drawing on real-world experience, pivotal clinical trial data, and updated consensus guidelines, she provided clinicians with a pragmatic framework for managing immune effector–related adverse events across both inpatient and outpatient care settings.

A Rapidly Expanding Therapeutic Landscape

Kareem began by outlining the rapid growth of immune effector therapies in multiple myeloma. BCMA-directed CAR T-cell products, including ide-cel and cilta-cel, remain central to treatment strategies. At the same time, bispecific antibodies such as teclistamab, elranatamab, linvoseltamab, and the GPRC5D-targeted agent talquetamab have significantly expanded available options. Although these agents share a common T cell–redirecting mechanism, they differ substantially in activation kinetics, toxicity onset, and adverse event profiles.

Across both clinical trials and real-world cohorts, immune effector therapies are consistently associated with CRS, ICANS, prolonged cytopenias, and a substantial infectious burden. Kareem emphasized that appreciating these mechanistic and temporal differences is critical for optimizing safety without compromising therapeutic efficacy.

CRS: Early Recognition and Rapid Response

CRS remains the most frequently encountered immune effector–related toxicity. Kareem reviewed the American Society for Transplant and Cellular Therapy 2019 CRS grading criteria, emphasizing fever, hypotension, and hypoxia as the defining diagnostic features. She noted that the timing of CRS varies significantly by therapeutic modality, with CAR T cell–associated CRS typically emerging within the first week after infusion and peaking between days 7 and 14. In contrast, CRS associated with bispecific antibodies often occurs within hours of administration and is generally shorter in duration.

The underlying cytokine surge, driven primarily by IL-6, IFN-γ, and tumor necrosis factor-α, is both predictable and highly amenable to early intervention. Kareem underscored that time to tocilizumab administration is one of the most powerful modifiable factors influencing clinical outcomes. She emphasized that prompt initiation of IL-6 blockade, with escalation to corticosteroids when indicated, effectively controls symptoms without diminishing antimyeloma efficacy.

Prophylactic CRS Prevention: A New Standard Emerges

Building on this concept, Kareem highlighted emerging data supporting prophylactic cytokine modulation, particularly during initiation of bispecific antibody therapy. Data from the MajesTEC-1 study demonstrated that administering prophylactic tocilizumab prior to the first bispecific antibody dose significantly reduced the incidence of CRS while preserving response rates and MRD depth. These findings have influenced evolving practice patterns, with the NCCN 2026 Multiple Myeloma Guidelines now recognizing prophylactic IL-6 blockade as a reasonable strategy in selected patients.

Kareem noted that the field is entering an era in which preemptive cytokine modulation may fundamentally reshape how clinicians approach T-cell redirection therapies, shifting management from reactive intervention to anticipatory prevention.

ICANS and Neurotoxicity: Precision in Assessment and Intervention

Although less common than CRS, ICANS represents a potentially severe and time-sensitive complication. Kareem explained that ICANS typically develops within 2 to 8 days following therapy and may occur concurrently with or after CRS. Clinical manifestations range from mild confusion and language disturbances to tremors and seizures.

She emphasized the continued utility of the Immune Effector Cell–Associated Encephalopathy (ICE) score as a standardized bedside assessment tool. Management relies primarily on corticosteroids, as IL-6 blockade does not effectively treat ICANS due to limited penetration. In refractory cases, emerging evidence supports the use of anakinra as an adjunctive therapy.

Delayed Neurotoxicity: The Emerging Parkinsonian Syndrome

One of the most concerning topics of Kareem’s presentation was delayed neurotoxicity, a syndrome increasingly recognized weeks to months after CAR T-cell therapy. This entity is characterized by parkinsonian features such as tremor, rigidity, and bradykinesia, as well as cranial nerve palsies and cognitive changes. Delayed neurotoxicity has been most prominently associated with cilta-cel in the CARTITUDE program, with pharmacovigilance data demonstrating increased reporting of parkinsonism and cranial nerve disorders.

Kareem highlighted emerging evidence suggesting that absolute lymphocyte count may serve as a clinically meaningful biomarker of risk. Data from the International Myeloma Working Group registry indicate that patients with an absolute lymphocyte count exceeding 3.0 × 109/L may have up to a 9-fold increased risk of delayed neurotoxicity. She stressed that monitoring lymphocyte kinetics is no longer theoretical, but a practical tool for identifying high-risk patients. Management strategies include corticosteroids, intravenous immunoglobulin, and intrathecal therapy in select refractory cases, along with extended neurologic monitoring beyond day 100 for all CAR T-cell recipients.

Cytopenias: A Persistent and Underrecognized Burden

Hematologic toxicity remains a pervasive and often underappreciated consequence of immune effector therapy, affecting most treated patients. Kareem discussed the CAR-HT score, a validated risk-stratification tool that incorporates baseline hemoglobin, platelet count, absolute neutrophil count (ANC), C-reactive protein, and ferritin levels. Patients with high CAR-HT scores experience more prolonged neutropenia, higher infection rates, and increased nonrelapse mortality.

She emphasized that cytopenias should be anticipated rather than managed reactively. Appropriate use of growth factor support, careful timing to avoid exacerbating CRS, holding bispecific antibodies until adequate neutrophil recovery, and risk-adapted antimicrobial prophylaxis are essential components of care. As Kareem noted, predictable toxicity becomes preventable when addressed with structured, preemptive strategies.

Infections: A Major Driver of Morbidity and Mortality

Infectious complications remain a leading cause of morbidity and mortality following immune effector therapy. Kareem noted that infection risk peaks between days 30 and 100 after treatment initiation and remains elevated with ongoing bispecific antibody exposure. Infection rates approach 70% in major BCMA-directed trials, driven by hypogammaglobulinemia, corticosteroid exposure, cytokine blockade, and prolonged cytopenias.

She reviewed guideline-based prophylactic strategies, including extended antiviral therapy, antibacterial prophylaxis during neutropenia, antifungal coverage for high-risk patients, Pneumocystis jirovecii prophylaxis, and immunoglobulin replacement for severe hypogammaglobulinemia. Emerging real-world data further support these measures, with retrospective analyses demonstrating that primary intravenous immunoglobulin (IVIG) prophylaxis substantially reduces severe infections and significantly prolongs infection-free survival in patients receiving bispecific antibodies.

GPRC5D-Directed Toxicities: A Distinct Clinical Syndrome

Talquetamab, the first GPRC5D-directed bispecific antibody, exhibits a distinct toxicity profile driven by on-target, off-tumor effects. These include dysgeusia, xerostomia, nail dystrophy, and dermatologic toxicities that can significantly impair quality of life and threaten treatment adherence. Kareem emphasized the importance of early recognition and proactive supportive care, including topical therapies, nutritional support, and prompt involvement of dermatology and supportive care specialists, to mitigate symptoms and prevent unnecessary discontinuation.

Toward Rational Dose De-Escalation

Kareem concluded by discussing emerging evidence supporting dose optimization strategies, particularly for talquetamab. Data from the MonumenTAL-1 study suggest that reduced-intensity dosing schedules administered every 2 to 4 weeks can maintain therapeutic efficacy while significantly reducing high-grade skin and nail toxicities. She noted that this evolution reflects the maturation of the bispecific antibody field, shifting from maximal dosing toward rational, patient-centered optimization.

Introduction

Muhammad Umair Mushtaq, MD, associate professor of medicine in the Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas (KU) Medical Center, delivered a comprehensive presentation titled “Tumor-Infiltrating Lymphocyte (TIL) Therapy in Metastatic Melanoma.” His review traced the evolution of TIL therapy from a laboratory concept to an FDA-approved, clinically accessible option for patients with advanced melanoma who have exhausted standard treatments. Mushtaq detailed the biologic rationale, manufacturing workflow, pivotal clinical data, safety considerations, and future directions, underscoring that TIL therapy has progressed from experimental to practical and scalable within contemporary oncology practice.

The Unmet Need in Advanced Melanoma

Despite transformative advances with immune checkpoint inhibitors (ICIs) and BRAF/MEK-targeted therapies, outcomes remain suboptimal for a substantial subset of patients with metastatic melanoma. Approximately 40% to 65% of patients demonstrate primary resistance to ICIs, and up to one-third of initial responders relapse within 2 years. Following failure of both immune and targeted therapies, chemotherapy response rates fall below 10%, with a median survival of less than 7 months. As Mushtaq emphasized, this population represents one of the most challenging postimmunotherapy settings, positioning TIL therapy as a strategy to reengage antitumor immunity when conventional options have been exhausted.

What TIL Therapy Brings to the Table

TIL therapy leverages the patient’s own tumor-reactive T cells—immune cells that naturally migrate into the tumor microenvironment and recognize tumor antigens. The process entails surgical resection of a tumor lesion, isolation, and ex vivo expansion of TILs using IL-2 and activating signals, followed by reinfusion of billions of activated lymphocytes after lymphodepleting chemotherapy. In contrast to CAR T cells, which are engineered to target a single antigen, TILs are polyclonal and recognize multiple tumor-associated antigens simultaneously. This breadth of reactivity addresses tumor heterogeneity, reduces the risk of antigen escape, and sustains immune pressure across diverse tumor clones. The first commercial TIL product, lifileucel (LN-144), received FDA approval in 2024 based on phase 2 data demonstrating durable responses in heavily pretreated metastatic melanoma.

How Lifileucel Is Manufactured and Delivered

Mushtaq outlined the lifileucel treatment pathway in detail. Tumor samples measuring at least 1.5 cm are surgically resected and shipped to a central manufacturing facility, where TILs are expanded ex vivo over approximately 22 days in the presence of IL-2 and anti-CD3, typically yielding more than 1.8 × 109 viable cells. Prior to infusion, patients undergo lymphodepleting chemotherapy with cyclophosphamide

(60 mg/kg intravenously daily for 2 days) and fludarabine (25 mg/m² intravenously daily for 5 days). Lifileucel is then administered as a onetime intravenous infusion, followed by up to 6 doses of high-dose IL-2 (600,000 IU/kg). From tumor resection through infusion, the overall course is generally completed within 3 to 4 weeks. As Mushtaq noted, the process is intensive yet finite, intended to reset the immune landscape with a single intervention.

Clinical Evidence

Pivotal Trials and Long-Term Outcomes

The pivotal C-144-01 phase 2 study (NCT02360579) enrolled patients with metastatic melanoma who had received at least 2 prior systemic therapies, including ICIs and, when appropriate, BRAF/MEK inhibitors. In the initial cohort of 66 patients, the ORR was 36%, including 2 CRs and 20 partial responses. The median time to best response was 1.4 months, and the median duration of response (DOR) was not reached at

18 months of follow-up. An expanded pooled analysis of 153 patients demonstrated an ORR of 31%, a median overall survival (OS) of 13.9 months, and survival beyond 4 years in 22% of patients—an unprecedented outcome in this refractory setting. Most grade 3/4 adverse events were hematologic and attributable to lymphodepleting chemotherapy and IL-2, including cytopenias, febrile neutropenia, and transient hypotension. These events were largely manageable with standard supportive care, and no unexpected immune-related or significant neurologic toxicities were observed.

How TIL Therapy Compares With Existing Modalities

Checkpoint inhibitors function by reinvigorating endogenous T cells within the tumor microenvironment, and their efficacy depends on the presence and durability of those cells. Once T cells
are depleted, irreversibly exhausted, or rendered anergic, ICIs may lose effectiveness. TIL therapy overcomes this limitation by replacing the exhausted T-cell compartment with newly expanded, tumor-reactive lymphocytes. Compared with CAR T-cell therapy, TILs do not require genetic modification, potentially reducing on-target, off-tumor toxicity. Their polyclonal composition mitigates relapse driven by single-antigen loss, and the finite nature of treatment—a onetime infusion followed by a short IL-2 course—may be more acceptable to patients than prolonged maintenance strategies. For many, the possibility of durable remission following a time-limited intervention is compelling.

Safety and Practical Considerations

The toxicity profile of lifileucel is predictable and largely time-limited, driven primarily by lymphodepleting chemotherapy and IL-2 administration. Common events include transient cytopenias, fever, hypotension, and capillary leak–like symptoms. These toxicities are typically reversible with supportive measures such as intravenous fluids, vasopressors when indicated, growth factor support, transfusions, and infection prophylaxis. With growing experience, many centers have optimized IL-2 dosing, shortened inpatient stays, and standardized supportive care pathways. As Mushtaq emphasized, successful delivery requires preparation and multidisciplinary coordination rather than apprehension.

Updated Data and Real-World Experience

Extended pooled analyses continue to demonstrate durable benefit, with median DOR remaining unreached and a subset of patients maintaining remission beyond 36 months. Early real-world experience suggests outcomes comparable to those reported in clinical trials, supporting broader adoption beyond major academic centers. Ongoing registries are evaluating predictors of benefit, including lactate dehydrogenase levels, tumor burden, and baseline lymphocyte counts, to refine patient selection and optimize treatment timing.

Future Directions for TIL Therapy

Looking ahead, Mushtaq highlighted multiple avenues for continued development. Clinical trials are evaluating TIL therapy in additional malignancies, including non–small cell lung cancer, cervical cancer, ovarian cancer, and other solid tumors. Combination strategies with ICIs may further enhance T-cell persistence and tumor infiltration. Manufacturing innovations aim to shorten culture times, automate processes, and establish regional production hubs to reduce cost and turnaround time. Exploratory efforts are also investigating allogeneic or off-the-shelf TIL approaches, although challenges related to antigen matching and safety remain. As Mushtaq concluded, the future of TIL therapy lies not in replacing checkpoint inhibition, but in complementing it—uniting immune reinvigoration with

cellular replacement.

 

Mushtaq discussed the difficulty of treating patients with metastatic melanoma after immunotherapy. Tumor-infiltrating lymphocyte therapy offers deep and durable responses in one-third of this population.

The manufacturing and delivery of lifileucel can be “logistically challenging” to arrange, according to Mushtaq. He highlighted these processes of lifileucel treatment and affirmed the tumor-infiltrating lymphocytes' efficacy in the immunotherapy-pretreated metastatic melanoma population.

Why This Topic Matters

CAR T-cell therapy has transformed the treatment landscape for hematologic malignancies, producing deep and durable remissions in diseases once considered uniformly fatal. As the technology matures, attention is increasingly shifting toward a more challenging frontier—solid tumors—where immunologic, structural, and biological barriers have historically limited progress.

Anup Kasi, MD, MPH, associate professor of medicine and a specialist in gastrointestinal (GI) oncology at KU Medical Center, delivered a comprehensive presentation titled “Role of CAR T in GI Cancers.” His talk examined both the promise and the limitations of applying CAR T-cell technology to GI malignancies, emphasizing how innovation, scientific rigor, and sustained translational effort are gradually—but meaningfully—moving the field forward.

The Duality of Promise and Challenge

Kasi opened by revisiting the well-documented success of CAR T-cell therapy in hematologic cancers. These engineered cellular therapies offer exquisite target specificity, the potential for long-term disease control, and a level of personalization that surpasses traditional systemic treatments. As “living drugs,” CAR T cells can persist in vivo, surveil for residual malignant cells, and mediate durable immune responses.

This biologic rationale supports efforts to extend CAR T-cell therapy into solid tumors, including hepatocellular carcinoma (HCC), gastric and gastroesophageal junction (GEJ) cancers, and pancreatic, cholangiocarcinoma, and colorectal malignancies. Emerging tumor-associated antigens such as GPC3 and claudin 18.2 (CLDN18.2) offer opportunities for precision immunotherapy in these settings.

However, Kasi underscored that the obstacles in solid tumors remain substantial. These include a dense and hypoxic tumor microenvironment, immunosuppressive cytokine networks, heterogeneous antigen expression, physical barriers to effective T-cell trafficking, and overlapping antigen expression between malignant and normal tissues. As he noted, success in this arena requires not only engineering the cell but also re-engineering the ecosystem in which it must function.

Targeting GPC3 in HCC

Insights From C-CAR031

Among the most compelling advances discussed was the C-CAR031 phase 1 study (NCT05155189), a first-in-human trial evaluating a GPC3-directed, TGF-β–resistant “armored” CAR T-cell therapy in advanced HCC. GPC3 is an attractive target because it is an oncofetal antigen highly expressed in HCC, while showing minimal expression in healthy adult tissues.

The C-CAR031 construct incorporates a dominant-negative TGF-β receptor designed to counteract one of the most potent immunosuppressive pathways within the tumor microenvironment.

Early Clinical Signals

Kasi characterized the early clinical findings as encouraging and instructive. The therapy demonstrated a favorable safety profile, with no unexpected dose-limiting toxicities. CRS was generally manageable and predominantly low grade, while early signals of biologic activity—including reductions in α-fetoprotein levels and radiographic tumor shrinkage—were observed in heavily pretreated patients.

He emphasized that meaningful clinical responses in late-line HCC are notable given the disease’s limited effective systemic options, reinforcing the concept that armored CAR T-cell platforms may help overcome key microenvironmental barriers.

CLDN18.2

A Promising Target in Gastric and GEJ Cancers

The discussion then turned to CLDN18.2-directed CAR T-cell therapy, which is gaining traction in gastric and GEJ malignancies. Kasi highlighted the CT041-ST-01 trial (NCT04581473) assessing satricabtagene autoleucel, a pivotal phase 2 study comparing CLDN18.2 CAR T-cell therapy with physician’s choice in previously treated gastric and GEJ cancers.

The trial met its primary end point for PFS, demonstrated objective responses across multiple subgroups, and showed that some patients achieved durable disease control beyond 6 months. Toxicities were consistent with expected cytokine-mediated effects and were largely low grade and reversible. According to Kasi, the ability to achieve consistent disease control without prohibitive toxicity represents a meaningful advance and one of the strongest clinical signals for CAR T-cell therapy in GI cancers to date.

KU Cancer Center

Driving Innovation Through Translational Research

Kasi also highlighted the expanding cellular therapy portfolio at KU Cancer Center, underscoring the institution’s growing leadership in GI-focused immunotherapy. Ongoing and emerging programs include CLDN18.2 bispecific T-cell engagers, GPC3-directed CAR T-cell constructs for HCC, mesothelin-targeted CAR T-cell therapies for cholangiocarcinoma and peritoneal mesothelioma, and P-MUC1C-ALLO1, an allogeneic CAR T-cell platform targeting MUC1C in pancreatic, colorectal, and ovarian cancers.

In addition, T-cell receptor therapies targeting KRAS G12D, one of the most common oncogenic drivers in GI malignancies, are under active development. Allogeneic CAR T-cell approaches offer potential advantages in scalability, logistics, and time to treatment. As Kasi emphasized, this work reflects an integrated clinical ecosystem that brings together molecular oncology, immunology, and translational science.

Reframing CAR T-Cell Therapy for Solid Tumors

Despite the enthusiasm, Kasi cautioned that CAR T-cell therapy for solid tumors remains an evolving—not yet mature—technology. Persistent scientific challenges include impaired T-cell trafficking, immune exclusion driven by suppressive stroma, heterogeneous antigen density, and the risk of off-tumor toxicity.

To address these barriers, multiple strategies are under investigation, including combinations with immune checkpoint inhibitors, cytokine modulation to enhance CAR T-cell persistence, oncolytic viruses to remodel the tumor microenvironment, logic-gated CAR designs to improve specificity, and dual- or multitarget constructs to limit antigen escape. He stressed the importance of precision patient selection guided by antigen profiling and biomarker-driven enrollment, supported by emerging tools such as liquid biopsy monitoring, spatial transcriptomics, and functional imaging of CAR T-cell trafficking.

A New Chapter in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains one of the most aggressive and therapeutically refractory malignancies in oncology. Despite incremental advances with platinum-based chemotherapy and the incorporation of PD-L1 inhibitors into frontline treatment, outcomes following disease relapse remain poor. Median survival after progression rarely exceeds 6 months, and response rates to second-line therapies are disappointingly low.

Daniel Carrizosa, MD, MS, director of thoracic oncology at Atrium Health Levine Cancer Institute, delivered a compelling presentation titled “Developments of T-Cell Engager Therapies in Lung Cancer: Taking a BiTE Out of Small Cell.” His talk centered on the rapidly advancing field of DLL3-directed BiTEs, a therapeutic class that has reignited optimism in a disease long characterized by stagnation.

Carrizosa contextualized these agents within the broader immuno-oncology landscape, emphasizing their ability to mobilize a patient’s endogenous T cells to directly target tumor antigens, effectively bridging innate and adaptive immune responses.

DLL3 Biology: Targeting What Makes Small Cell Distinct

To establish the biological rationale for BiTE therapy in SCLC, Carrizosa began by reviewing the molecular features of DLL3. Unlike many tumor-associated antigens, DLL3 exhibits a uniquely restricted expression profile: It is present in more than 80% of SCLC tumors, absent from normal adult tissues, and highly enriched in neuroendocrine malignancies. This pattern makes DLL3 an especially attractive and specific therapeutic target.

DLL3 initially gained attention as the target of the antibody-drug conjugate (ADC) rovalpituzumab tesirine (Rova-T). Although early studies suggested potential activity, the program was ultimately halted because of unacceptable toxicity and insufficient durability of response. Importantly, however, the failure of Rova-T did not invalidate DLL3 as a target.

How BiTEs Work

Precision Without Permanence

BiTEs are engineered molecules composed of 2 linked single-chain antibody fragments. One arm binds CD3 on T cells, while the other targets DLL3 on tumor cells. This dual engagement creates an immunologic synapse that rapidly activates cytotoxic T cell–mediated tumor killing, independent of antigen presentation or costimulatory signaling.

Carrizosa highlighted several advantages of BiTEs over cellular therapies such as CAR T cells, including off-the-shelf availability, predictable pharmacokinetics, adjustable dosing, and reversibility of toxicity. Importantly, BiTEs do not require genetic modification of immune cells.

Tarlatamab in Clinical Trials

From DeLLphi-300 to DeLLphi-301

The focal point of Carrizosa’s presentation was the clinical development of tarlatamab, the first-in-class DLL3-directed BiTE.

Early-phase data from the phase 1 DeLLphi-300 study (NCT03319940) demonstrated proof of concept in heavily pretreated patients with relapsed SCLC. Objective response rates approached 25%, with disease control exceeding 60%, even in a population with median survival expectations of only 4 to 5 months.

These findings paved the way for the pivotal phase 2 DeLLphi-301 trial (NCT05060016), which compared tarlatamab with investigator-selected chemotherapy. The results were striking. Median OS improved to approximately 14 months with tarlatamab compared with 8 months with standard therapy. PFS was similarly prolonged, and some responses persisted beyond 12 months, suggesting the emergence of a survival “tail” reminiscent of early checkpoint inhibitor breakthroughs.

From a safety standpoint, CRS occurred in roughly half of patients but was overwhelmingly low grade and manageable with step-up dosing, premedication, and early use of tocilizumab. ICANS was rare, occurring in fewer than 3% of patients. No new safety signals emerged with longer follow-up.

Positioning BiTEs in the SCLC Treatment Landscape

Carrizosa next addressed where tarlatamab fits within the current therapeutic paradigm for SCLC. Although frontline platinum-etoposide combined with PD-L1 blockade achieves initial disease control, relapse is nearly universal. Beyond lurbinectedin and topotecan, effective treatment options remain limited.

In this context, a 20% to 25% response rate with tarlatamab represents a clinically meaningful advance. Responses were observed across both platinum-sensitive and platinum-resistant disease, including in patients previously exposed to immune checkpoint inhibitors. Moreover, symptom burden and quality of life often stabilized during treatment.

Beyond Tarlatamab

Next-Generation DLL3 and Bispecific Platforms

The success of tarlatamab has accelerated the development of next-generation bispecific and multispecific constructs. Among these are trispecific T cell–activating constructs that incorporate a

DLL3-binding domain, a CD3-binding domain, and an albumin-binding domain to extend half-life.

These platforms offer the potential for less frequent dosing, improved pharmacologic control, and eventual outpatient administration. In parallel, combination strategies are being explored, including BiTEs paired with checkpoint inhibitors, chemotherapy, radiation, or oncolytic viruses to enhance antigen release and immune priming.

Managing Toxicity

Practical Lessons From Clinical Experience

Effective CRS mitigation remains central to the safe administration of BiTE therapy. Carrizosa emphasized structured step-up dosing schedules, inpatient monitoring during the first cycle, standardized premedication protocols, and early intervention with tocilizumab as best practices. Notably, no treatment-related deaths were reported in pivotal studies.

Financial and Logistical Considerations

Beyond clinical considerations, BiTE therapy introduces logistical and economic challenges. Initial inpatient monitoring, infusion-based administration, and evolving reimbursement frameworks require careful planning. Encouragingly, Carrizosa noted that payers are increasingly adopting CAR T cell–like coverage models, improving patient access to these novel therapies.

Broader Implications

Reimagining Immunotherapy for Solid Tumors

The success of DLL3-directed BiTEs extends beyond SCLC, offering proof that thoughtful antigen selection, controlled T-cell activation, and rational dosing can overcome the immunologic barriers of traditionally “cold” tumors. Ongoing trials are evaluating DLL3 targeting in large-cell neuroendocrine carcinoma and extrapulmonary small cell cancers.

The Case for CAR T

A Decade of Approvals and Adoption

Jose Sandoval-Sus, MD, assistant member of Moffitt Malignant Hematology and Cellular Therapy at Memorial Healthcare System in Pembroke Pines, Florida, opened his presentation with a timeline spanning 2017 through 2024 that underscored the speed with which CAR T-cell therapy entered routine clinical practice. Initial approvals in pediatric and young adult B-cell acute lymphoblastic leukemia and R/R diffuse large B-cell lymphoma (DLBCL) were followed by expanded indications in follicular lymphoma (FL) and mantle cell lymphoma (MCL), with more recent extensions into chronic lymphocytic leukemia and additional relapsed settings. The overarching message was that CAR T-cell therapy is no longer confined to a niche salvage role. With each successive approval, more patients have become eligible earlier in their disease course, supported by advances in manufacturing efficiency, improved recognition and management of treatment-related toxicities, and increasing experience across a growing number of treatment centers. This foundation set the stage for a deeper examination of how pivotal and randomized trials have reshaped the role of CAR T-cell therapy relative to traditional transplant-based strategies.

Third Line and Beyond in LBCL

Proof of Concept and Durability

Sandoval-Sus reviewed the foundational trials that established CAR T-cell therapy as a viable option for heavily pretreated LBCL. The phase 1/2 ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel) demonstrated an ORR of 83% and a CR rate of 58%, with strong early activity and a 5-year OS approaching 47%. The phase 2 JULIET trial (NCT02445248), evaluating tisagenlecleucel (tisa-cel), reported an ORR of 53% and a CR rate of 39%, confirming its feasibility across different expansion kinetics. The phase 1 TRANSCEND-NHL 001 trial (NCT02631044), assessing lisocabtagene maraleucel (liso-cel), reported an ORR of 73% and a CR rate of 53%, with notably low rates of high-grade CRS and a 5-year OS of approximately 38%. Collectively, these studies demonstrated durable survival plateaus in a population for whom standard salvage therapies had historically offered little benefit.

Importantly, Sandoval-Sus emphasized that these outcomes have been largely replicated in real-world practice. Large registry data sets evaluating axi-cel and liso-cel have shown slightly attenuated but still clinically meaningful long-term PFS and OS, including a 2-year PFS survival rate of approximately 50% in ZUMA-1. The maintenance of survival plateaus outside major academic centers underscores the feasibility of delivering CAR T-cell therapy across a broad range of clinical settings.

Second-Line LBCL

Head-to-Head Trials That Redefined the Standard

The presentation then shifted to the pivotal second-line studies that directly compared CAR T-cell therapy with salvage chemotherapy followed by ASCT. In the phase 3 ZUMA-7 trial (NCT03391466), axi-cel demonstrated superior outcomes in patients with primarily refractory or early relapsing large B-cell lymphoma, with significantly higher response and CR rates, prolonged event-free survival (EFS), and improved 3-year OS compared with standard therapy. Although toxicities such as CRS and ICANS were common, they were anticipated and largely manageable, establishing axi-cel as a second-line standard of care for eligible patients.

Similarly, results from the phase 3 TRANSFORM trial (NCT03575351) showed that liso-cel significantly improved EFS and PFS compared with standard therapy, with higher CR rates and lower rates of high-grade toxicity. Three-year follow-up confirmed sustained benefits across efficacy end points, further solidifying liso-cel as a second-line benchmark. In contrast, the phase 3 BELINDA trial (NCT03570892) evaluating tisa-cel did not demonstrate improved outcomes over standard therapy. Sandoval-Sus highlighted prolonged manufacturing and infusion delays as key contributors to this result, emphasizing that in aggressive LBCL, speed to infusion is a critical determinant of outcome.

Real-world data from early second-line axi-cel cohorts have mirrored these trial findings, with high response rates and encouraging 1-year EFS and OS. These observations reinforce the shift toward CAR T-cell therapy as the preferred second-line approach, with autologous transplantation increasingly reserved for select clinical scenarios. Sandoval-Sus also previewed emerging frontline consolidation data from the phase 2 ZUMA-12 trial (NCT03761056), suggesting that earlier use of CAR T-cell therapy in high-risk disease may further deepen clinical benefit, pending confirmation in larger randomized studies.

Revolutionizing the Treatment of B-Cell Lymphomas

Latest Breakthroughs in CAR T-Cell Therapy

Earlier Use, Resistance, and Equitable Delivery

In closing, Sandoval-Sus outlined key priorities for the next 5 years, including strategies to mitigate early relapse through MRD and circulating tumor DNA–guided surveillance, exploration of earlier-line deployment in high-risk disease, and continued efforts to overcome resistance driven by antigen loss and T-cell exhaustion. He emphasized that successful implementation would depend not only on scientific innovation but also on addressing logistical constraints such as speed, capacity, and insurance coverage to ensure equitable access.

Bispecific Antibodies and Chemoimmunotherapy in Relapsed DLBCL
Summary of Key Themes

Marc S. Hoffmann, MD, underscored that while CAR T-cell therapy remains the preferred option for eligible patients, bispecific antibodies now occupy essential roles before, between, and after cellular therapy. Although epcoritamab and glofitamab demonstrate broadly comparable antitumor activity, their logistical profiles differ substantially, including route of administration, treatment cadence, and duration of therapy. Rapid step-up dosing strategies can safely accelerate disease control in aggressive presentations when paired with structured steroid prophylaxis and close monitoring. Combination approaches incorporating chemotherapy may deepen responses but introduce higher risks of myelosuppression and infection, making patient selection and supportive care capacity critical determinants of success. Importantly, regulatory decisions and regional practice considerations can limit the real-world availability of biologically promising regimens. Across all settings, Hoffmann emphasized that patient selection, institutional readiness, and supportive infrastructure often outweigh small differences in response rates.

Orienting Principles: Where Bispecifics Fit

Hoffmann reaffirmed that CAR T-cell therapy remains the cornerstone for patients who are fit with early relapse or primary refractory disease. However, real-world barriers—including comorbidities, geographic distance, marrow reserve limitations, aggressive disease kinetics, and payer constraints—frequently preclude idealized sequencing. Within this landscape, bispecific antibodies serve multiple functions: rapid debulking in high-burden relapse, definitive therapy for patients unable or unwilling to pursue CAR T-cell therapy, and salvage therapy after CAR T-cell therapy failure.

He emphasized that treatment decisions should begin with patient goals, disease tempo, and logistical realities, before moving to agent selection, dosing strategy, and consideration of chemotherapy integration.

Monotherapy Experience

Counseling Beyond Response Rates

Rather than focusing on marginal differences in response rates, Hoffmann framed the choice between epcoritamab and glofitamab around feasibility, cadence, and patient logistics. Epcoritamab is administered subcutaneously with step-up priming followed by a full 48-mg dose, initially on a weekly schedule that later transitions to biweekly and monthly dosing. Observation is required after the first full dose, with steroid premedication to mitigate CRS.

In contrast, glofitamab is administered intravenously following mandatory obinutuzumab pretreatment, with step-up dosing to a fixed 30-mg dose on an every-3-week schedule as a time-limited course. This finite duration can be particularly appealing to patients balancing travel, employment, or caregiver responsibilities. Hoffmann advised clinicians to prioritize visit frequency, infusion infrastructure, monitoring capacity, and patient proximity to the treatment center when selecting between agents.

Why Rapid Step-Up Matters

A central theme of the presentation was the judicious use of rapid step-up dosing during cycle 1 for patients with bulky or rapidly progressive disease, organ compromise, or tenuous performance status. The goal is to achieve full therapeutic exposure within days rather than weeks, thereby stabilizing disease and alleviating symptoms. Hoffmann emphasized that accelerated dosing does not compromise safety when paired with structured steroid prophylaxis, mandatory observation during early doses, and clearly defined institutional algorithms for CRS, infection management, and escalation of care. As he noted, faster treatment is not synonymous with looser standards; rather, it can be safer when supported by robust systems.

Chemotherapy-Bispecific Combinations

Promise and Trade-Offs

The rationale for combining bispecific antibodies with chemotherapy lies in rapid tumor debulking, reduced tumor burden, and the potential to attenuate CRS severity, while maintaining sustained T-cell engagement for deeper remissions. However, these benefits come at the cost of increased myelosuppression, higher infection risk, and a greater likelihood of hospitalization, particularly in older or frail patients. As a result, careful patient selection and strong supportive care infrastructure are essential prerequisites for safely delivering combination regimens.

Glofitamab Plus GemOx (STARGLO)

Efficacy vs Adoption

Hoffmann reviewed the phase 3 STARGLO trial (NCT04408638), which evaluated glofitamab plus gemcitabine and oxaliplatin (GemOx) compared with rituximab-GemOx (R-GemOx) in transplant-ineligible R/R DLBCL. The combination demonstrated improvements in both PFS and OS, with early and sustained separation of survival curves. CRS events clustered in cycle 1 and were generally low grade with appropriate pretreatment and prophylaxis, while cytopenias and infections reflected expected GemOx-related toxicity. Despite these efficacy signals, the regimen was not approved in the US due to concerns regarding limited US enrollment and the relevance of the control arm. Hoffmann emphasized that trial design, external validity, and regulatory context ultimately determine whether a regimen enters routine practice.

Epcoritamab-Based Combinations in ASCT-Ineligible

and Eligible Patients

In patients who are older, heavily pretreated, or ASCT ineligible—including those previously exposed to CAR T-cell therapy—epcoritamab combined with GemOx has produced rapid responses, high complete remission rates, and durable disease control in selected cohorts. Toxicities have been manageable with step-up dosing, steroid prophylaxis, growth factor support, antimicrobial prophylaxis, and clear fever management pathways.

For patients who are transplant eligible with high risk of relapse, Hoffmann discussed integrating epcoritamab with platinum-based salvage regimens such as rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) to deepen metabolic responses prior to ASCT. Although early follow-up suggests encouraging posttransplant outcomes, cumulative toxicity and the need for coordinated logistics—including stem cell collection, imaging, and transfusion support—limit this strategy to centers with substantial operational capacity.

A Safety Blueprint for the Bispecific Era

Hoffmann outlined a comprehensive safety framework encompassing standardized premedication and step-up protocols, clearly defined CRS and ICANS triage pathways, proactive management of cytopenias and infections, and detailed cycle-1 scheduling that specifies observation periods, escalation criteria, and communication responsibilities. This infrastructure transforms accelerated dosing from a theoretical concept into a reproducible clinical pathway.

Treatment-Related Mortality

Keeping Risk in Focus

In older or non–transplant-eligible populations, treatment-related mortality remains clinically meaningful, particularly during early cycles. Mitigation strategies include rigorous precycle assessments, proactive growth factor planning, early initiation of intravenous antibiotics for febrile neutropenia, and transparent discussions with patients regarding the balance between rapid disease control and incremental risk when chemotherapy is layered onto bispecific therapy.

A Practical Algorithm for Real-World Decision-Making

Hoffmann concluded with a pragmatic framework emphasizing early assessment of CAR T-cell eligibility and urgency of disease control, thoughtful selection between monotherapy and combination strategies, and continuous reassessment of goals, quality of life, and next-line options. Central to this approach is the recognition that successful outcomes depend not only on biological efficacy but also on deliverability within the patient’s real-world context.

Mastering the Management of Adverse Effects of

Cellular Therapies in Lymphoma

As the clinical use of CAR T-cell therapy and other immune effector cell (IEC) platforms expands, the ability to recognize, grade, and manage treatment-related toxicities has become as critical as selecting the appropriate therapeutic product. In her presentation, Tiba Al Sagheer, PharmD, BCOP, BCACP, pharmacy quality improvement coordinator for transplant and cellular therapy and a hematology clinical pharmacy specialist at Miami Cancer Institute, positioned clinicians at the intersection of immunobiology and bedside care, translating consensus guidelines and institutional algorithms into pragmatic, stepwise strategies. These approaches aim to shorten time to intervention, reduce unnecessary steroid exposure, preserve antitumor efficacy, and anticipate complications unique to the cellular therapy era.

The Toxicity Landscape

Why Grading Comes First

Cellular therapies deliver unprecedented antitumor activity but are associated with a distinct, overlapping toxicity spectrum. Al Sagheer emphasized 5 domains clinicians must anticipate and systematically address: CRS, ICANS, hematologic toxicity, immunologic and infectious complications—including hypogammaglobulinemia and severe infections—and secondary malignancy risk. Because these events frequently coexist and evolve together, consistent grading is not merely documentation; it functions as operational triage that dictates activation of order sets, escalation of monitoring, intensive care unit (ICU) involvement, and timely initiation of tocilizumab or corticosteroids.

Toxicity frequency and severity are influenced by tumor burden, baseline inflammatory state, lymphodepletion intensity, and CAR costimulatory domain. Embedding these variables into preinfusion checklists and postinfusion monitoring pathways shifts programs from late salvage to early rescue.

CRS: Speed, Structure, and a Steroid-Sparing Strategy

CRS reflects supraphysiologic immune activation following IEC therapy. Early manifestations include fever, tachycardia, rigors, hypotension, hypoxia, and laboratory evidence of systemic inflammation. Severe CRS may progress to arrhythmias, capillary leak, shock, multiorgan dysfunction, or death. Risk is heightened by high disease burden, elevated inflammatory markers, baseline thrombocytopenia, intense lymphodepletion, larger cell doses with brisk expansion, and CD28-based costimulation, which is associated with earlier onset compared with 4-1BB constructs.

Practical bedside tools, such as the Endothelial Activation and Stress Index (EASIX) and modified EASIX scores, convert routine laboratory values—creatinine, lactate dehydrogenase, and platelet count—into actionable risk stratification. CRS grading hinges on fever, hypotension, and hypoxia; once antipyretics or cytokine blockade resolve fever, escalation is driven by oxygen and vasopressor requirements to avoid “grade drift” during hemodynamic deterioration.

Tocilizumab (8 mg/kg intravenously, maximum 800 mg per dose) remains the cornerstone of first-line therapy, with early administration shortening CRS duration without compromising antitumor efficacy. Corticosteroids are added when hypotension or hypoxia persists after IL-6 blockade or per product-specific protocols, with dose and frequency guided by CRS grade and trajectory to minimize cumulative exposure. For refractory CRS, anakinra and siltuximab are common next steps; in highly selected cases at experienced centers, Janus kinase (JAK) inhibitors or agents such as dasatinib may be considered. The guiding principle is physiology directed, methodical escalation rather than reliance on steroids alone.

Product-specific nuances inform prevention strategies. Many centers maintain separate algorithms for axi-cel or brexu-cel, favoring earlier steroid intervention, whereas liso-cel pathways reflect later toxicity onset. Risk-adapted prophylaxis—short dexamethasone courses around infusion and earlier tocilizumab triggers in high-risk patients—can reduce grade 3 or higher CRS and overall steroid burden without attenuating efficacy.

ICANS: A Distinct Neuroinflammatory Syndrome

ICANS is not simply CRS localized to the CNS. It encompasses a spectrum from subtle language and cognitive changes to dysgraphia, agitation, seizures, and cerebral edema. Because sedating medications can obscure neurologic decline, routine ICE scoring provides a reproducible framework for serial assessments.

Risk factors mirror those of CRS, including high disease burden, elevated inflammatory markers, high cell doses and expansion, and CD28-based constructs. Emerging data suggest associations between pre–CAR T-cell therapy clonal hematopoiesis and severe ICANS in select cohorts, and risk refinement may be enhanced by combining modified EASIX with C-reactive protein (CRP) and ferritin trends.

Management principles differ from CRS. Corticosteroids—typically dexamethasone or methylprednisolone—are first-line therapy, whereas grade 3 or higher events warrant prompt ICU admission. Levetiracetam is standard for seizure prophylaxis, and continuous electroencephalogram (EEG) monitoring is recommended when mental status fluctuates or seizures are suspected. For refractory ICANS, anakinra is increasingly used as a steroid-sparing adjunct. In highly selected, focal, and severe cases managed at experienced centers, intrathecal cytarabine or methotrexate has been associated with rapid improvement, although this remains a specialized practice.

When ICANS and CRS coexist, systemic cytokine storm is addressed with tocilizumab, whereas neurotoxicity remains steroid driven, supported by early respiratory and hemodynamic management.

Supportive-Care Bundles That Change Outcomes

Effective CRS and ICANS management extends beyond pharmacologic orders to comprehensive supportive-care bundles that prevent deterioration and shorten hospitalization. Early neurology consultation is essential for worsening ICE scores or focal deficits, with vigilance for airway protection and avoidance of sedatives that confound neurologic assessment. Infectious diseases expertise guides cultures, antimicrobial prophylaxis, and stewardship in the context of cytopenias and steroid exposure. Hematology input informs the timing of growth factor support outside the peak CRS, the consideration of thrombopoietin agonists for persistent thrombocytopenia, and decisions regarding bone marrow evaluation for atypical cytopenia patterns. Rehabilitation and psychosocial services address steroid myopathy, ICU deconditioning, delirium, and caregiver burnout. This team-based approach reframes toxicity management as a coordinated, multidisciplinary effort.

remain product-specific to balance toxicity control with maintained efficacy. Second, modulation of the cytokine axis with prophylactic anakinra—administered preinfusion or triggered by early fever—appears feasible and may reduce high-grade ICANS in select scenarios. Some centers are exploring combinations with BTK or JAK inhibition or alternative lymphodepletion regimens, such as bendamustine-based approaches, to further modulate risk. The unifying principle is selective, risk-adapted use rather than blanket prophylaxis.

IEC-Associated Hematotoxicity

The Silent Morbidity Driver

Unlike the dramatic onset of CRS or ICANS, ICAHT evolves over weeks and drives infection risk, transfusion requirements, health care utilization, and nonrelapse mortality. Risk increases with high marrow tumor burden, low baseline counts, elevated CRP or ferritin, multiple prior therapies, CD28 costimulation with intense cytokine exposure, and severe early CRS or ICANS—underscoring the interplay between baseline reserve and inflammatory load.

Structured frameworks provide shared language and guidance. The CAR-HT score predicts the severity and duration of preinfusion cytopenias, while European Hematology Association/European Society for Blood and Marrow Transplantation ICAHT grading stratifies postinfusion cytopenias by timing, depth, duration, and platelet-specific thresholds. Management centers on infection prevention with P jirovecii pneumonia and herpes virus prophylaxis, antifungal coverage in prolonged neutropenia or steroid exposure, and consideration of opportunistic pathogens in delayed recovery. Hematopoietic support includes judicious timing of granulocyte colony-stimulating factor (G-CSF), use of thrombopoietin agonists for sustained thrombocytopenia with bleeding risk, and rational transfusion strategies. When recovery deviates from expected patterns, reassessment of disease status, marrow function, and drug exposures should align with ICAHT pathways.

IEC-Associated HLH-Like Syndrome

Recognize Early, Act Decisively

IEC-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS) is a hyperinflammatory HLH-like syndrome that may occur concurrently with CRS, after apparent CRS resolution, or as an isolated late complication. Hallmarks include rapidly rising ferritin, worsening cytopenias, hypofibrinogenemia, coagulopathy, transaminitis, and multiorgan dysfunction. Because it can emerge after overt CRS has resolved, vigilance is essential. First-line therapy consists of anakinra administered every 6 to 12 hours with dexamethasone titrated to severity. Ruxolitinib is considered for persistent hyperinflammation, with etoposide or interferon-gamma blockade reserved for life-threatening, refractory cases at highly experienced centers. The clinical challenge lies in achieving robust cytokine control while limiting steroid exposure in immunocompromised, neutropenic patients.

Secondary Malignancy Risk

A Long-Term Obligation

Secondary malignancies—including myeloid neoplasms, solid tumors, and rare T-cell malignancies—are emerging survivorship considerations as more patients achieve durable remission. Structured long-term follow-up, meticulous documentation, and patient education regarding new symptoms and screening are now integral components of IEC programs.

The Next Generation

Faster, Smarter, and Off the Shelf

Looking ahead, Sandoval-Sus highlighted next-generation innovations aimed at addressing the remaining limitations of CAR T-cell therapy. Rapid manufacturing platforms such as YTB323 have reduced production times to less than 48 hours, a dramatic improvement over traditional multiweek processes. In a phase 2 cohort, YTB323 demonstrated high response and CR rates, a median PFS of approximately 15 months, and low rates of severe CRS and neurotoxicity. For patients with unstable disease, shortening the vein-to-vein interval may be lifesaving and could reduce reliance on bridging therapy.

Dual-target CAR T-cell constructs, such as zamtocabtagene autoleucel targeting CD19 and CD20, have been developed to mitigate antigen escape. Early clinical data demonstrated meaningful response rates, minimal high-grade toxicity, and relatively low rates of antigen-negative relapse, supporting dual targeting as a viable resistance-mitigation strategy. In parallel, allogeneic “off-the-shelf” CAR T-cell products such as ALLO-501 eliminate the need for individualized apheresis and patient-specific manufacturing. In early-phase studies, ALLO-501 demonstrated encouraging response durability with no GVHD, minimal neurotoxicity, and only low-grade CRS. These inventory-based platforms have the potential to expand access, particularly for centers distant from manufacturing hubs.

Beyond LBCL

CAR T in MCL, FL, and MZL

Sandoval-Sus also reviewed the expanding role of CAR T-cell therapy beyond LBCL. In mantle cell lymphoma, the phase 2 ZUMA-2 trial (NCT02601313) established brexucabtagene autoleucel (brexu-cel) as a benchmark therapy in patients previously exposed to Bruton kinase (BTK) inhibitors, with durable survival outcomes despite high-risk disease features. Nonetheless, adverse biology, such as blastoid morphology and TP53 mutation, remains associated with earlier relapse, highlighting the importance of effective bridging strategies, including noncovalent BTK inhibitors.

In follicular lymphoma, long-term follow-up from the phase 2 ZUMA-5 trial (NCT03105336) demonstrated sustained CRs and prolonged PFS, with a substantial proportion of patients remaining progression-free at 5 years. These findings suggest that functional cure may be achievable for a subset of patients with multiple relapsed disease. Similar durability has been observed with tisa-cel and liso-cel in later-line follicular lymphoma. In marginal zone lymphoma (MZL), although patient numbers are smaller, response rates and long-term outcomes remain highly encouraging, positioning CAR T-cell therapy among the most active available options in this setting. Sandoval-Sus emphasized thoughtful treatment sequencing in indolent lymphomas, often favoring bispecific antibodies first while reserving CAR T-cell therapy for situations where long-term disease control is the primary objective.

Safety, Practical Care, and Hidden Toxicities

The safety discussion revisited well-characterized toxicities such as CRS and ICANS, while emphasizing construct-specific differences in timing and severity. Axi-cel is associated with earlier and more intense toxicity, whereas liso-cel typically demonstrates later-onset and lower-grade events. These timelines inform monitoring strategies and escalation thresholds, with standardized management pathways incorporating preemptive anti–IL-6 therapy, early corticosteroids, and selective use of anakinra in refractory cases.

Equally important, Sandoval-Sus drew attention to “hidden toxicities” that are often underappreciated, including manufacturing delays, disease progression during bridging, infectious complications during immune reconstitution, and the substantial resource demands placed on certified treatment centers. He argued that rapid manufacturing and allogeneic platforms represent not only scientific advances but also critical access solutions that can reduce wait times and broaden eligibility.

From Concept to Clinic

As IEC programs mature, prevention has become a central objective. Two approaches dominate. First, steroid-based prophylaxis using short, protocolized dexamethasone courses around infusion, coupled with earlier tocilizumab thresholds, can reduce grade 3 or higher toxicities and total steroid exposure, particularly with axi-cel therapy. Timing and dosing

Dynamic Infection

Management in T-Cell Engagers

and CAR T-Cell Therapy

Introduction

The expanding use of IEC therapies—including CAR T-cell therapy and BiTEs—has transformed outcomes across multiple hematologic malignancies. Alongside these advances, however, infections have emerged as a dominant and potentially preventable source of morbidity and nonrelapse mortality. In her presentation, Aneela Majeed, MD, a transplant infectious disease specialist at the Cleveland Clinic, outlined a comprehensive, risk-adapted framework for infection prevention, surveillance, and management in patients receiving IEC therapies, emphasizing that effective infection control is now inseparable from successful cellular therapy delivery.

Why This Topic Matters

As CAR T-cell therapy and bispecific antibodies expand across disease settings, infections have become a leading driver of nonrelapse mortality. Randomized trials and real-world cohorts consistently demonstrate high infection rates across platforms and antigen targets. These risks demand a structured and dynamic approach that integrates baseline risk stratification, pathogen screening, time-phased antimicrobial prophylaxis, rapid empiric therapy, immunoglobulin replacement, disciplined antimicrobial stewardship, and revaccination strategies. Tailoring these interventions to local epidemiology and individual patient risk is essential for the safe and effective delivery of IEC therapies.

Framing the Landscape

Infection Burden in IEC Therapies

Majeed contextualized IEC therapies as highly effective yet intrinsically prone to infection. Prolonged cytopenias, mucosal barrier injury, exposure to corticosteroids or tocilizumab, B-cell aplasia, and T-cell dysfunction converge to heighten susceptibility to infection.

Pooled analyses underscore the magnitude of this risk. A meta-analysis of 45 studies encompassing 3591 patients reported an overall infection rate of approximately 34%, with grade 3 or higher infections in 16% and infection-attributable mortality near 2%, most commonly driven by pneumonia, upper respiratory infections, and bacteremia. A broader synthesis of 18 clinical trials and 28 real-world cohorts, including nearly 7600 patients, demonstrated that infections accounted for approximately half of all nonrelapse deaths, with respiratory and bloodstream infections predominating.

In bispecific antibody therapy—particularly in multiple myeloma—the signal is even stronger. Across pooled analyses, roughly half of patients experienced infections, one-fourth developed grade III/IV infections, and infection-related deaths accounted for approximately one-fourth of fatalities. BCMA-targeting bispecifics are associated with higher rates of neutropenia and severe infection compared with non–BCMA-targeting agents. Collectively, these data establish infection as a central determinant of outcomes and resource utilization in IEC programs.

The “Net State of Immunosuppression” Model

Majeed framed infection susceptibility through 3 interacting domains: host immune impairment, environmental exposures, and organ-specific or comorbidity-related vulnerabilities. T-cell dysfunction, B-cell aplasia, and prolonged neutropenia intersect with seasonal and health care–associated exposures, while organ damage further compounds risk. Together, these elements define the patient’s “net state of immunosuppression,” which should guide screening intensity, prophylaxis selection, and follow-up strategies.

Stratifying risk across defined treatment phases—lymphodepletion, the first 30 days, days 31 to 90, and beyond—allows clinicians to calibrate interventions, avoiding undertreatment and unnecessary antimicrobial exposure.

Screening and Baseline Evaluation

Pretherapy evaluation should be structured and systematic. Recommended assessments include targeted viral baselines such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) when indicated, seasonal respiratory pathogen testing, fungal diagnostics in neutropenic or symptomatic patients, baseline immunoglobulin (IgG) measurement to guide postinfusion monitoring, and evaluation for latent infections, including tuberculosis and viral hepatitis, in appropriate settings. Establishing these baselines enables rapid interpretation of posttherapy findings and timely intervention.

 

Antimicrobial Prophylaxis

Timing and Risk Alignment

Effective prophylaxis must align with neutropenia depth, immune reconstitution, and platform-specific risk. Invasive fungal infections occur in approximately 2% to 8% of patients following IEC therapy, with Candida infections clustering early and mold infections emerging later, particularly between days 31 and 90. Routine antifungal prophylaxis is not universally indicated. Mold-active azoles such as posaconazole or voriconazole are preferred for patients who are high risk, while echinocandins serve as alternatives when azoles are contraindicated.

Viral Prophylaxis and Surveillance

CMV reactivation occurs in roughly 10% of CAR T-cell recipients and is associated with worse outcomes. Risk-adapted surveillance enables preemptive therapy—typically with ganciclovir or valganciclovir—once institutional viral load thresholds are reached, particularly in patients exposed to corticosteroids or with profound lymphopenia. EBV reactivation and human herpesvirus 6 (HHV-6) encephalitis are less frequent but require targeted evaluation in patients with unexplained encephalopathy. Seasonal respiratory viruses remain a major driver of late morbidity, reinforcing the importance of vaccination and early antiviral therapy.

Recognizing and Treating Suspected Infection

Fever or clinical instability in IEC recipients warrants immediate action. Broad-spectrum empiric antibiotics should be initiated for fever of 38.0 °C or higher, new or worsening hemodynamic or respiratory compromise, or suspected sepsis—even in the absence of fever.

Preferred empiric regimens include cefepime, piperacillin-tazobactam, or meropenem, with vancomycin or linezolid added when methicillin-resistant Staphylococcus aureus, catheter-associated infection, soft tissue involvement, or instability is suspected. Early de-escalation based on cultures, biomarkers, and imaging is essential to limit toxicity and resistance.

A standardized fever workup includes blood cultures from all central lines and a peripheral draw, chest imaging, complete blood cell counts, metabolic panels, inflammatory markers, respiratory viral polymerase chain reaction testing, and fungal biomarkers when indicated.

Distinguishing CRS From Infection

CRS and infection share overlapping clinical features but differ in timing and context. CRS typically occurs within 1 to 2 weeks after CAR T-cell infusion and often lacks focal findings, whereas infection may occur at any time and is more likely to present with localizing symptoms or radiographic abnormalities. Because differentiation is often challenging, initial management commonly addresses both possibilities in parallel while diagnostic data mature.

Immune Reconstitution

IVIG and G-CSF

Hypogammaglobulinemia is common following IEC therapy. After CD19-directed CAR T-cell therapy,

IgG suppression may persist for up to 18 months. With BCMA-directed therapies, IgG levels below

400 mg/dL occur in approximately 69% of patients within 2 to 3 months, and a substantial proportion remain hypogammaglobulinemic beyond 1 year.

IVIG replacement is appropriate in patients with severe hypogammaglobulinemia early after therapy, those with recurrent infections, or those with active infection and low IgG levels. G-CSF is recommended for grade 3 or higher neutropenia to shorten neutropenia duration and reduce infection risk.

Vaccination

Timing and Clinical Value

Although humoral responses may be attenuated, T cell–mediated benefits persist. Reimmunization is recommended with influenza and COVID-19 vaccines approximately 3 months after therapy, RSV vaccination at a similar interval, and pneumococcal and other nonlive vaccines at 5 to 6 months. Live vaccines are generally deferred for more than 2 years and considered only with documented immune recovery. Patients should be counseled that a lack of measurable antibody responses does not eliminate clinical benefit.

Antimicrobial Stewardship

A center-based stewardship framework is essential to balance infection prevention with antimicrobial overuse. Key elements include discontinuing empiric antibiotics after 48 hours in afebrile patients without evidence of infection, escalating diagnostics when fever persists, early infectious disease consultation, and minimizing unnecessary broad-spectrum exposure. These strategies reduce resistance, toxicity, and cost while preserving patient safety.

Practical Care Pathway Across the IEC Timeline

Before therapy, comprehensive risk stratification, baseline screening, vaccination planning, and patient education are essential. During the first 30 days, vigilance for sepsis, early fungal disease, and CRS is paramount, supported by protocolized antibacterial and antiviral prophylaxis and selective antifungal coverage. Between days 31 and 90, mold infection risk rises, IVIG replacement is initiated when indicated, CMV surveillance continues, and reimmunization begins. Beyond 90 days, persistent hypogammaglobulinemia in a subset of patients necessitates continued monitoring, stewardship-guided antibiotic use, and survivorship-focused counseling.

CAR T-Cell Therapy vs Bispecifics

Key Differences

Unlike single-infusion CAR T-cell therapy, bispecific antibodies are administered continuously or intermittently, resulting in more sustained immunosuppression. BCMA-targeting bispecifics require closer IgG monitoring, earlier IVIG initiation for recurrent sinopulmonary infections, and ongoing respiratory virus surveillance throughout treatment. Integrating infection management directly into bispecific treatment pathways improves safety and continuity of care.

Operationalizing Fever Pathways in the CRS/ICANS Era

Standardized “IEC fever bundles” embedded in the electronic medical record improve response time and diagnostic accuracy. Persistent fever should prompt mandatory infectious disease consultation and, when neurologic symptoms are present, neuroimaging, lumbar puncture, and HHV-6 testing to distinguish ICANS from CNS infection. Such protocols reduce delays in both immunosuppressive and antimicrobial therapy.

Team-Based Care and Quality Improvement

Majeed emphasized that optimal infection management requires coordinated multidisciplinary care involving oncology, infectious diseases, pharmacy, and nursing. Maintaining prophylaxis algorithms, auditing antimicrobial use, updating empiric protocols based on local microbiology, and reinforcing patient education transform infection prevention into measurable quality metrics within IEC programs.

Epidemiology and the Adult-Pediatric Outcome Gap

Sunil H. Abhyankar, MD, professor of medicine and director of the Midwest Stem Cell Therapy Center and medical director of cell processing and apheresis at KU Medical Center, began by contextualizing the epidemiology of acute lymphoblastic leukemia (ALL), highlighting the persistent survival disparity between children and adults. Although children treated with intensive, risk-adapted regimens achieve high cure rates, adults—particularly those beyond the adolescent young adult (AYA) range—have historically experienced inferior outcomes. Contributing factors include a higher prevalence of adverse disease biology, reduced tolerance for intensive therapy, and challenges related to adherence and supportive care.

Redefining Outcomes in Adult Acute Lymphoblastic

Leukemia Through Cellular Therapy

The First Revolution

Pediatric-Inspired Regimens for AYAs and Adults

A pivotal moment in adult ALL therapy was the phase 2 CALGB 10403 trial (NCT00558519), which applied a pediatric-inspired regimen to patients aged 18 to 39 years. Incorporation of L-asparaginase, intensified consolidation, and meticulous supportive care resulted in a marked improvement in EFS, approximately 78 months compared with 30 months in historical adult cohorts. These findings demonstrate that dose-intensive pediatric-style regimens are feasible for AYAs and selected adults, and that outcomes can approach those observed in pediatric populations when treatment intensity and supportive care are optimized. Although these approaches have not fully closed the adult-pediatric survival gap, they have reset expectations and established a stronger platform upon which immunotherapies could build.

The Second Revolution

CAR T-Cell Therapy for B-ALL

Historical Origins and Antigen Selection

The second major transformation in ALL management emerged from early reports of dramatic responses in relapsed pediatric ALL treated with CD19-directed CAR T cells, even in some cases without lymphodepleting chemotherapy. CD19 proved to be an ideal target because it is broadly expressed across precursor and mature B cells, present in most B-cell malignancies, and absent from hematopoietic stem cells and nonhematopoietic tissues. This biology allows selective B-cell aplasia without destruction of the stem cell compartment and underpins the success of CD19-directed CAR T-cell platforms across lymphoid malignancies.

Pediatric and AYA Outcomes

The ELIANA Trial

The phase 2 ELIANA trial (NCT02435849) evaluated tisa-cel in children and young adults with R/R B-cell ALL (B-ALL) and demonstrated striking efficacy. The complete remission rate at 3 months was 81%, with all responders achieving MRD negativity. EFS and OS at 6 months were 73% and 90%, respectively, and at 12 months were 50% and 76%. CAR T cells persisted in peripheral blood for up to 20 months, supporting sustained immune surveillance. Although toxicities were common, they were manageable in experienced centers, with CRS occurring in approximately 77% of patients and neurotoxicity in roughly 40%. ELIANA firmly established tisa-cel as a transformative salvage therapy in pediatric and AYA B-ALL.

Adult Experiences

MSK 19-28z and ZUMA-3

Early adult studies mirrored the high initial remission rates observed in pediatric cohorts, although durability was more limited. At Memorial Sloan Kettering Cancer Center, the 19-28z CD19 CAR T-cell product induced complete remission in 83% of adults with R/R B-ALL, with a median EFS of 6.1 months and median OS of 12.9 months. These outcomes represented a major advance in a heavily pretreated population while highlighting the challenge of sustaining long-term disease control.

The phase 1/2 ZUMA-3 trial (NCT02614066) further clarified the role of CAR T-cell therapy in adult ALL. Among treated patients with a median age of 40 years, brexu-cel achieved a CR/CR with incomplete hematologic recovery rate of 71%, with 97% of responders attaining MRD negativity. Median duration of remission was approximately 12.8 months, and 4-year OS approached 40%. Rates of grade 3 or higher CRS and neurotoxicity were consistent with other CD19 CAR T-cell platforms and were largely manageable with standardized care pathways. Collectively, these experiences established CAR T-cell therapy as a standard salvage option in adult B-ALL and demonstrated that a meaningful subset of patients can achieve multiyear survival.

Toxicity Management and the Role of Construct Design

The field has progressed from first-generation CAR constructs designed primarily to demonstrate efficacy to more refined platforms that balance potency and tolerability. Intermediate-affinity CARs such as obecabtagene autoleucel (obe-cel) employ CD19 single-chain variable fragments with faster off-rates, enabling more physiologic T-cell engagement, reduced peak cytokine release, mitigation of CRS and ICANS severity, and improved persistence with less T-cell exhaustion. These engineering advances reflect the transition from constructs that “work” to those that “work better and more safely.”

Mechanisms of Relapse and Strategies to Prevent It

Despite high initial response rates, relapse and nonresponse remain significant challenges. Mechanisms include antigen escape through CD19 loss or downregulation, T-cell exhaustion with limited persistence, immunosuppressive tumor microenvironments, and Fas-mediated CAR T-cell apoptosis. These factors help explain why long-term disease control in adult series often plateaus around 40% to 50% at 1 year, reinforcing the need for multiantigen targeting and functional armoring strategies.

Multivalent and Armored CAR Platforms

To address antigen escape, next-generation CAR designs simultaneously target multiple B-cell antigens. Trispecific duoCAR platforms targeting CD19, CD20, and CD22 aim to reduce escape via single-antigen loss, broaden coverage across heterogeneous leukemic clones, and enhance response durability. Manufacturing approaches incorporating IL-7 and IL-15 during ex vivo expansion seek to preserve memory-like T-cell phenotypes associated with superior in vivo persistence.

Armored CAR T cells represent another strategy, with cytokines such as IL-18 engineered into the construct to enhance cytolytic activity and reprogram the tumor microenvironment. Early data from lymphoma cohorts treated after failure of second-generation CAR T-cell therapy have demonstrated encouraging response rates, supporting the translational relevance of these approaches for relapsed B-ALL.

Manufacturing Innovation and Access

A major emphasis of the presentation was the development of in-house CAR T-cell manufacturing programs. Through extensive validation, regulatory engagement, and rigorous in-process and quality control systems, academic centers can produce autologous CAR T-cell products with consistent potency and safety while significantly shortening vein-to-vein times. These capabilities are particularly critical in rapidly proliferative diseases such as ALL.

Allogeneic CAR T-cell platforms offer additional promise through rapid availability, standardized quality, and scalability. However, overcoming GVHD risk and host rejection remains essential, with emerging solutions including T-cell receptor knockout, HLA engineering, and alternative effector cell platforms such as NK or γδ T cells.

Integrating CAR T-Cell Therapy With Transplant

In adult ALL, allogeneic stem cell transplantation remains an important consolidative strategy for selected patients achieving remission after CAR T-cell therapy. Decisions regarding transplantation depend on MRD depth, CAR T-cell persistence, patient comorbidities, donor availability, and patient preference. As CAR T-cell durability improves, the role of transplant is becoming increasingly individualized, with some patients able to defer transplantation following deep, sustained remission.

The Evolving ALL Cell Therapy Landscape

Rebecca Gonzalez, PharmD, BCOP, FASTCT, is a clinical pharmacy specialist in blood and marrow transplantation and cellular immunotherapy at Moffitt Cancer Center. She framed contemporary ALL management within a rapidly diversifying immunotherapy ecosystem. For R/R ALL, current and emerging strategies include CD19-directed CAR T-cell therapies such as tisa-cel and brexu-cel, BiTEs, ADCs, and dual-target or alternative antigen approaches including CD19/CD22, CD22, and CD123. These modalities are not simply incremental additions; they meaningfully reshape treatment sequencing, immunobiology, and toxicity risk. As constructs become more sophisticated and targets broaden, toxicity patterns may shift, reinforcing the need for product-specific, adaptable management pathways rather than uniform, one-size-fits-all approaches.

How Construct Design Shapes Toxicity

A central theme of the presentation was that CAR construct design is clinically consequential, not merely an engineering detail. Single-chain variable fragment (scFv) affinity and specificity influence the intensity and tempo of T-cell activation. High-affinity binders may drive rapid expansion and pronounced cytokine release, increasing the risk of high-grade CRS and ICANS. In contrast, lower-affinity or fast off-rate binders, such as the CAT19 scFv, are intended to modulate activation while retaining antileukemic potency. The costimulatory domain further shapes kinetics: CD28-based CARs often expand more rapidly with higher early cytokine peaks, whereas 4-1BB–based CARs may confer slower expansion with longer persistence.

Gonzalez emphasized that these design features translate into recognizable, product-specific patterns in fever curves, inflammatory markers, and neurotoxicity trajectories. Clinicians are therefore encouraged to interpret early laboratory and clinical signals in the context of the specific product administered, recognizing that many downstream clinical events begin at the receptor level.

Obe-Cel and Tumor-Burden–Adjusted Split Dosing

Obe-cel was presented as a practical example of aligning product design with a dosing strategy intended to modulate toxicity. In the phase 1b/2 FELIX trial (NCT04404660), obe-cel is administered as split dosing—an initial infusion on day 0 followed by a second infusion on day 9 (±2 days), with the option to delay up to day 20—after standard fludarabine/cyclophosphamide lymphodepletion. Adult patients treated in this setting are often older than those enrolled in pediatric trials (median age, ~50 years), typically have an ECOG performance status around 1, frequently present with high marrow blast percentages before lymphodepletion, and commonly have prior exposure to blinatumomab and/or inotuzumab.

The clinical message is 2-fold. First, split dosing provides a mechanism to attenuate early inflammatory risk, particularly among patients with substantial tumor burden. Second, bridging

therapy—pre–CAR T-cell debulking—remains central to reducing toxicity risk while maintaining

CAR T-cell efficacy.

Mapping the Toxicity Spectrum

CRS, ICANS, IEC-HS, and ICAHT

CRS and ICANS were situated within a broader spectrum of IEC-related systemic toxicities. CRS is an early inflammatory syndrome characterized by fever, hypotension, and hypoxia. ICANS may overlap with CRS or occur later and ranges from mild tremors and word-finding difficulty to confusion, seizures, and cerebral edema. IEC-HS represents a hemophagocytic-like hyperinflammatory syndrome associated with hyperferritinemia, cytopenias, coagulopathy, transaminitis, and sometimes bone marrow hemophagocytosis; it is distinct from, though related to, classic HLH/macrophage activation syndrome. ICAHT refers to prolonged cytopenias that increase infection risk, extend hospitalization, and delay subsequent therapy.

Etiologic contributors to ICAHT include the marrow effects of lymphodepleting chemotherapy, cumulative myelotoxic exposures, high baseline disease burden, and immune-mediated marrow injury.

Baseline Risk Stratification

Quantifying Risk

To strengthen decision-making beyond clinical gestalt, Gonzalez reviewed practical risk-stratification scoring systems. Modified EASIX, calculated as (lactate dehydrogenase × CRP)/platelet count, has been associated with increased risk of severe CRS and ICANS. CAR-HT is a composite tool in which scores of 2 or higher predict severe, prolonged neutropenia and higher infection risk. ALL-specific HT scores adapt hematotoxicity prediction by removing ferritin and explicitly incorporating disease burden, reflecting the high proportion of high-HT patients in ALL cohorts.

Collectively, these tools help identify patients who require intensified monitoring, earlier inpatient admission, and lower thresholds for intervention, particularly during the early postinfusion window.

First Principle

Rule Out Mimics

Before diagnosing CRS, the recommended approach begins with a disciplined differential diagnosis. Clinicians should evaluate for bacterial, viral, and fungal infections; drug reactions; and cardiopulmonary or other comorbid events such as pulmonary embolism or heart failure. Only after alternative diagnoses are reasonably excluded should CRS be graded using established criteria, based on fever plus the most severe hemodynamic and respiratory parameters. Organ-specific toxicities are documented separately using the Common Terminology Criteria for Adverse Events and do not modify the CRS grade. This framework helps prevent diagnostic anchoring and reduces the risk of missing sepsis or other life-threatening non-CRS etiologies.

CRS Management

Structured Escalation

CRS management is organized as a stepwise, time-sensitive escalation strategy. For grade 1 to 2 CRS, supportive care with antipyretics, intravenous fluids, and close monitoring is appropriate, with early tocilizumab considered when persistent fever is accompanied by evolving hypoxia or hypotension. For higher-grade or worsening CRS (grade 2-4), prompt tocilizumab is prioritized; corticosteroids such as dexamethasone are added when CRS is severe, persistent, or refractory; and organ support—vasopressors, supplemental oxygen, or ventilatory assistance—is provided as clinically required.

Product-specific institutional pathways, including those tailored to tisa-cel and brexu-cel, can be integrated within these escalation frameworks. In reported series, early or risk-adapted tocilizumab use in patients with high–tumor burden appears to reduce severe CRS without compromising CAR T-cell expansion.

ICANS: Anticipate, Monitor, Treat Early

In contrast to CRS, ICANS requires a neurologically centered strategy. Recommended practices include frequent bedside neuroassessments using the ICE score or equivalent tools, low thresholds for EEG and brain imaging (MRI preferred; CT when MRI is unavailable), and early inpatient admission for any new neurologic symptoms that arise in the outpatient setting. Antiseizure therapy, most commonly levetiracetam, may be used prophylactically or reactively.

Corticosteroids remain the mainstay for moderate to severe ICANS. High-dose steroids are appropriate for grade 3 to 4 events, and when steroid exposure is brief—often less than 72 hours—tapering may not be necessary. Gonzalez emphasized that although severe ICANS can be self-limited, delayed recognition and delayed treatment carry the risk of irreversible neurologic injury, reinforcing the clinical principle that “time is brain.”

Refractory or Complex Scenarios

Expanding the Tool Kit

For steroid-refractory toxicity, mixed CRS/ICANS presentations, or hyperinflammatory syndromes, additional agents may be considered. Options include siltuximab for IL-6 ligand blockade and anakinra for IL-1 receptor blockade, administered intravenously or subcutaneously, often at 100 mg every 6 to 12 hours with higher cumulative doses in severe cases. Emerging evidence suggests that anakinra can lead to rapid improvement in select patients with high-grade neurotoxicity.

In severe neurotoxicity accompanied by cerebrospinal fluid inflammation or concern for CNS disease, intrathecal therapy using hydrocortisone with or without methotrexate and/or cytarabine has been described, with dosing adapted from adult and pediatric experience. These approaches are best reserved for centers with established expertise in CNS-directed therapy during CAR T-cell treatment.

IEC-HS: Recognizing a Distinct Hyperinflammatory Syndrome

IEC-HS is described as a clinicopathologic entity that often emerges as CRS improves. It is characterized by marked hyperferritinemia, worsening cytopenias, coagulopathy, transaminitis, and, in some cases, bone marrow hemophagocytosis. Reported incidence varies by product but is typically in the single-digit percentage range for tisa-cel, brexu-cel, and obe-cel. Severe IEC-HS may progress to multiorgan failure.

Because monotherapy responses are often limited, combination regimens—most commonly dexamethasone plus anakinra, with consideration of ruxolitinib in selected cases—have been proposed as rational strategies while prospective data continue to accumulate. Biomarkers such as soluble IL-2 receptor may support diagnosis and response assessment.

ICAHT: Prolonged Cytopenias as a Phase-of-Care Issue

Gonzalez reframed ICAHT as a phase-of-care challenge requiring structured pathways rather than isolated, reactive decisions. Early cytopenias often reflect the expected effects of lymphodepletion, acute infection, and prior therapy, whereas later cytopenias raise concern for immune dysregulation, persistent disease, or secondary myeloid neoplasms such as myelodysplastic neoplasms or acute myeloid leukemia. A time-based approach includes early-phase strategies such as G-CSF support (with caution during active CRS or ICANS) and close surveillance for infection and tumor lysis. In intermediate and late phases, persistent cytopenias despite growth factor support warrant bone marrow evaluation and assessment for relapse, secondary malignancy, or autoimmune etiologies.

Vaccination is intentionally delayed following CAR T-cell therapy, generally at least 3 to 6 months for inactivated vaccines and approximately 1 year for live vaccines. IVIG replacement is considered for IgG levels below 400 mg/dL or for patients experiencing recurrent infections at higher IgG thresholds.

Practical Supportive-Care Levers

G-CSF, TPO Agonists, Stem Cell Boosts

Risk scores and clinical context guide escalation of supportive measures. In patients with high hematotoxicity risk, prophylactic G-CSF may be considered as early as day +2. In lower-risk patients, a reactive strategy is reasonable, such as initiating G-CSF when the ANC falls below 500/µL between days +7 and +21 in the absence of ongoing CRS. Thrombopoietin (TPO) receptor agonists such as eltrombopag or romiplostim may be considered for grade 3 or higher thrombocytopenia after alternative causes have been excluded, with a typical trial duration of 4 to 6 weeks and discontinuation if no response is observed. For multilineage, transfusion-dependent cytopenias in the absence of relapse or secondary malignancy, CD34+ stem cell boosts—autologous or allogeneic—may be used when available.

Overall, the strategy is incremental and individualized, grounded in product biology and
patient-specific risk.

 

Al-Ola Abdallah, MD, looks toward future ICE-T congresses and what he hopes can be accomplished with these meetings.

Infection Prevention

Prophylaxis and Timing

Infection prevention remains a cornerstone of safe cellular therapy delivery. When feasible, vaccination should be completed at least 2 weeks before CAR T-cell infusion. Vaccination after CAR T-cell therapy is deferred until meaningful immune reconstitution, typically 3 to 6 months for inactivated vaccines and longer for live vaccines. Antiviral, P jirovecii, and antifungal prophylaxis should be tailored to local epidemiology, the depth and duration of cytopenias, and prior therapies. IgG levels are monitored monthly early after CAR T-cell therapy, with monitoring extended to every 3 to 6 months once stable, and IVIG replacement is used to reduce recurrent sinopulmonary infections.

Tumor lysis prophylaxis, including allopurinol and aggressive hydration, should be

implemented in patients with high white blood cell counts, elevated lactate dehydrogenase,

bulky disease, or splenomegaly.

Real-World Comparisons in Young Adults

Tisa-cel vs Brexu-cel

To bridge pediatric and adult practice, Gonzalez reviewed multicenter, real-world comparisons of patients aged 18 to 26 years treated with tisa-cel in pediatric networks vs brexu-cel in the adult Real-World Outcomes Collaborative of CAR T in Adult ALL network. CRS rates were relatively low in both cohorts, although ICANS was observed more frequently with brexu-cel despite similar CRS severity. Grade 4 neutropenia appeared more common with brexu-cel (approximately 80% vs 58%; P ≈ .08). Length of hospitalization (approximately 2 weeks) and infection rates (around 25%) were similar. These findings support the delivery of both products safely in this overlapping age group when centers apply robust monitoring and escalation protocols.

Outpatient vs Inpatient Delivery

Operational Considerations

Differences in the timing and severity of toxicity have direct implications for clinical operations. Centers with strong triage infrastructure, 24/7 access, and proximity to emergency services may safely deliver select therapies in the outpatient setting for appropriately selected lower-risk patients. In contrast, patients with high tumor burden, elevated hematotoxicity scores, or adverse baseline features are generally best served by inpatient monitoring during peak toxicity risk windows. Standardized order sets, predefined triggers for fever and neurologic symptoms, early neurology involvement, and nursing-driven escalation algorithms provide the operational foundation that translates guidelines into reliable bedside care.

Future Directions

Bending the Toxicity Curve

Gonzalez highlighted 3 major levers likely to shape a more favorable toxicity curve. First, more effective bridging strategies are needed to reduce disease burden before CAR T-cell infusion. Second, early cytokine interception—through risk-adapted preemptive or early tocilizumab, with or without short-course steroids in high-burden cohorts—may reduce severe CRS without meaningfully compromising CAR expansion or persistence. Third, next-generation CAR designs, including dual-target and affinity-tuned constructs, aim to preserve deep antileukemic activity while attenuating hyperinflammatory responses. As these strategies mature, the clinical objective is to decouple remission depth from toxicity burden, expand eligibility, and improve quality of life.

Conclusion

Findings from the 2025 ICE-T Symposium underscore the central role of T cell–redirecting therapies across hematologic malignancies and emerging solid tumor settings. Bispecific antibodies and CAR T-cell therapies deliver high response rates with expanding use in earlier lines; however, durability remains constrained by antigen escape, immune exhaustion, and treatment-related toxicities, particularly infections and cytopenias. A consistent shift toward multiantigen targeting, optimized sequencing, and personalized strategies is evident, with next-generation constructs including trispecifics and allogeneic platforms aiming to overcome resistance and improve access. Ultimately, long-term success will depend on balancing efficacy with durability, toxicity mitigation, and real-world deliverability, positioning immune-based therapies as a cornerstone of modern oncology care.

Vasomotor symptoms, more commonly known as hot flashes, remain a prevalent and distressing sequela of androgen deprivation therapy (ADT) for patients with prostate cancer, often significantly impacting quality of life. CancerNetwork® spoke with Bradley J. Stish, MD, the section head of radiation oncology and a radiation oncologist specializing in genitourinary cancers at Mayo Clinic, about the phase 2 Alliance A222001 trial (NCT04600336) evaluating the use of oxybutynin (Ditropan) as a nonhormonal intervention for managing these symptoms. Data suggest a dose-dependent benefit, with 5 mg twice daily offering the most robust symptom reduction, although a 2.5-mg, twice-daily dose remains a viable starting point for patients with baseline anticholinergic concerns.

Stish further highlighted the rapid onset of relief, comparable to agents such as venlafaxine (Effexor) or gabapentin (Neurontin), with improvements often noted within the first 1 to 2 weeks. Although xerostomia is a common adverse effect, management strategies such as hydration, sugar-free gum, and humidification can support treatment adherence. Although oxybutynin has a long-established safety profile in urology, Stish noted that future phase 3 research should prioritize evaluating its long-term neurocognitive impact in older patient populations.

Ultimately, Stish suggested these findings may provide clinicians with an accessible, flexible tool to mitigate the broad interference that hot flashes exert on sleep, work, and social activities, reinforcing the importance of proactive symptom management across both specialty and primary care settings.

Q / Given a clear dose-dependent benefit with oxybutynin at the 5-mg, twice-daily dose, would you recommend starting all patients at the 5-mg dose, or is there a specific patient profile where the 2.5-mg dose might be clinically preferable?

Stish / When we’re thinking about which dose to use clinically in patients, the study provided us with good data that are open to flexibility for both patients and physicians or providers. If you’re trying to get the biggest bang for your buck in terms of the reduction of hot flash symptoms, I think 5 mg twice daily was the clear winner in our study. But we still saw a meaningful improvement in many symptoms with the 2.5-mg, twice-daily dose.

Many times, this becomes a discussion between the physician and the patient regarding their goals of treatment, and whether there are any specific factors in their case that may make you inclined to consider a lower dose. We know some of the [adverse] effects of the drug can be pretty predictable—things like dry mouth or constipation—and if there’s a patient who may have baseline symptoms in both of those domains, it may be wiser to start at a lower dose and see if you can get an effect that’s desirable, knowing you can always increase that dose if the effect isn’t quite what was hoped originally. Similarly, if we have patients who start at the 5-mg, twice-daily dose, and we’re seeing [adverse] effects that are bothersome or prohibitive, physicians can feel comfortable decreasing that dose in half. Having that flexibility is nice for both patients and physicians to ensure that they can find the right dose for their specific situation.

Highlighting Oxybutynin Impact on ADT-Induced Hot Flashes in Prostate Cancer

Q / What strategies do you employ to manage dry mouth while maintaining the 6-week treatment adherence seen in the study?

Stish / Our protocol didn’t necessarily specify any measures, so this really becomes about clinician experience and strategies they’ve learned over time, and sometimes [patients] come up with their own strategies. When it comes to dry mouth, frequent hydration is a good tool to manage [it]. That can feed into other symptoms. Knowing that patients with prostate cancer can be dealing with urinary symptoms, if [they’re] drinking lots of fluids, there can be a downstream effect there, literally. But certainly, drinking small volumes of sugar-free liquids is helpful.

We don’t want to introduce a lot of excess sugars in the mouth and cause dental problems as an [adverse] effect. Sugar-free gum is another good strategy to help manage that. Sucking on hard, sugar-free candies is another way to promote those salivary glands in the mouth to stimulate more secretion of saliva. Then, humidification, especially in some of our colder climates in the winter months, if you have indoor heating running, that can dry out the air in the house. The idea of keeping a humidifier where you’re sleeping [because sleep] is a common time when people notice dry mouth more regularly. Those are strategies that I’ve seen employed that have been effective at managing [dry mouth].

Then, as we mentioned previously, think about the dose that you’re using and whether there can be a modification of the dose that might be reasonable to achieve the same effect while decreasing the [adverse] effect profile of the drug.

Q / How does “speed to relief” within the first week compare with other nonhormonal options like venlafaxine or gabapentin?

Stish / We were heartened to see [a] rapid onset of symptom improvement with oxybutynin. This compares similarly with other drugs that have been studied in this regard. In most of the studies looking at hot flash remedies for men on hormone therapy, we’ve seen a quick reduction in symptoms within the first 1 to 2 weeks, whether that’s gabapentin, venlafaxine, or megestrol, among others, that have been looked at in this realm. It’s nice to know that we generally have a few different options that all have this rapid onset of symptom relief. You do not have to wait a long time to see the benefits of taking this drug.

Q / Which specific domains of interference, such as sleep, work, or social activities, show the most significant improvement with oxybutynin?

Stish / It’s hard to compare across domains in terms of which is the most significant. You can get a numerically significant improvement in one domain, but it’s maybe a small part of your life. If, for example, work is one of those domains, but you’re a retired person, that may not be as important to you as sleep or other things. The takeaway was that we saw broad and deep improvement across many domains with the oxybutynin.

It wasn’t restricted to one specific access or symptom that was caused by the hot flashes. We have patients who come in and say, “The worst thing about the hot flashes is how they interfere with my sleep,” or “The worst part about my hot flashes is I can’t be as physically active. I’m not able to golf or go fishing as much as I was before.” We can look at this study and say this drug wasn’t restricted to one small part of quality-of-life improvement in these patients, and we can tell them that there’s a good chance that they will benefit [from an improvement of] the symptom or the domain that is being bothered and is most affected.

Q / What do we know about the long-term safety and durability of oxybutynin for chronic hot flash management?

Stish / This study was specifically looking at a 6-week study protocol. We don’t have follow-up beyond that 6-week time frame for these patients, but because oxybutynin is a drug that’s been around for many years and has been used in thousands of patients to manage bladder symptoms as the most common use, we have experience with patients being on this drug for long periods of time. The clinical experience has shown that, generally, the [adverse] effect profile is fairly predictable.

It’s tolerable for most patients, and we don’t see significant increases in safety concerns over extended periods of time. While our study wasn’t specifically designed to assess long term safety and effectiveness, there’s no reason to think that it shouldn’t be reasonable to use this drug for periods of time longer than 6 weeks, as long as the patient is closely monitoring their symptoms and following up regularly with their clinicians to report any concerns and be monitored for any unexpected long-term [adverse] effects.

Q / Do you believe that oxybutynin should be considered a first-line nonhormonal standard of care for ADT-induced hot flashes, and has this already changed the prescribing patterns at institutions such as Mayo Clinic?

Stish / Our study was really important in demonstrating that oxybutynin is an excellent option for patients who are having hot flashes related to hormone therapy. It was meant to add to the existing literature and the options that are available. Our goal was to provide clinicians and patients with yet another option to manage their symptoms if [they] were affecting their quality of life or negatively impacting the way they went through their day-to-day functions.

Any of us can aspire to future studies, trying to compare some of these active agents directly, head-to-head. It’s challenging to compare across studies that were done slightly differently in different eras with different groups of patients. We try not to draw direct comparisons between the studies that were done previously in agents other than oxybutynin, but in a broad strokes picture, we can say we saw similar trends across all these studies.

All of these are good drugs and good options, and we’d rather let clinicians and patients decide for themselves which one works best for them, understanding that there are some pros and cons of all of these agents, and that if one doesn’t work, you can then pivot to a different option that may be more effective for you.

Q / What would be the key priorities for a phase 3 confirmatory study?

Stish / We’ve talked about where we go from here in terms of learning more about oxybutynin and then hot flash management in patients with prostate cancer. A few things that are clear about our study are that having a larger patient cohort is always beneficial. [Can] these results be replicated in a broader group of patients? The more patients you accumulate, the more specific niches or nuances of the prostate cancer domain, or men with hot flash domain, that you get. You get a broader age range of patients, patients from different socioeconomic backgrounds, different geographies, [or] different states of their disease. Then [you] can start asking nuanced questions about whether oxybutynin works differently in some of these subgroups of patients than it does in others.

The other thing that we would look at is: Can we extend this out to see if there is a longer benefit or any concerns about using this in a longer time frame? One of the questions that is appropriately raised, and is unanswered, about oxybutynin is: Does this have an impact on memory or neurocognition? This is one of those things that gets mentioned a lot in the literature. There is some pharmacologic rationale behind how oxybutynin can have effects on memory, especially in older patients, recognizing that many patients with prostate cancer are older rather than younger. High-quality studies assessing how this impacts neurocognition through standardized testing and rigorous reporting haven’t been done, and that’s something that would be of interest to study if we were to move forward to phase 3 studies.

Q / Is there anything else that you would like to highlight that we have not already discussed?

Stish / [I want to] highlight this symptom that is maybe underrecognized in some aspects of clinical medicine. Those of us who treat patients with prostate cancer on a routine basis, obviously, are quite aware of this. But we may have clinicians who are primary care providers who have a small number of patients who have prostate cancer, and bringing this awareness to them that a drug they are probably comfortable in prescribing in oxybutynin is something that could be used to manage hot flash symptoms, and they wouldn’t necessarily need to rely on a specialist like a urologist or a medical oncologist or a radiation oncologist to help handle that symptom.

Also, encouraging patients that if they are dealing with hot flash symptoms, it’s not just something they have to deal with. There are options to help them manage. They should feel comfortable talking to their clinicians and care teams about some of these strategies and whether it’s right for them to help decrease those symptoms if they’re negatively impacting their quality of life.

Reference

Stish BJ, Mazza GL, Nauseef JT, et al. Alliance A222001: oxybutynin versus placebo for the treatment of hot flashes in patients receiving androgen-deprivation therapy for prostate cancer. J Clin Oncol. Published online January 26, 2026. doi:10.1200/JCO-25-01486

 

Bradley J. Stish, MD, spoke about the clinical rationale for the dose selection of oxybutynin for hot flash symptom management in prostate cancer treatment. He specifically highlighted key circumstances where a reduced dose of
2.5 mg may be warranted for select patients.

Investigators for the double-blind, phase 3 C-POST study (NCT03969004) randomly assigned 415 participants with high-risk LA cSCC to receive cemiplimab or placebo after surgery and postoperative RT.13 With a median follow-up of 24 months, cemiplimab improved disease-free survival (DFS; primary end point) vs placebo (24-month DFS, 87.1% vs 64.1%; HR, 0.32; 95% CI, 0.20-0.51; P < .001).14 Freedom from local-regional (9 vs 40 events; HR, 0.20; 95% CI, 0.09-0.40) and distant (10 vs 26 events; HR, 0.35; 95% CI, 0.17-0.72) recurrence was also improved with cemiplimab vs placebo. Although there was a numerical trend toward improved overall survival (OS) with cemiplimab, this association had not achieved statistical significance at the time of the reported interim analysis (Table).14 Adjuvant cemiplimab was approved by the FDA for adults with cSCC at high risk for recurrence after surgery and RT, and it is a category 1 NCCN-preferred treatment following RT for patients with cSCC and extremely high-risk nodal and non-nodal features and negative postoperative margins.3,15

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Evaluate the latest efficacy and safety findings from key trials assessing immune checkpoint inhibitors as monotherapy or in combination regimens for the treatment of advanced cutaneous squamous cell carcinoma (cSCC)

• Assess the mechanistic and clinical differences between PD-1 and PD-L1 inhibitors used for the management of advanced cSCC

• Incorporate patient- and disease-specific characteristics into individualized treatment plans using immunotherapy for advanced cSCC

Release Date: May 18, 2026

Expiration Date: May 18, 2027

Accreditation/Credit Designation

Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Sun Pharmaceutical Industries, Inc.

Off-Label Disclosure/Disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

How to Receive Credit

1. Read this activity in its entirety.

2. Go to https://www.gotoper.com/ime26mxfcscc-postref to access and complete the posttest.

3. Answer the evaluation questions.

4. Request credit using the drop-down menu.

You may immediately download your certificate.

To learn more about this topic including information on managing cutaneous squamous cell carcinoma with immune checkpoint inhibitor combinations and in solid organ transplant recipients, go to https://www.gotoper.com/ime26mxfcscc-activity

CME Provider Contact information

Physicians’ Education Resource®, LLC

259 Prospect Plains Road, Building H,

Cranbury, NJ 08512

onc-info@gotoper.com

Pembrolizumab was also evaluated in the adjuvant setting in the double-blind, phase 3 KEYNOTE-630 study (NCT03833167), which enrolled 450 patients with high-risk LA cSCC following surgery and RT.16 In this study, however, the PD-1 inhibitor failed to meet the primary end point of improved recurrence-free survival (RFS), defined as time from randomization to the first event of local or regional recurrence of index lesion, distant metastasis, or death due to any cause (24-month RFS; 78.3% for pembrolizumab vs 68.6% for placebo; HR, 0.76; 95% CI, 0.53-1.10; P = .07243). Although no study participants died due to treatment-related adverse events, pembrolizumab demonstrated a numerically worse OS (24-month OS, 87.3% with pembrolizumab vs 90.7% with placebo; HR, 1.47; 95% CI, 0.87-2.48) with a median study follow-up of 28.6 months.

The FDA has approved the PD-1 inhibitors cemiplimab and pembrolizumab, and the PD-L1 inhibitor cosibelimab, for the treatment of advanced cSCC not amenable to curative surgery and/or RT, based on phase 2 studies (Figure).17-19 Participants in the EMPOWER-CSCC-1 phase 2 study (NCT02760498) with either metastatic (group 1) or LA (group 2) cSCC received 3mg/kg cemiplimab every 2 weeks.20 Participants in group 1 had not received a prior PD-1/PD-L1 inhibitor.21 Participants in group 2 were not candidates for surgery or RT.22 With a median follow-up of 18.5 months, group 1 had an objective response rate (ORR) of 50.8%, median progression-free survival (PFS) of 18.4 months, and median OS of 57.7 months.20 With a median follow-up of 15.5 months, group 2 had an ORR of 44.9% and a median PFS of 18.5 months, and median OS was not reached. A third group of patients with metastatic cSCC who received a fixed dose of cemiplimab 350 mg intravenously every 3 weeks achieved an ORR of 46.4%.

One hundred fifty-nine participants with advanced cSCC received pembrolizumab in the phase 2 KEYNOTE-629 study (NCT03284424).23 The ORR was 51.9% for patients with LA disease (median follow-up, 52.4 months) and 35.2% for patients with recurrent/metastatic (R/M) disease (median follow-up, 64.7 months). The median PFS was 14.4 months and 5.7 months in the LA and R/M cohorts, respectively. The median OS was not reached in the LA cohort, and 23.8 months in the R/M cohort.

And in a third phase 2 study (NCT03212404), participants with LA or metastatic cSCC received cosibelimab.24 Unlike cemiplimab and pembrolizumab, cosibelimab is a PD-L1 inhibitor that has a functional Fc region that may bind and activate natural killer (NK) cells.25 With a median follow-up of

29.3 months for the patients with metastatic cSCC and 24.1 months for the patients with LA cSCC, the ORRs were 50.0% and 54.8%, respectively.24

The rate of severe immune-related AEs (irAEs) associated with cosibelimab was 3.6%,24 which was lower than the rates reported in the phase 2 studies of pembrolizumab (8.8%, grade ≥3 immune-mediated AEs and infusion reactions) and cemiplimab (10.7% to 19.2%, any grade ≥3 irAE in groups 1, 2, or 3).26,27 By blocking PD-L1 interactions with PD-1 and CD80, but sparing PD-L2 to PD-1 binding,28 anti–PD-L1 inhibition is thought to maintain some checkpoint signaling, thereby reducing autoimmunity.29,30 Furthermore, by blocking PD-L1 interaction with CD80, PD-L1 inhibitors may enhance T-cell expansion and prevent induction of T-cell anergy.31

key References

10. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 Inhibition. N Engl J Med. 2017;377(25):2500-2501. doi:10.1056/NEJMc1713444

14. Rischin D, Porceddu S, Day F, et al. Adjuvant cemiplimab or placebo in high-risk cutaneous squamous-cell carcinoma. N Engl J Med. 2025;393(8):774-785. doi:10.1056/NEJMoa2502449

24. Ruiz ES, Muñoz-Couselo E, Montaudié H, et al. Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: results from a pivotal open-label study with a median follow-up of ≥2 years. J Am Acad Dermatol. 2026;94(1):48-56. doi:10.1016/j.jaad.2025.09.009

Activity

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the United States, accounting for about 20% of nonmelanoma skin cancers (NMSCs).1 While patients with cSCC have a higher rate of all-cause mortality compared with the general population,2 estimating the incidence and cancer-specific mortality of the disease is challenging, as NMSCs are not monitored by cancer registries.1 Here are 3 things you should know about cSCC.

The National Comprehensive Cancer Network (NCCN) risk stratification criteria identify patients with cSCC who are at low, high, or very high (including lesions greater than 4 cm in diameter) risk for local recurrence, metastases, or death.3 Although the majority of cSCCs are successfully treated with primary surgical intervention with or without radiation therapy (RT),4 the risk for metastatic disease in patients with cSCC is 4% overall and 7% to 13% for solid organ transplant recipients.5,6

Historically, systemic treatments for locally advanced (LA)/unresectable or metastatic cSCC have relied on platinum-based chemotherapy and EGFR inhibitors, but these are associated with disappointingly low (event-free) survival rates.7-9 Checkpoint inhibitors (CPIs) are a logical treatment for cSCC given the disease’s high TMB and risk associated with immunosuppression.5,6,10 The mutational landscape of cSCC is dominated by cytidine-to-thymidine transitions associated with repair of UV-B radiation-mediated DNA damage,11 and encompasses an exceedingly high median TMB compared with other solid tumors.10

While TMB is highly correlated with response to PD-1 inhibitors in solid tumors,10 the TMB between individual cases of cSCC varies widely. In a real-world cohort study of 61 patients with advanced cSCC, a higher median TMB was associated with response to CPI therapy (25.4 vs 10.6 mut/Mb, P = .02).12

Faculty, Staff, and
Planners’ Disclosures

This activity was written by PER®
editorial staff based on a program developed with Drs Salama, Hamid, Larkin, and Patel.

In accordance with ACCME Guidelines, PER® has identified and resolved all conflict of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.

Disclosures (Dr Salama): Advisor, Consultant, Speaker, Honoraria Recipient: Bristol Myers Squibb, Delcath, IDEAYA, Immunocore, Natera, Pfizer, Regeneron; Grant/Research Funding: Ascentage, Bristol Myers Squibb, IDEAYA, Immunocore, Merck, Olatec Therapeutics, Regeneron, Replimune, Seagen

Disclosures (Dr Hamid): Advisor, Consultant, Speaker, Honoraria Recipient: Alkermes, Amgen, BeiGene, BioAtla, BMS, Eisai, Ellipses, Georgiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instil Bio, IO Bio, Iovance, Janssen, KSQ, Merck, Moderna, NGM Bio, Novartis, Obsidian, Pfizer, Regeneron, Roche Genentech, Sun Pharma, Tempus, Vial, Zelluna; Grant/Research Funding: Arcus, Aduro, Akeso, Amgen, BioAtla, BMS, CytomX, Exelixis, Roche, GSK, Immunoocore, Idera, Incyte, Iovance, Merck, Moderna, Nextcure, Novartis, Pfizer

Disclosures (Dr Larkin): Advisor, Consultant, Speaker, Honoraria Recipient: Apple Tree, Aptitude, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Calithera, Cancer Research UK, Dynavax, ecancer, Eisai, Ervaxx, EUSA Pharma, GSK, Immunocore, Incyte, iOnctura, Iovance, Ipsen, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, touchEXPERTS, touchIME, Ultimovacs, YKT Global; Grant/Research Funding: Achilles Therapeutics, AVEO, Bristol Myers Squibb, Covance, Immunocore, MSD, Nektar Therapeutics, The NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Novartis, Pfizer, Pharmacyclics, Roche

Disclosures (Dr Patel): Advisor, Consultant, Speaker, Honoraria Recipient: Daiichi Sankyo, IO Biotech, Medison, MSD, Natera, Novartis, Obsidian, Pfizer, Replimune, Scancell, TriSalus Life Sciences, Veda Trials; Grant/Research Funding: 7 Hills, Immatics, iOnctura, Iovance, Linnaeus, Replimune

The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with ineligible companies.

Chief, Translational Research and Immunotherapy, Director, Melanoma Therapeutics, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Director, Cutaneous Malignancies, Cedars-Sinai, Cancer Director of Experimental Therapeutics, Cedars-Sinai Los Angeles, CA

James M. G. Larkin, MD, PhD

Consultant Medical Oncologist,
The Royal Marsden NHS Foundation Trust, London, England

Professor of Medicine and Ophthalmology, Dr William Robinson Endowed Chair in Cancer Research, University of Colorado, Anschutz Medical Campus, Aurora, CO

Associate Professor, Director, Melanoma Program, Duke Cancer Institute, Duke University School of Medicine, Durham, NC

Immune checkpoint inhibition is the standard of care for unresectable cSCC.

 

PD-1 inhibitors have been studied in the adjuvant setting with mixed results.

cSCC has a remarkably high median tumor mutational burden (TMB).

CME POSTTEST QUESTIONS

1 You are referred a patient with a suspicious 4.2-cm skin lesion on her forearm

identified by her primary care doctor. Further workup confirms cutaneous squamous cell carcinoma with well defined borders, well-differentiated disease, and no evidence of nodal, perineural, or vascular involvement. What risk category would this tumor

fall under?

A. Low risk

B. High risk

C. Very high risk

2 Which of the following reflects a theoretical advantage of PD-L1 inhibition compared with PD-1 inhibition in cancer immunotherapy?

A. Enhanced ADCC via disruption of the binding of PD-L1, but not PD-L2, to PD-1

B. Enhanced recruitment of NK cells, which are more strongly suppressed by PD-L1-related signaling

C. Reduced immune-related adverse events by sparing PD-L2:PD-1 binding

D. Reduced immune-related adverse events through preferential activation of regulatory T cells

3 In the phase 3 KEYNOTE-630 study of adjuvant pembrolizumab vs placebo after
curative-intent surgery and radiotherapy for high-risk, locally advanced cSCC, which of the following end points was significantly improved with adjuvant pembrolizumab?

A. Overall survival (OS), but not recurrence-free survival (RFS)

B. RFS, but not OS

C. RFS and OS

D. Neither RFS nor OS

DNA (ctDNA) blood-based testing can facilitate optimal subsequent ET selection.4 Here are 3 things you should know about using selective ER degraders (SERD) to treat hormone receptor–positive/HER2-negative aBC.

There are multiple FDA-approved SERDs available for patients with hormone receptor–positive/HER2-negative aBC harboring a targetable alteration, as shown in the Table.5-9 Activating ESR1 mutations, which are rarely detected in primary breast tumors,3 occur in about 11% to 55% of metastatic BCs previously treated with aromatase inhibitors (AI).10-12 Investigators for the open-label phase 3 EMERALD study (NCT03778931) randomly assigned 477 patients with ER+/HER2-negative aBC after progression on 1 to 2 prior lines of ET with a CDK4/6 inhibitor (CDK4/6i) to receive elacestrant monotherapy vs standard of care (SOC) endocrine monotherapy.13 Elacestrant prolonged progression-free survival (PFS) vs SOC in patients with an ESR1 mutation (6-month PFS rates, 40.8% vs 19.1%; HR, 0.55; 95% CI, 0.39-0.77; P = .0005). In a post hoc analysis of patients with ESR1-mutated disease, prior ET plus CDK4/6i use for 12 months or longer was associated with a significant improvement in median PFS for elacestrant vs SOC (8.6 vs 1.9 months; HR, 0.41; 95% CI, 0.26-0.63).14 Two studies evaluating real-world outcomes in patients with ESR1-mutated ER+/HER2-negative aBC demonstrated a durable benefit in time to next therapy for elacestrant monotherapy, including for patients with 3 or more lines of prior therapy or concomitant PIK3CA mutations.15,16

Faculty, Staff, and Planners’ Disclosures

This activity was written by PER® editorial staff based on a program developed with Drs Mahtani, Abou Hussein, and Kang.

In accordance with ACCME Guidelines, PER® has identified and resolved all conflict of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.

Disclosures (Dr Mahtani): Consultant: Agendia, Arvinas, AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Hologic, Lilly, Novartis, Pfizer, Sermonix, Stemline; Grant/Research Support: Gilead Sciences

Disclosures (Dr Abou Hussein): Advisor, Consultant, Fee-for-Service Recipient: AstraZeneca; Speakers Bureau: Lilly

Disclosures (Dr Kang): Advisor, Consultant, Fee-for-Service Recipient: AstraZeneca, BioNTech, Caris Life Sciences, Daiichi Sankyo, Gilead, Novartis, Pfizer, Stemline Therapeutics

The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with ineligible companies.

CME POSTTEST QUESTIONS

1 A 63-year-old postmenopausal woman was diagnosed with metastatic breast cancer (ER+; HER2 IHC 1+, FISH negative; PIK3CA/AKT/PTEN wild-type, ESR1 wild-type). She received an aromatase inhibitor plus a CDK4/6 inhibitor as first-line therapy for

18 months but is now progressing in bone and lung. She is very eager to start

treatment. Which of the following is the best guideline-concordant next step?

A. Obtain blood-based circulating tumor DNA to repeat next-generation sequencing (NGS)

B. Obtain a new tissue sample to repeat NGS

C. Start everolimus plus exemestane

D. Start fulvestrant plus a different CDK4/6 inhibitor

2 A 57-year-old postmenopausal woman presented with de novo ER+/HER2-negative (IHC 1+) metastatic breast cancer to the bone in 2019. She was started on letrozole plus palbociclib and after 5 years presents with progression in the bones and 2 new liver metastases. An NGS panel shows ESR1D538G, ESR1Y537S, and PIK3CA1047R mutations. Her LFTs are normal, and she is asymptomatic. Significant comorbidities include well-controlled diabetes and migraines. You are discussing treatment with elacestrant. Which of the following would be most appropriate to share with

the patient?

A. Efficacy may be enhanced given the long prior duration of CDK4/6 inhibitor

B. Efficacy may be enhanced given the coexisting PIK3CA mutation

C. Endocrinology follow-up is needed to mitigate potential hyperglycemia

D. Neurology follow-up is needed to mitigate potential headaches

3 In updated findings from the EMBER-3 trial, addition of imlunestrant to abemaciclib demonstrated which of the following compared with imlunestrant alone for advanced, hormone receptor–positive, HER2-negative breast cancer?

A. Improved PFS only in the subgroup with a PI3K pathway mutation

B. Improved PFS only in the subgroup with no PI3K pathway mutation

C. Improved PFS in all patients

D. Similar PFS in all patients

To learn more about this topic,

including information on selecting therapies for patients with hormone receptor–positive/HER2-negative aBC harboring both PI3K pathway alterations and ESR1 mutations, go to

https://www.gotoper.com/mbcc26smtdserds-activity

CME Provider Contact information

Physicians’ Education Resource®, LLC

259 Prospect Plains Road, Building H,

Cranbury, NJ 08512

onc-info@gotoper.com

About Using Selective Estrogen Receptor Degraders in Hormone Receptor–Positive,

HER2-Negative Advanced Breast Cancer

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Implement best practices for molecular testing in HR+/HER2-negative metastatic breast cancer, including selection of tissue vs liquid biopsy and indications for repeat testing at progression

• Apply clinical trial and real-world evidence to select and sequence oral selective estrogen receptor degraders (SERD) after progression on CDK4/6 inhibitor plus endocrine therapy

• Develop treatment strategies for dual resistance, integrating evidence for targeting the PI3K/AKT pathway in patients with co-occurring ESR1 and PIK3CA pathway alterations

Release Date: May 18, 2026

Expiration Date: May 18, 2027

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This activity is supported by an educational grant from Stemline Therapeutics, Inc.

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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

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Investigators for the phase 3 evERA trial (NCT05306340) compared everolimus in combination with either giredestrant or SOC ET in 373 patients with ER+/HER2-negative aBC progressed on or after ET plus a CDK4/6i.30 The evERA population, which included 55% of patients having ESR1 mutations, had improved PFS in both the intention-to-treat (ITT; median PFS, 8.77 vs 5.49 months; HR, 0.56; 95% CI, 0.44-0.71;

P < .0001) and ESR1-mutated (9.99 vs 5.45 months; HR, 0.38; 95% CI, 0.27-0.54; P < .0001) groups with the giredestrant-everolimus vs SOC ET-everolimus. A subgroup analysis of evERA demonstrated significant improvements in PFS for both the ESR1-mutated and ITT populations regardless of PIK3CA mutations and PIK3CA/AKT1/PTEN alterations.31

An estimated 55% of hormone receptor-positive/HER2-negative aBCs have at least 1 PIK3CA/AKT1/PTEN alteration,32 which are typically present at baseline.33 Alpelisib and capivasertib, both oral inhibitors of the PI3K pathway (Figure 2),36 are FDA approved for use with fulvestrant to treat PI3K pathway–altered hormone receptor–positive/HER2-negative aBC after progression on prior ET based on PFS data from the phase 3 SOLAR-1 (NCT02437318) and CAPItello-291 (NCT04305496) studies.8,9,34-36

Gedatolisib is an intravenous drug that targets all class I PI3K isoforms and mTOR complexes 1 and 2 as demonstrated in Figure 2.36,37 Investigators for study 1 of the open-label phase 3 VIKTORIA-1 trial (NCT05501886) randomly assigned patients with hormone receptor–positive/HER2-negative,

PIK3CA-wild-type aBC progressed on prior AI plus CDK4/6i therapy to receive fulvestrant plus gedatolisib plus palbociclib (arm A), fulvestrant plus gedatolisib (arm B), or fulvestrant alone (arm C), with crossover permitted upon disease progression.38 Improved PFS was demonstrated for arm A vs arm C

(9.3 vs 2.0 months; HR, 0.24; 95% CI, 0.17-0.35; P < .001) and arm B vs arm C (7.4 vs 2.0 months;

HR, 0.33; 95% CI, 0.24-0.48; P < .001).39

Key References

13. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) vs standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase 3 EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/jco.22.00338

30. Mayer E, Tolaney S, Martin M, et al. LBA16 Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+/HER2- aBC) previously treated with a CDK4/6 inhibitor (i): primary results of the phase 3 evERA BC trial. Ann Oncol. 2025;36:S1561-S1562. doi:10.1016/j.annonc.2025.09.026

39. Hurvitz SA, Layman RM, Curigliano G, et al. VIKTORIA-1 trial of gedatolisib plus fulvestrant with or without palbociclib in hormone receptor-positive/HER2-/PIK3CA wild-type advanced breast cancer. J Clin Oncol. Published online March 9, 2026. doi:10.1200/jco-25-02643

Activity

Approximately 70% to 80% of breast cancers (BCs) overexpress the estrogen receptor (ER),1 and mutations in the ESR1 ligand binding domain can lead to constitutive, estradiol-independent activation resulting in endocrine therapy (ET) resistance.2,3 While some genomic alterations remain relatively constant throughout BC treatment (eg, PIK3CA), others, like ESR1 mutations, commonly arise in response to selective therapeutic pressure.2,3 Reassessing the genomic signature of hormone receptor–positive/HER2-negative advanced BC (aBC) at the time of each progression using circulating tumor

Investigators for the open-label phase 3 EMBER-3 trial (NCT04975308) randomly assigned 874 patients with ER+/HER2-negative aBC that had recurred or progressed on an AI with or without a CDK4/6i to receive SOC or imlunestrant with or without abemaciclib.17 For patients with ESR1-mutated disease, the median PFS was 5.5 months vs 3.8 months for imlunestrant monotherapy vs SOC (HR, 0.62; 95% CI, 0.47-0.82; nominal P = .0007).18 With a maturity of 50% in the ESR1-mutated cohort, the data also demonstrated improved overall survival with imlunestrant monotherapy vs SOC (median OS, 34.5 months vs 23.1 months; HR, 0.60; 95% CI, 0.43-0.86; P = .0043).

Investigators for the double-blind, placebo-controlled phase 3 SERENA-6 trial (NCT04964934) screened 3256 patients for ESR1 mutations using blood-based ctDNA testing every 2 to 3 months.19 Upon detection of a new ESR1 mutation, 315 patients with ER+/HER2-negative aBC but no radiologic progression after receiving at least 6 months of first-line AI plus CDK4/6i were randomly assigned to continue their original CDK4/6i plus AI vs switching the AI to camizestrant and continuing the CDK4/6i. At the second data cutoff, the median PFS was significantly improved with camizestrant vs continuing original therapy (median PFS, 16.6 vs 9.2 months; HR, 0.46; 95% CI, 0.34-0.62; P < .00001).20

Phase 2 and 3 studies have also demonstrated benefit with SERD-based combinations upon clinical disease progression on first-line treatment for ER+/HER2-negative aBC. In the EMBER-3 trial, the addition of abemaciclib to imlunestrant improved PFS (median PFS, 10.9 vs 5.5 months; HR, 0.59; 95% CI, 0.47-0.74; nominal P < .0001),21 a benefit that was observed regardless of ESR1 and PI3K pathway mutational status.

Activation of the PI3K/AKT/mTOR pathway, which can be targeted with mTOR inhibitors such as everolimus, is associated with the development of endocrine resistance in hormone receptor–positive BCs, as illustrated in Figure 1.22-27 Investigators for the phase 2 ELEVATE trial (NCT05563220) are evaluating elacestrant in combination with different agents, including everolimus, for patients with ER+/HER2-negative aBC following 1 to 2 lines of ET with or without a CDK4/6i.28 The median PFS was 8.3 months with elacestrant plus everolimus and 14.3 months with elacestrant plus abemaciclib. Investigators for the double-blind, phase 3 ADELA trial (NCT06382948) are evaluating the addition of everolimus to elacestrant for patients with ER+/HER2-negative, ESR1-mutated aBC progressing on ET plus a CDK4/6i.29

Medical Oncologist, Chief of Breast Medical Oncology, Baptist Health Miami Cancer Institute, Miami, FL

Assistant Professor of Medicine, Cooper Medical School of Rowan University, Co-Director, Janet Knowles Breast Cancer Center, Cooper University Health Care, Camden, NJ

Medical Director, Women’s Health Breast Oncology, Assistant Professor, Division of Medical Oncology and Therapeutics Research, City of Hope Orange County, Irvine, CA

SERD monotherapy is an option for patients with ESR1-mutated, ER+/HER2-negative aBC progressing on prior ET, including those who have received multiple prior therapies or who have a concomitant PIK3CA mutation.

SERD-based combinations improve outcomes for patients with ER+/HER2-negative aBC with biochemical or clinical disease progression.

The addition of PI3K pathway inhibitors to SERDs improves outcomes for patients with hormone receptor–positive/HER2-negative aBC that has progressed on prior ET.

hazard ratio was 0.49 (95% CI, 0.35-0.70) for patients with de novo HER2+ MBC, and 0.63 (95% CI, 0.46-0.87) for those with recurrent disease, demonstrating a clinically meaningful benefit in both subsets. PFS after the next subsequent line of therapy was also significantly higher in the experimental arm (median not reached vs 36.5 months; hazard ratio, 0.60; 95% CI, 0.45-0.79; P = .00038). Overall response rates (ORR) also favored the T-DXd plus pertuzumab arm (85.1%) vs 78.6% in the THP arm, with 73.3% and 54.9% in response at 24 months, respectively.

The most common grade 3 or higher treatment-related adverse events (TRAE) were neutropenia (23.9%), hypokalemia (10.2%), and anemia (8.4%) with T-DXd plus pertuzumab.3 With THP, they were neutropenia (33.2%), leukopenia (17.5%), and diarrhea (5.2%). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving T-DXd plus pertuzumab (all grade 1 or 2, with the exception of two grade 5 events) and in 1.0% of those receiving THP (all grade 1 or 2). Left ventricular dysfunction occurred in 11.0% of patients in the T-DXd plus pertuzumab arm (1.8%, grade 3; 0.3%, grade 4), compared with 7.1% in the control arm (1.8%, grade 3; no grade 4 events).

CME POSTTEST QUESTIONS

1 A 46-year-old woman was diagnosed with hormone receptor–positive (HR+)/HER2-positive (HER2+) de novo metastatic breast cancer. Assuming availability and regulatory approval, which of the following options would you recommend for first-line therapy to optimize progression-free survival?

A. Taxane  plus trastuzumab  plus pertuzumab

B. Trastuzumab deruxtecan (T-DXd)

C. T-DXd  plus pertuzumab

D. Ado-trastuzumab emtansine (T-DM1)

E. T-DM1  plus pertuzumab

2 A 55-year-old postmenopausal woman with HR+/HER2+ metastatic breast cancer has completed 6 cycles of trastuzumab and pertuzumab induction with a partial response. She would like to transition to maintenance therapy. Which of the following maintenance strategies is most appropriate for this patient?

A. Endocrine therapy (ET) plus palbociclib alone

B. Trastuzumab plus pertuzumab continuation alone

C. Trastuzumab plus pertuzumab plus ET

D. Trastuzumab plus pertuzumab plus ET plus palbociclib

3 A 51-year-old woman with HER2+ metastatic breast cancer has completed 6 cycles of docetaxel, trastuzumab, and pertuzumab with a confirmed partial response. She is transitioning to maintenance therapy. Based on phase 3 evidence, which of the following maintenance regimens has demonstrated superior progression-free survival compared with trastuzumab plus pertuzumab alone?

A. Neratinib plus trastuzumab

B. Trastuzumab emtansine

C. Trastuzumab deruxtecan

D. Tucatinib plus trastuzumab plus capecitabine

E. Tucatinib plus trastuzumab plus pertuzumab

To learn more about this topic,

including information on the frontline management of HER2+ MBC, including perspectives from experts on how they are integrating these new data into their practices, go to

https://www.gotoper.com/mbcc26her2maintenance-activity

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About Frontline and Maintenance Therapy for HER2+ Metastatic Breast Cancer

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Assess emerging clinical evidence supporting current and novel treatment strategies in the frontline setting for HER2+ metastatic breast cancer

• Develop individually tailored induction and maintenance regimens based on patient and disease characteristics

Release Date: May 18, 2026

Expiration Date: May 18, 2027

Accreditation/Credit Designation

Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Educational Grant Support

This activity is supported by an educational grant from Pfizer, Inc.

Off-Label Disclosure/Disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

How to Receive Credit

1. Read this activity in its entirety.

2. Go to https://www.gotoper.com/mbcc26her2maintenance-postref to access and complete the posttest.

3. Answer the evaluation questions.

4. Request credit using the drop-down menu.

You may immediately download your certificate.

Based on the significant improvement in outcomes seen with the addition of CDK4/6 inhibitors to ET for patients with HR+/HER2-negative MBC, the phase 3 PATINA trial (NCT02947685) was designed to test whether adding a CDK4/6 inhibitor to maintenance therapy with ET + trastuzumab and pertuzumab (HP) would similarly benefit patients with HR+/HER2+ MBC.4

A total of 518 patients with HR+/HER2+ MBC who did not have disease progression after 4 to 8 cycles of chemotherapy plus HER2-targeted therapy were randomly assigned to receive maintenance therapy with either ET  plus HER2-targeted therapy alone or in combination with palbociclib.4 Median PFS was significantly improved with palbociclib compared with control (44.3 vs 29.1 months; hazard ratio, 0.75; 95% CI, 0.59- 0.96; P = .02). Grade 3/4 neutropenia occurred in 10.0% of patients in the palbociclib arm vs 3.6% in the control arm.

A prespecified secondary analysis was conducted to evaluate the incidence and timing of central nervous system (CNS) progression, although baseline CNS imaging was not mandated.5 In the intent-to-treat population, CNS progression occurred in 13.4% of patients in the palbociclib arm and 19.5% of patients in the control arm. When the 20 patients with CNS metastases at baseline were excluded, the cumulative risk of CNS progression or death was 13.0% vs 19.2% at 36 months for palbociclib vs control (P=.0378), suggesting palbociclib may help to prevent or delay the development of CNS metastases in this setting (Table 2).5

The phase 3 HER2CLIMB05 (NCT05132582) trial enrolled 654 patients with HER2+ MBC without evidence of progression following 4 to 8 cycles of induction therapy with THP.6 Eligibility criteria also required patients to have no or asymptomatic brain metastases at baseline, confirmed by MRI. Patients were randomly assigned to maintenance therapy with HP plus either tucatinib or placebo.

“I think many of us are considering, in the hormone receptor–negative patients, using a maintenance strategy [incorporating] tucatinib.”

—Dr Reshma Mahtani, DO

The inclusion of tucatinib in the maintenance regimen significantly increased median PFS vs HP alone (24.9 vs 16.3 months; hazard ratio, 0.641; 95% CI, 0.514-.799; P < .0001).6 Although benefit was observed regardless of HR status, magnitude appeared greater in the HR-negative subpopulation (hazard ratio, 0.554; 95% CI, 0.403-0.761; P = .0002) than in the HR+ subset (hazard ratio, 0.725; 95% CI, 0.535-0.983; P = .0389). The most common TRAEs (any grade) in the tucatinib arm were diarrhea (72.7%; grade ≥ 3, 6.1% ), nausea (33.1%; grade ≥ 3, 0.9%), and elevated liver enzymes (alanine aminotransferase: 28.2%; grade ≥ 3, 13.5%; and aspartate aminotransferase: 25.8%; grade ≥ 3, 7.1%). OS data were immature at this analysis.

Key References

3. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2026;394(6):551-562. doi:10.1056/NEJMoa2508668.

4. Metzger O, Mandrekar S, Goel S, et al. Palbociclib for hormone-receptor-positive, HER2-positive advanced breast cancer. N Engl J Med. 2026;394(5):451-462. doi:10.1056/NEJMoa2511218.

6. Dieras V, Curigliano G, Martin M, et al. HER2CLIMB-05: a phase III study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as first-line maintenance therapy for HER2+ metastatic breast cancer. J Clin Oncol. Published online December 10, 2025. doi:10.1200/JCO-25-02600

Activity

HER2-positive (HER2+) metastatic breast cancer (MBC) is a fertile area for research and development, with 2 key new HER2-directed therapies introduced in recent years: antibody-drug conjugate trastuzumab deruxtecan (T-DXd) and tyrosine kinase inhibitor tucatinib. These agents have demonstrated efficacy initially in previously treated disease, and they are now moving into the frontline setting. Similarly, agents that have established themselves for HER2-negative disease, such as the CDK4/6 inhibitor palbociclib, are also moving into HER2+ MBC. Here are 3 things you should know about evolving paradigms in the frontline management of HER2+ MBC.

For more than a decade, a taxane backbone coupled with trastuzumab and pertuzumab (THP) has been the preferred first-line standard of care for most patients with HER2+ MBC, based on the pivotal phase 3 CLEOPATRA study (NCT00567190), which demonstrated both a progression-free survival (PFS) and an overall survival (OS) advantage for combined HER2 targeting vs trastuzumab only.1,2 However, that standard has now been challenged by recently published data from the phase 3 DESTINY-Breast09 trial (NCT04784715).3

DESTINY-Breast09 enrolled 1157 patients with HER2+  MBC who had not received prior systemic cytotoxic therapy for metastatic disease (1 prior line of endocrine therapy [ET] was allowed).3 Patients were randomly assigned to treatment with T-DXd plus pertuzumab; T-DXd plus placebo; or THP. Only results from an interim analysis of the T-DXd plus pertuzumab vs the THP arms have been reported to date.

Median PFS was significantly longer with T-DXd plus pertuzumab than in the control arm (40.7 vs 26.9 months; hazard ratio, 0.56; 95% CI, 0.44-0.71;

P < .00001), as seen in Table 1.3 Benefits were similar across preplanned subgroups, including hormone receptor status, PIK3CA mutation status, brain metastases at baseline, and prior exposure to anti-HER2 therapies. The

Faculty, Staff, and Planners’ Disclosures

This activity was written by PER® editorial staff based on a program developed with Drs O'Shaughnessy, Mahtani, McArthur, and Tarantino.

In accordance with ACCME Guidelines, PER® has identified and resolved all conflict of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.

Disclosures (Dr O’Shaughnessy): Consultant: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, BioNTech, Byondis, Carrick Therapeutics, Daiichi Sankyo, DAVA Oncology, Eisai, Eli Lilly and Company, Fishawack Health, G1 Therapeutics, Genentech, Genzyme, Gilead Sciences, GSK, Loxo Oncology, Merck, Novartis, Ontada, Pfizer, Pierre Fabre, Puma Biotechnology, Roche, Samsung Bioepis, Sanofi, Seagen, Stemline Therapeutics, Taiho Oncology, Verily

Disclosures (Dr Mahtani): Consultant: Agendia, Arvinas, AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Hologic, Lilly, Novartis, Pfizer, Sermonix, Stemline; Grant/Research Support: Gilead Sciences.

Disclosures (Dr McArthur): Consultant: Amgen, Arvinas, AstraZeneca, Bristol Myers Squibb, Calithera, Celgene, Daiichi-Sankyo, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Peregrine, Pfizer, Puma, Seattle Genetics, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, and TapImmune; Grant/Research Support: Bristol Myers Squibb, BTG, MedImmune/AstraZeneca, Merck.

Disclosures (Dr Tarantino): Advisor, Consultant, Speaker, Honoraria Recipient: AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Menarini/Stemline, Novartis, Roche; Grant/Research Funding: AstraZeneca

The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with ineligible companies.

Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Director, Breast Cancer Research Program, Texas Oncology, US Oncology, Dallas, TX

Medical Oncologist, Chief of Breast
Medical Oncology, Baptist Health
Miami Cancer Institute, Miami, FL

Heather McArthur, MD, MPH

Professor of Internal Medicine, Clinical Director, Breast Cancer Program, Komen Distinguished Chair in Clinical Breast Cancer Research, UT Southwestern Medical Center, Dallas, TX

Clinical Fellow, Breast Oncology Center, Dana-Farber Cancer Institute,
Harvard Medical School, Boston, MA

The DESTINY-Breast09 regimen beats the CLEOPATRA standard as first-line therapy for HER2+ MBC.

Inclusion of a CDK4/6 inhibitor to maintenance ET plus
anti-HER2–targeted therapy improves outcomes in hormone receptor–positive (HR+)/HER2+ MBC.

HER2CLIMB05 demonstrates the benefit of a HER2-directed tyrosine kinase inhibitor–based maintenance approach.

 

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