Between the Lines

Dr. Mazyar Shadman from Fred Hutchinson Cancer Center and Dr. Andrew Lipsky from Columbia University discuss the evolving first-line treatment landscape for chronic lymphocytic leukemia (CLL) in the era of BTK inhibition.

The program covers two major therapeutic strategies: continuous therapy with second-generation covalent BTK inhibitors (zanubrutinib or acalabrutinib) and time-limited venetoclax-based combinations including venetoclax-obinutuzumab, acalabrutinib-venetoclax, or zanubrutinib-venetoclax. Key biomarkers including TP53 aberrations and IGHV mutational status inform treatment selection, with TP53 aberrations favoring continuous BTK inhibitor therapy.

Highlighted data includes 78-month SEQUOIA follow-up showing 74% progression-free survival at 6 years for zanubrutinib monotherapy, pirtobrutinib's emerging frontline and sequencing data, and real-world evidence supporting treatment selection. The discussion addresses MRD testing utility, elderly patient management, and treatment sequencing after progression. Two clinical cases illustrate individualized decision-making incorporating molecular risk factors, comorbidities, disease burden, and patient preferences.

Dr. Ajai Chari and Dr. Rahul Banerjee open the discussion by examining how the treatment landscape for relapsed/refractory multiple myeloma (RRMM) has evolved in the era of CD38-based quadruplet regimens. Dr. Banerjee reviews the growing adoption of quadruplet therapy across newly diagnosed patient populations, including transplant-eligible and selected transplant-ineligible patients, and discusses how these approaches are reshaping expectations for outcomes and disease control.

Dr. Joshua Zeidner from University of North Carolina Lineberger Comprehensive Cancer Center and Dr. Jorge Cortes from O'Neal Cancer Center at University of Alabama Birmingham discussed the evolution of chronic myeloid leukemia (CML) treatment from a historically fatal diagnosis to a manageable chronic condition. The transformation began with imatinib's 2001 approval, followed by second-generation tyrosine kinase inhibitors (dasatinib, nilotinib) and third-generation agents (bosutinib), culminating in asciminib's recent introduction as an allosteric inhibitor.

Current practice emphasizes shared decision-making incorporating patient lifestyle factors, comorbidities, and treatment goals, particularly treatment-free remission aspirations. Asciminib has simplified frontline selection due to its superior safety profile and efficacy across patient populations. Both physicians advocate for patient-centered approaches to molecular response milestones, balancing guideline adherence with individual context rather than strict adherence to numerical thresholds.

Dr. Sarah Goldberg from Yale University School of Medicine and Dr. Misako Nagasaka from UCI Health discuss subcutaneous amivantamab every 4 weeks plus lazertinib as a first-line option for EGFR-mutated advanced non–small cell lung cancer. The discussion examines the MARIPOSA efficacy and overall survival data that established amivantamab plus lazertinib as a category 1 preferred first-line regimen, the dosing evolution from intravenous Q2W through subcutaneous Q2W in PALOMA-3 to the subcutaneous Q4W formulation studied in PALOMA-2 cohort 5, and proactive management strategies, including the COCOON dermatologic regimen and prophylactic anticoagulation, that support tolerability and treatment persistence.

Dr. Martin Voss and Dr. Matthew Campbell discuss the phase 3 LITESPARK-011 study in advanced renal cell carcinoma, reviewing evolving treatment strategies after progression on immunotherapy with a focus on the rationale and clinical impact of combining belzutifan with lenvatinib versus cabozantinib. The experts highlight key efficacy, safety, and mechanistic insights, while emphasizing how these findings may influence real-world treatment sequencing and decision-making.

This program explores evolving strategies in the management of chronic lymphocytic leukemia (CLL), with insights from Drs. Ian Flinn and Danielle Brander. The discussion focuses on the integration of BTK inhibitors and BCL2-targeted therapy, particularly zanubrutinib and venetoclax, highlighting their efficacy, safety, and practical application. Experts emphasize individualized treatment, balancing disease characteristics, comorbidities, and patient preferences, while considering therapy duration and the role of minimal residual disease (MRD)-guided approaches. The program examines fixed-duration and combination regimens, noting advantages in patients with high tumor burden or bulky disease. Long-term data from the ALPINE study demonstrate durable remissions with zanubrutinib versus ibrutinib in relapsed/refractory CLL, with low rates of atrial fibrillation, hypertension, and infections. Overall, the program underscores the importance of tailoring therapy, sequencing targeted agents thoughtfully, and understanding long-term outcomes, providing practical guidance for clinicians managing both frontline and relapsed/refractory CLL patients in an evolving therapeutic landscape.

Experts discuss recent advances in circulating tumor DNA (ctDNA) testing for muscle-invasive bladder cancer (MIBC), highlighting findings from three key ESMO 2025 studies, CheckMate 274, SunRISe-4, and IMvigor011, and emphasizing the growing role of ctDNA in identifying high-risk patients and guiding more personalized treatment strategies.

The MARIPOSA update series explores the evolving treatment landscape for EGFR-mutant non–small cell lung cancer (NSCLC), highlighting how the amivantamab plus lazertinib combination outperforms osimertinib as a first-line therapy. Through updated analyses from ESMO 2025, it demonstrates that this dual EGFR-MET targeting approach significantly reduces mechanisms of acquired resistance—especially MET amplification and secondary EGFR mutations—resulting in longer progression-free and overall survival. The findings reinforce the biologic rationale for early combination therapy, reduced mutational heterogeneity, and the potential to reshape long-term outcomes for patients with EGFR-mutant NSCLC

Panelists discuss how emerging data and guidelines reinforce quadruplet therapy as the foundation of NDMM treatment, supported by the ADVANCE trial’s findings on efficacy, safety, and applicability across risk groups. They highlight how precision testing, risk assessment, and evolving biologic therapies continue to refine individualized patient care.

Experts discuss the evolving landscape of relapsed or refractory multiple myeloma treatment, highlighting the transformative role of T-cell–redirecting therapies, such as bispecific antibodies and chimeric antigen T cells, while emphasizing the importance of innovative approaches, optimized sequencing, toxicity management, and expanded access—particularly through outpatient and hybrid care models in community settings—to ensure safe, effective, and convenient treatment across diverse patient populations.

Experts discuss the critical advancements in biomarker-driven frontline treatment for high-risk chronic lymphocytic leukemia (CLL), emphasizing the SEQUOIA trial’s evidence supporting targeted Bruton tyrosine kinase inhibitor monotherapy and combination therapies with venetoclax as effective, personalized, and well-tolerated options that improve progression-free survival and patient quality of life.

Panelists discuss how proactive dermatologic management using the protocol from the COCOON randomized, controlled trial (RCT) can significantly reduce grade 2 or higher skin-related adverse events from 73% to 41% in EGFR-mutated non–small cell lung cancer patients treated with amivantamab, emphasizing the shift from reactive to preventive care strategies to improve quality of life and treatment adherence.

Panelists discuss how the 3-year follow-up data from the KEYNOTE-B61 study demonstrate that pembrolizumab plus lenvatinib represents a new standard of care for advanced non–clear cell renal cell carcinoma (RCC), achieving impressive response rates of approximately 51%, median progression-free survival of 17.9 months, and median overall survival of 41.5 months across various histological subtypes, including papillary, chromophobe, translocation, and unclassified RCC.

Experts discuss how multidisciplinary care, pathology review, surgical quality, and circulating tumor DNA (ctDNA) testing together personalize colorectal cancer surveillance and treatment, improving early detection, guiding therapy decisions, reducing patient anxiety, and enhancing long-term outcomes across diverse clinical settings.

Panelists discuss how 5-year follow-up data from the CARTITUDE-1 study demonstrate that chimeric antigen receptor T-cell therapy with ciltacabtagene autoleucel achieved durable remissions in heavily pretreated patients with multiple myeloma, with 30% remaining progression free at 5 years and some patients achieving what may be considered a functional cure, potentially transforming multiple myeloma from an incurable to a curable disease.

Mazyar Shadman, MD, MPH, and Sayeef Mirza, MD, MPH, FACP, discuss how real-world data from over 1500 patients demonstrates that CAR T-cell therapy (CAR T) toxicities like cytokine release syndrome and neurotoxicity occur predominantly within the first 2 weeks post infusion, supporting the potential for reduced monitoring requirements and improved patient access to these lifesaving treatments.

Panelists discuss how CD38 antibody–based four-drug regimens are transforming frontline multiple myeloma treatment by improving efficacy, deepening and sustaining MRD responses, and expanding use across patient populations through individualized dosing—establishing a new standard of care while paving the way for integration of novel immunotherapies and potential shifts in transplant strategy.

Binod Dhakal, MD; and Leonid Shunyakov, MD, discuss how talquetamab (targeting GPRC5D) represents a breakthrough therapy for patients with relapsed/refractory multiple myeloma, demonstrating unprecedented 3-year overall survival rates of 45% to 61% with lower infection risks compared with BCMA-directed therapies, while addressing optimal sequencing strategies, outpatient management approaches, and the potential for earlier-line usage to maximize patient outcomes.

Alexander Spira, MD, PhD, FACP, FASCO​, and Randi Rabin, MPH, MSc,​ PA-C, discuss how proactive dermatologic adverse event management—specifically through the COCOON protocol—enhances treatment adherence, reduces toxicity, and improves quality of life for patients with EGFR-mutant non–small cell lung cancer receiving amivantamab plus lazertinib.

Martin Dietrich, MD, PhD ​and Roy Herbst, MD ​discuss how the evolving first-line treatment options for EGFR-mutated non-small cell lung cancer, including osimertinib monotherapy, osimertinib plus chemotherapy, and amivantamab plus lazertinib, have reshaped the landscape, with a strong emphasis on overall survival benefits and the role of combination therapies in improving patient outcomes.

John Marshall, MD​, and Mark Lewis, MD​, discuss how circulating tumor DNA (ctDNA) testing in colorectal cancer offers promising clinical utility across the care continuum, from early detection to treatment monitoring, with trials like BESPOKE and SWOG 80702 demonstrating its potential to guide personalized therapy decisions, predict outcomes based on minimal residual disease status, complement traditional imaging in challenging cases, and transform patient care through a patient-centric approach that requires ongoing research to establish standardized protocols.

Experts discuss the analyses on the impact of tumor burden at progression and changes in IMDC risk scores in the CLEAR trial, providing prognostic insights in advanced RCC with lenvatinib plus pembrolizumab.

Experts discuss the 3-year follow-up results from the phase 3 TRANSFORM study, comparing liso-cel with standard of care with salvage chemotherapy followed by autologous stem cell transplant (ASCT) as second-line treatment in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).

David Ilson, MD, PhD; Sunnie Kim, MD; and Raji Shameem, MD,​ discuss how first-line nivolumab plus chemotherapy has demonstrated sustained survival benefits in advanced gastric cancer, with PD-L1 combined positive scores helping guide patient selection. Long-term safety data support its role as standard of care, particularly benefiting patients with PD-L1–high disease, though unmet needs remain in subgroups with PD-L1–low disease.

Joshua K. Sabari, MD, and Martin Dietrich, MD, PhD, examine both the evolution of first-line EGFR TKIs as standard treatment for EGFR-mutated metastatic non-small cell lung cancer and the ongoing clinical challenges in managing resistance, toxicities, and treatment sequencing in this space.

Panelists discuss how the CLEAR trial highlights the efficacy of lenvatinib plus pembrolizumab over sunitinib in advanced renal cell carcinoma, focusing on patterns of progression and the implications for subsequent therapy.

Panelists discuss how nivolumab plus relatlimab may offer a similar efficacy to nivolumab plus ipilimumab in advanced melanoma, with a potentially better safety profile, based on an indirect treatment comparison using data from the RELATIVITY-047 and CheckMate 067 trials.