Antibody-Drug Conjugates in Advanced/Metastatic Non–Small Cell Lung Cancer

The contents of this supplement may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products.

Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Clinical Care Targeted Communications Group, LLC; the editorial staff; or any member of the editorial advisory board. Clinical Care Targeted Communications Group, LLC, is not responsible for accuracy of dosages given in articles printed herein. The appearance of advertisements in this publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. Clinical Care Targeted Communications Group, LLC, disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements.

ABSTRACT

Although significant progress has been achieved in the management of metastatic non–small cell lung cancer (mNSCLC), treatment options remain limited for patients whose disease progresses following standard immune checkpoint inhibitor and platinum-based chemotherapy. Moreover, after disease progression on targeted therapies in patients with NSCLC who harbor actionable oncogenic alterations, remaining options offer limited benefit. Antibody-drug conjugates (ADCs) are an emerging novel class of agents with the potential to improve outcomes in the current NSCLC treatment landscape. With their unique mechanism of action, ADCs are designed to deliver highly potent cytotoxic agents more directly to specific tumor cells. Identifying optimal cell surface-based ADC targets is an important consideration. Established ADC targets in NSCLC are HER2, MET, and TROP2 (with FDA-approved therapies available), and emerging targets include HER3, B7-H3, integrin-β_⁶, and EGFR. ADC therapy in all-comer NSCLC populations has failed to demonstrate significant overall survival advantages to date; however, ongoing studies in biomarker-selected subsets have shown promise, as have strategies using novel targets and payloads. Future data from ongoing trials will offer greater clarity, further define the role of ADCs within the treatment paradigm, and help address the unmet needs of patients with advanced/mNSCLC, particularly as these agents are increasingly explored in earlier lines of therapy and in combination with immune checkpoint inhibitors and tyrosine kinase inhibitors.

Keywords: advanced/metastatic NSCLC; antibody-drug conjugates; TROP2; HER2; HER3; MET; EGFR

Introduction

Lung cancer remains the leading cause of cancer-related death in both men and women in the United States, despite considerable advances in its management with the introduction of novel agents.¹ In non–small cell lung cancer (NSCLC), which accounts for more than 80% of lung cancer cases, the survival outcome has significantly improved in recent years, with 5-year relative survival increasing from 17.78% in 2004 to 37.76% in 2022.² However, the prognosis of patients with advanced disease remains dismal, with fewer than 10% of patients with metastatic NSCLC (mNSCLC) surviving 5 years after diagnosis.^1-4

Traditionally, a platinum-based chemotherapy (PBC) regimen was the mainstay first-line (1L) treatment option for patients with mNSCLC lacking actionable genomic alterations (AGAs), but it was associated with significant systemic toxicities and offered only limited efficacy.^5,6 The addition of an immune checkpoint inhibitor (ICI) to PBC in the 1L substantially improved survival and is now the standard of care (SOC) for many patients with non-AGA mNSCLC.⁷ However, following progression and in patients who are refractory to initial treatment, the remaining therapeutic options are limited and suboptimal, with second-line (2L) chemotherapy conferring only modest benefit but having significant potential for deteriorating quality of life (QOL).^7,8 Similar challenges face patients with AGA-positive NSCLC once AGA-targeted strategies have been exhausted.⁹ There is a need for new and more effective approaches for subsequent lines of treatment.

Novel therapeutic agents and combinations hold promise for improving clinical outcomes while minimizing toxicity. Antibody-drug conjugates (ADCs) are emerging as a potential therapeutic option in various cancers, including NSCLC. While fundamentally cytotoxic, they deliver highly potent cytotoxic payloads more directly to tumor cells, with the goal of reducing off-target effects.¹⁰ In addition, they exert therapeutic effects by inhibiting signaling in biologically active targets, such as in patients with HER2 mutations.

In this review, we discuss the challenges and unmet needssurrounding the management of advanced or mNSCLC after progression on 1L therapy. These include identifying the limited options and remaining gaps with use of the current SOC in the 2L and beyond, addressing recent setbacks in clinical trials in this patient population, examining ADCs as a novel therapeutic class of agents that may overcome the limitations of current SOC, reviewing the emerging ADC therapeutic targets in NSCLC and recent progress from phase 2 and 3 clinical trials with ADCs, and, finally, exploring potential strategies with ADC-based combination therapies that are on the horizon.

Challenges and Unmet Needs Surrounding Second-Line Treatment of mNSCLC

The use of ICIs in the 1L with or without PBC has transformed the treatment landscape of non-AGA advanced/mNSCLC. However, most patients experience disease progression due to intrinsic or acquired resistance to ICI, and patients have limited options following failure of their 1L treatment.¹¹ Over the past decades, docetaxel with or without ramucirumab has remained one of the standard 2L therapy options based on the results of the REVEL trial (NCT01168973), highlighting the lack of significant progress in this setting. Unfortunately, therapies in the 2L setting and beyond are associated with suboptimal efficacy and substantial toxicities.

Concerted efforts are directed to addressing the urgent need for more efficacious and tolerable options. The recently reported Pragmatica-Lung study(SWOG S2302; NCT05633602) exemplifies such efforts, testing the chemotherapy-free combination of ramucirumab and pembrolizumab in patients previously treated with ICIs. Although the study did not demonstrate an overall survival (OS) advantage for the combination, it confirmed feasibility of a chemotherapy-free regimen and suggested possible benefit in certain subgroups, such as patients with squamous histology.¹² This unmet need is similarly evident in AGA-positive and EGFR-mutated NSCLC, for which effective treatments with durable responses following tyrosine kinase inhibitor (TKI) resistance are lacking, underscoring the importance of novel strategies across molecularly defined subgroups.^13,14

Central nervous system (CNS) involvement is a significant therapeutic challenge that patients face when considering treatment strategies in the 2L and beyond. Brain metastasis (BM) is prevalent in NSCLC; BM is found in 10% to 30% of patients at initial diagnosis, with the rate increasing throughout the disease course.^15-18 In advanced NSCLC with AGAs, such as EGFR-mutated and ALK-rearranged NSCLC, the incidence of BM is higher, accounting for approximately 25% of patients at diagnosis and a 3-year cumulative incidence ranging from 29.4% to 60.3%.^19,20 In addition, approximately 20% of patients will have BM as their first site of recurrence following definitive treatment for NSCLC. BM not only significantly contributes to poor prognosis, performance status, QOL, and morbidity, but it is also a main cause of death.²¹ Therefore, finding therapies that are effective against CNS disease is of paramount importance.

Goal of Care and Treatment Decision Factors

The primary therapeutic objectives for advanced NSCLC in the 2L setting and beyond are to optimize disease control, delay tumor progression, and prolong survival while minimizing toxicity and impact on QOL.²² To achieve this, treatment must balance efficacy with toxicity. Key factors driving treatment decisions in advanced NSCLC include disease stage, performance status, age, and comorbidities.^23,24 The presence of BM at diagnosis, which has a significant correlation with poor performance status and survival, may also play a role in the treatment decision.²⁴ In the contemporary treatment landscape, selection of 2L therapy is often informed by disease characteristics that guided 1L treatment choices. Key disease-specific factors such as histology, PD-L1 expression, and the presence of oncogenic driver alterations continue to influence management decisions after progression. Patients harboring AGAs (eg, EGFR, ALK, ROS1, BRAF V600E, NTRK, MET exon 14, and RET) typically receive mutation-directed targeted therapies in the 1L setting, which shapes subsequent treatment sequencing.²⁵ For those without such alterations, PD-L1 status determines the initial use of ICIs, either as monotherapy or in combination with chemotherapy.

Upon progression, specific molecular subsets guide 2L treatment selection. For instance, the presence of the KRAS G12C mutation confers eligibility for oral KRAS G12C inhibitors, which are now SOC in previously treated patients. Similarly, ADCs that target HER2 and MET are approved for the 2L and beyond in NSCLC involving HER2 mutation or HER2 overexpression and in disease involving MET overexpression, respectively.²⁵

Given that patients with advanced NSCLC may experience high symptom burden, early integration of palliative care after diagnosis is recommended, as it has been shown to significantly enhance both QOL and OS while reducing the need for aggressive end-of-life interventions.²⁶ Throughout shared decision-making in the treatment course, incorporation of optimal supportive care in the setting of a multidisciplinary care team, including palliative care, is an integral aspect of care for all patients with advanced lung cancer.

Limitations Surrounding the Current Standard of Care in the Second-Line Setting

Among other treatment options, docetaxel with or without the anti-VEGFR2 monoclonal antibody (mAb) ramucirumab is the foundation of 2L therapy in non-AGA advanced/mNSCLC following treatment with a platinum doublet and a checkpoint inhibitor. Clinical response to single-agent docetaxel has been modest, with a historical overall response rate (ORR) of 7.1%. While a combination treatment approach with ramucirumab has shown improved outcomes,it is associated with increased toxicity and only modest additional clinical benefit.²⁷

Real-world data show poor clinical outcomes for patients who were previously treated with ICI and PBC, including short time to treatment discontinuation and time to next line of therapy, as well as reduced OS.²⁸ Results of a recent real-world study showed that adding ramucirumab to docetaxel after PBC was not associated with a survival benefit; the median progression-free survival (PFS) and OS remained poor at 2.9 and 7.2 months, respectively.²⁹ Repeated use of ICI and PBC was also noted, suggesting a lack of effective options in this space.²⁸ Similarly, in the phase III Pragmatica-Lung (SWOG S2302; NCT05633602), ramucirumab plus pembrolizumab did not improve OS compared with SOC (median OS, 10.1 vs 9.3 months; HR, 0.99), although feasibility and potential benefit in squamous subgroups were noted.¹² These limited clinical outcomes heighten the unmet need for more effective 2L treatment options for those whose disease progresses after ICI and PBC.³⁰

Phase 3 REVEL Trial

In the phase 3 REVEL trial, the combination of docetaxel and ramucirumab demonstrated a median OS of 10.5 months and a PFS of 4.5 months, as compared with 9.1 and 3.4 months, respectively, achieved with docetaxel alone. The combination led to an ORR of 23%, significantly higher than the 14% reported with docetaxel alone; however, an exploratory analysis revealed similar modest benefit for patients with disease progression during or after 1L PBC regardless of the nature of 1L therapy.³¹

Docetaxel-based therapies are associated with significant toxicity. In the REVEL trial, the most common treatment-emergent adverse event (TEAE) of grade 3 or higher was neutropenia, seen in 49% of patients receiving the docetaxel and ramucirumab combination and in 40% of patients receiving docetaxel alone. Other significant TEAEs of at least grade 3 included leukopenia (12%-14%), febrile neutropenia (10%-16%), fatigue (10%-14%), and hypertension (2%-6%) across the 2 treatment arms.³¹ Despite this increased toxicity, the FDA approved the combination of docetaxel plus ramucirumab in 2014 based on the modest survival benefit noted in this population with otherwise very limited alternatives.²⁷

Clinical Studies in the Setting of Progression After Initial ICI and PBC

Earlier trials with docetaxel-based regimens, including REVEL, were conducted before ICIs were approved in immunotherapy-naive patients, raising questions about whether their results accurately reflect outcomes in patients who experienced progression after 1L ICI and PBC therapy.²⁷ Efforts toward addressing this gap are shown in the outcomes of studies, such as the phase 2 prospective single-arm SCORPION (jCRTs041190077) and retrospective multicenter REACTIVE study (UMIN000042333), in determining the clinical significance of docetaxel and ramucirumab as a 2L therapy after disease progression on an ICI and PBC.^32,33 Although results must be interpreted cautiously in the absence of data from large randomized controlled studies, the clinical benefit of docetaxel and ramucirumab may be further reduced by the residual effect of prior ICI exposure.^27,32 In both of these studies, the combination of docetaxel and ramucirumab improved ORR in line with earlier phase 3 results; however, little to no impact on PFS or OS was seen in the post-ICI setting compared with docetaxel alone.²⁷ The control arm of all recent phase 2/3 trials—notably, CONTACT-01 (NCT04471428), LEAP-008 (NCT03976375), SAPPHIRE (NCT03906071), CANOPY-2 (NCT03626545), S1800A (NCT03971474), ATALANTE-1 (NCT02654587), and SWOG2302 Pragmatica-Lung—did not show any significant outcome difference for docetaxel as compared with historical pre-ICI data.^12,34-39 The key data points from clinical trials with results that failed to show benefit in the 2L setting are summarized in Table 1.^{12,34-36,38,39}

ICI-Based Combinations

Phase 3 CONTACT-01 Trial

In the phase 3 CONTACT-01 trial, reintroduction of an ICI given in combination with a multitargeted TKI, cabozantinib, was studied to evaluate if it could restimulate an immune response in previously treated patients with mNSCLC who had progressed after ICI.³⁴ Eligible patients were randomly assigned to receive either atezolizumab plus cabozantinib or docetaxel. The TKI cabozantinib targets multiple receptors, including MET, RET, VEGFR, and ROS1. Although numerical improvements of PFS and duration of response (DOR) were observed in favor of atezolizumab plus cabozantinib over docetaxel, the primary end point of OS was not met in this study (median OS, 10.7 vs 10.5 months, respectively).³⁴

Overall incidences of TEAEs were consistent with the previously known profiles of each drug and comparable between arms. However, the incidence of grade 5 AEs, treatment interruptions, and dose modifications was higher in the group that received atezolizumab plus cabozantinib than in the docetaxel arm.³⁴

Phase 3 LEAP-008 Trial

Based on encouraging data observed in patients with advanced melanoma and renal cell carcinoma after progression on ICI, the phase 3 LEAP-008 trial assessed the efficacy of the combination of pembrolizumab plus lenvatinib in the 2L setting in mNSCLC.³⁵ Patients with any PD-L1 status whose disease progressed after prior therapy with ICI and PBC and no AGAs were randomly assigned to receive either pembrolizumab plus lenvatinib, docetaxel alone, or lenvatinib alone. In this study, the combined use of an ICI plus a VEGF TKI did not improve efficacy compared with docetaxel in mNSCLC, as it did not meet dual primary end points of OS and PFS or the secondary end point of ORR. TEAEs of at least grade 3 for pembrolizumab plus lenvatinib, docetaxel, and lenvatinib were 59.7%, 48.6%, and 57.4%, respectively.³⁵

Phase 3 SAPPHIRE Trial

Sitravatinib is a receptor TKI targeting TAM (TYRO3, AXL, Mer) receptors; it can shift a tumor microenvironment from an immunosuppressive to immunostimulatory state, making it an ideal candidate for combined use with an ICI to potentially overcome initial resistance.³⁶ Despite earlier promising results of improved OS over historic controls in advanced nonsquamous mNSCLC, when compared with docetaxel in the phase 3 SAPPHIRE trial, nivolumab plus sitravatinib failed to meet the OS end point and showed that the combination could not overcome ICI resistance in patients previously treated with ICI with PBC. Results of the SAPPHIRE trial also showed that combined use of an ICI and a TKI did not improve PFS, ORR, and DOR in the 2L setting in previously treated patients with advanced nonsquamous mNSCLC. Safety profiles of both arms were consistent with previous reports and showed more TEAEs of grade 3 or higher occurring in the docetaxel arm.³⁶

Phase 3 Pragmatica-Lung Trial

In another ICI-based approach, the phase 3 Pragmatica-Lung trial evaluated pembrolizumab plus ramucirumab vs physician’s choice of standard treatment in patients with advanced/mNSCLC previously treated with ICI and PBC. In the most recent interim analysis, OS did not differ between the arms, with an HR of 0.99 (95% CI, 0.81-1.22); median OS was 10.1 months for patients receiving pembrolizumab/ramucirumab and 9.3 months for those receiving SOC.¹² Also of note, the design of this trial allowed for the prospective enrollment of a real-world population with increased rurality and ethnic diversity.

Antibody-Drug Conjugates

Phase 3 CARMEN-LC03 Trial

Tusamitamab ravtansine, an ADC consisting of a humanized CEACAM5-directed mAb coupled with a cytotoxic payload, maytansinoid (DM4), was designed to exert its cytotoxic activity on CEACAM5-expressing tumor cells.³⁷ Despite the promise of results noted in early-phase trials, tusamitamab ravtansine did not meet a primary end point of improving PFS in the phase 3 CARMEN-LC03 trial when compared with docetaxel in patients with advanced nonsquamous mNSCLC.^37,38 Eligible patients were those with NSCLC with high expression of CEACAM5 ​(≥ 50% of tumor cells having an immunohistochemistry [IHC] of 2+) whose disease had progressed following ICI and PBC.³⁹ The final analysis showed that tusamitamab ravtansine monotherapy did not improve PFS when compared with docetaxel, despite showing an improved OS trend. Consequently, further clinical development of CEACAM-directed ADCs in NSCLC was discontinued in December 2023; their potential utility in managing other cancer types with high CEACAM-5 expression continues to be investigated.³⁸

ADCs Offer Promise Amid Treatment Challenges and Limitations

Despite earlier setbacks, ADCs continue to hold the potential to deliver effective and well-tolerated treatment options for patients with advanced/mNSCLC. However, given the considerable variability in both the necessity and optimal choice of biomarkers across different ADCs, there is a critical need to individualize the identification of ideal patient populations and associated biomarkers to accurately predict and enhance treatment response. Currently, there are 3 FDA-approved ADCs for the treatment of advanced/mNSCLC in the 2L and beyond setting: trastuzumab deruxtecan (T-DXd), telisotuzumab vedotin (Teliso-V), and datopotamab deruxtecan (Dato-DXd).

ADCs With FDA-Approved Indications in NSCLC

Trastuzumab Deruxtecan

HER2 is a transmembrane protein that belongs to the EGFR family. Dysregulation of HER2 signaling can occur in many tumor types, and it represents a highly heterogeneous group of diseases.⁴⁰ In NSCLC, the HER2 gene mutation occurs in about 2% to 4% of patients, and it is a predictive biomarker for ADCs. Unlike in breast cancer, the predictive or prognostic significance of HER2 amplification (found in 2%-4% in NSCLC cases) and HER2 overexpression (ranging from 2.5%-34% in NSCLC) has historically been less well-defined in NSCLC.⁴⁰ Specifically, HER2 overexpression at the IHC 3+ level is observed in approximately 1% to 5% of patients with NSCLC.⁴¹ Those with an HER2 IHC score of 3+ demonstrate poorer prognosis and reduced 5-year survival compared with patients with scores of 0 to 2, highlighting HER2 overexpression (score 3+) as an adverse prognostic factor, particularly in adenocarcinoma.⁴² Overall, these findings underscore the growing importance of accurately identifying HER2 overexpression in NSCLC to guide targeted therapies and improve patient outcomes.

T-DXdis an ADC consisting of the HER2-targeting mAb trastuzumab linked to deruxtecan via a tumor-selectable cleavable linker.⁴³ The phase 2 DESTINY-Lung01 trial (NCT03505710) demonstrated that previously treated patients with HER2-mutated NSCLC who received T-DXd at a dose of 6.4 mg/kg had an ORR of 55%, a median PFS of 8.2 months, and a median DOR of 9.3 months. However, the toxicity was pronounced, with interstitial lung disease (ILD) occurring in 26% of patients.⁴³ This prompted the phase 2 DESTINY-Lung02 trial (NCT04644237), in which previously treated patients with HER2-mutated NSCLC were randomly assigned to receive either 5.4 or 6.4 mg/kg of T-DXd every 3 weeks. The response rates were similar and clinically meaningful at both dose levels, with an ORR of 49.0% and 56.0% in the 5.4- and 6.4- mg/kg arms, respectively. The median DOR was 16.8 months for 5.4 mg/kg, while it was not estimable (NE) for 6.4 mg/kg, and patients received treatment for a median of 7.7 months with 5.4 mg/kg and 8.3 months with 6.4 mg/kg. The safety profile, including T-DXd–related ILD, favored the lower dose, with ILD occurring in 12.9% of patients receiving 5.4 mg/kg and 28% in those receiving 6.4 mg/kg.⁴⁴ Based on these results, in August 2022, the FDA granted accelerated approval to T-DXd given at 5.4 mg/kg every 3 weeks for patients with HER2-mutated NSCLC who have received prior systemic therapy, representing the first ADC drug approval in NSCLC.⁴⁵

T-DXd subsequently received an expanded FDA approval on April 5, 2024, for adult patients with unresectable or metastatic HER2-overexpressing (IHC 3+) solid tumors, including NSCLC, who have received prior systemic therapy. This approval was based on the efficacy and safety results demonstrated in the DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01, and DESTINY-CRC02 (NCT04744831) trials.⁴⁶ The single-arm, phase 2 DESTINY-Lung01 trial included subgroups of patients with previously treated NSCLC with HER2 overexpression (IHC 2+ or 3+).⁴⁷ The median treatment duration was 4.1 months for the 6.4-mg/kg group and 5.5 months for the 5.4-mg/kg group. ORR was lower at 26.5% in those treated with 6.4 mg/kg compared with 34.1% in those treated with 5.4 mg/kg. TEAEs of grade 3 or more occurred in 53% of patients receiving 6.4 mg/kg versus 22% in the 5.4-mg/kg group, including ILD in 20% and 5% of patients, respectively.⁴⁷

Of note, in the DESTINY-Lung01 trial, 32% of patients with HER2-overexpressing NSCLC had stable or treated CNS metastases without leptomeningeal disease, and their outcomes were comparable to the overall cohort.^47,48 Although the CNS activity of T-DXd in NSCLC is not fully characterized, it has demonstrated promising intracranial (IC) activity in other malignancies. In the TUXEDO-1 trial (NCT04752059) for HER2-positive breast cancer, IC response rates reached 73% in patients with active CNS metastases. Given the limited treatment options for patients with HER2-positive NSCLC who have active brain metastasis or leptomeningeal disease, further investigation of T-DXd in this population is warranted.⁴⁸ The efficacy and safety of T-DXd in the 1L setting are currently being evaluated in the phase 3 DESTINY-Lung04 trial (NCT05048797), which compares T-DXd with the SOC chemotherapy plus ICI combination in HER2-mutated NSCLC.⁴⁹

Telisotuzumab Vedotin

The MET proto-oncogene encodes the transmembrane receptor tyrosine kinase MET, also known as the HGF receptor.⁵⁰ Expressed on the cell surface, MET mediates key processes including proliferation, survival, motility, and invasion by activating downstream signaling pathways such as MAPK, PI3K-AKT-mTOR, and Wnt/b-catenin upon HGF binding. Aberrations in MET—including overexpression, gene amplification, or exon 14 skipping—can lead to constitutive oncogenic signaling independent of ligand binding.^51,52 MET is frequently dysregulated in a variety of cancers, particularly NSCLC, where overexpression occurs in approximately 20% of cases and gene amplification in 1% to 5%.⁵³ In NSCLC, MET alterations function both as primary oncogenic drivers, especially in exon 14 skipping cases, and as mediators of acquired resistance.⁵⁴ The combination of cell-surface localization, selective overexpression, and critical roles in oncogenic signaling underscores MET’s potential as a therapeutic target, including ADCs.

Teliso-V is the first-in-class MET-directed ADC composed of a mAb coupled with a microtubule inhibitor monomethyl auristatin E (MMAE) via a peptide linker.⁵⁵ After antibody binding and internalization by tumor cells expressing high MET expression, the linker is cleaved intracellularly and releases MMAE, which disrupts microtubules and induces cell death independent of MET signaling activity.⁵⁶ Unlike small-molecule MET inhibitors that require evidence of MET activation, such as gene amplification or exon 14 skipping, Teliso-V’s mechanism relies on surface receptor expression of MET as a delivery target rather than inhibition of MET signaling itself. This design allows effective cytotoxicity even in cases where MET signaling is not the primary oncogenic driver, as long as MET is sufficiently expressed on the surface.⁵⁶

An early phase 1 study demonstrated Teliso-V activity in patients with advanced NSCLC with a MET H-score of at least 150 (MET+) or MET amplification/exon 14 skipping mutations.⁵⁷ Efficacy was evaluated in the phase 2 multicenter, open-label LUMINOSITY study (NCT03539536). The trial included 84 patients with EGFR–wild-type, nonsquamous NSCLC with high MET protein overexpression who had received prior systemic therapy.⁵⁸ At the recommended dose of 1.9 mg/kg every 2 weeks, ORR was 35% and median DOR was 7.2 months, and these results were consistent regardless of prior treatment with platinum-based therapy alone or in combination with ICI. In a pooled safety population, the most common TEAEs were peripheral neuropathy, fatigue, decreased appetite, and peripheral edema.⁵⁸ Based on these results, on May 14, 2025, the FDA granted accelerated approval to Teliso-V for adults with locally advanced or mNSCLC with high MET overexpression, defined as at least 50% of tumor cells with strong (3+) staining as determined by an FDA-approved test, who have received prior systemic therapy.⁵⁹

In the primary analysis evaluating varying levels of MET overexpression, outcomes were more favorable in patients with high MET expression (≥ 50% IHC 3+) compared with those with intermediate expression (25%-50% IHC 3+). ORR was 34.6% in the high-MET group vs 22.9% in the intermediate group. Additionally, the DOR was longer in the high-MET group, at 9 months, compared with 7.2 months in the intermediate group.⁶⁰ In EGFR-mutated NSCLC or disease with squamous histology, the activity of Teliso-V as monotherapy was more limited, with previously reported results showing only modest efficacy.⁶¹ However, interim findings of a phase 1/1b study (NCT02099058) showed an ORR of 56% to 58% when Teliso-V was combined with osimertinib in patients with MET-overexpressing, nonsquamous, EGFR-mutated mNSCLC whose disease progressed on prior osimertinib.⁶² Teliso-V is being further evaluated as a single agent compared with docetaxel in the phase 3 TelliMET NSCLC-01 trial (NCT04928846) in previously treated patients with EGFR–wild-type nonsquamous mNSCLC with MET overexpression, defined as at least 25% tumor cells at 3+ by IHC.⁶³

Datopotamab Deruxtecan

Dato-DXd is a TROP2-directed ADC that has recently received FDA approval for the treatment of patients with EGFR-mutated NSCLC who have had prior exposure to EGFR-directed therapies and PBC. TROP2 is a transmembrane glycoprotein encoded by the gene TACSTD2.^64,65 Under normal physiological conditions, TROP2 acts as a calcium signal transducer and influences intracellular signaling pathways responsible for cell growth, proliferation, self-renewal, survival, and invasion.^55,64,66,67 TROP2 is expressed within many normal epithelial tissuesand is also highly expressed in many cancers, including a variety of epithelial-derived tumors, where it can promote tumor cell proliferation, invasion, and metastasis.^64,65,68,69 Involvement of TROP2 in the tumorigenic signaling pathway is shown in Figure 1.⁶⁴

TROP2 expression has important clinical implications in NSCLC, where it is broadly expressed across tumor histologies, with higher levels typically observed in squamous compared with nonsquamous subtypes, and is largely independent of PD-L1 expression or the presence of AGAs.^64,70 TROP2-expressing cells are present in approximately 75% to 92% of squamous cell carcinomas and 55% to 100% of lung adenocarcinomas.^69-72 In addition to its widespread expression, TROP2 expression levels appear to remain stable in NSCLC during anticancer treatment.⁷²

Overexpression of TROP2 has been correlated with unfavorable prognosis, increased metastasis risk, and reduced survival in NSCLC.^66,70,73 Prognostic value of TROP2 may also depend on its cellular localization within tumors; membranous TROP2 was associated with worse survival, whereas TROP2 intracellular retention conferred better survival/lower disease relapse rates.^66,74 Moreover, TROP2 is associated with primary resistance to checkpoint inhibition in advanced NSCLC.⁷⁵

Dato-DXd has the TROP2-targeting mAb covalently linked to a topoisomerase I inhibitor via a tetrapeptide-based cleavable linker.^76,77 The drug moiety deruxtecan is the cytotoxic payload that binds to DNA to form topoisomerase I-DNA complexes that induce DNA double-strand breaks upon intracellular internalization and release.⁷⁷ Dato-DXd delivers its cytotoxic payload to its target via a systemically stable but tumor-selective cleavable linker, allowing for a preferrable pharmacokinetic profile while reducing off-target toxicity, with a drug-antibody ratio (DAR) of 4. The released payload is cell membrane–permeable, which enables a bystander effect after DXd ADC internalization and linker cleavage, resulting in elimination of both target and neighboring cells present in the tumor microenvironment.⁷⁷ Figure 2 illustrates the mechanism of action for TROP2-directed ADCs.⁷⁸ After its approval for breast cancer, Dato-DXd was granted accelerated FDA approval on June 23, 2025, for the treatment of patients with EGFR-mutated NSCLC who have received prior EGFR-directed and platinum-based chemotherapy.^78-80 The approval in NSCLC was based on 2 clinical trials: TROPION-Lung01 (NCT04656652) and TROPION-Lung05 (NCT04484142).⁸⁰

TROPION-Lung01 Trial

The phase 3 randomized TROPION-Lung01 trial compared Dato-DXd with docetaxel in patients with previously treated advanced/mNSCLC with or without AGAs. The study included patients who were heavily pretreated, with 43.1% having received at least 2 prior lines of systemic therapy, and allowed enrollment of patients with clinically inactive or treated, asymptomatic BM. Patients were stratified based on geography, histology (squamous vs nonsquamous), presence of AGAs, and immediate prior use of an anti–PD-L1 ICI.⁸¹

The results from the final analysis showed a significant PFS improvement for Dato-DXd with a median PFS of 4.4 months (95% CI, 4.2-5.6 months) and 3.7 months (95% CI, 2.9-4.2 months) in the Dato-DXd and docetaxel arms, respectively.⁸² However, despite the OS results numerically favoring Dato-DXd, they did not reach significance in the overall trial population that included both squamous and nonsquamous histology.

When analyzed by the histological subgroups, the PFS benefit of Dato-DXd was primarily driven by the prespecified subgroup of patients with nonsquamous histology, for whom the median PFS was 5.5 months on Dato-DXd versus 3.6 months in the docetaxel arm (HR, 0.63; 95% CI, 0.51-0.79).⁸² This benefit of Dato-DXd in the nonsquamous histology subgroup was observed across all efficacy end points, including the dual primary end points of PFS and OS, as well as secondary end points such as ORR and DOR. The safety profile was manageable with no new safety signals identified.⁸³ TEAEs of at least grade 3 occurred in 25.6% of the Dato-DXd arm compared with 42.1% of the docetaxel arm; ILD of any grade was seen in 8.8% of those given Dato-DXd and 4.1% of those given docetaxel. Treatment discontinuation occurred in 8.1% versus 12.1% of those given Dato-DXd or docetaxel, respectively.⁸² Despite the OS not meeting the significance threshold in the intention-to-treat population, data in patients with nonsquamous histology might support the clinical use of Dato-DXd.⁸³

TROPION-Lung05

In the phase 2 TROPION-Lung05 trial, 137 previously treated patients with advanced/mNSCLC harboring AGA (56.9% with EGFR mutations and 24.8% with ALK rearrangements) received Dato-DXd at a dose of 6 mg/kg every 3 weeks.⁸⁴ The efficacy of Dato-DXd was greater in patients with EGFR mutations, who achieved an ORR of 43.6%, compared with 23.5% in those with ALK rearrangements and 35.8% in the overall patient population. The overall median DOR was 7 months with the overall disease control rate of 78.8%. TEAEs of at least grade 3 occurred in 28.5%, with stomatitis being the most common TEAE.⁸⁴

In a previous analysis from the TROPION-Lung05 study, an exploratory end point evaluated the IC efficacy of Dato-DXd in patients with advanced/mNSCLC harboring AGAs. Of 53 patients with BM at baseline, 18 patients had measurable IC target lesions.⁸⁵ The IC ORR in these patients was 22% (95% CI, 6%-48%), and a reduction in the sum of diameters of brain lesions was seen in 56% of patients. Systemic efficacy and safety of Dato-DXd were comparable between patients with or without baseline BM.⁸⁵ These findings suggested that Dato-DXd exhibits IC activity in patients with heavily pretreated mNSCLC with AGAs, warranting further investigation of Dato-DXd in patients with BM. Building upon these observations, a recent post hoc analysis of TROPION-Lung 01 further characterized the IC activity of Dato-DXd in patients with baseline BM, including those with untreated lesions or progression following radiotherapy.⁸⁶ Dato-DXd demonstrated numerically improved IC response rates and PFS compared with docetaxel. Among patients with measurable disease, the confirmed ORR was 38%, and all evaluable patients achieved CNS disease control, whereas no IC responses were observed with docetaxel. All 6 CNS responders had nonsquamous histology, including 2 with EGFR-mutated tumors.⁸⁶ Collectively, these results reinforce the potential for IC efficacy of Dato-DXd in advanced or mNSCLC with BM.

TL-01 and TL-05 Pooled Data in EGFR-Mutated NSCLC

In the pooled analysis of 117 patients with previously treated, EGFR-mutated, advanced NSCLC from TROPION-Lung01 (n = 39) and TROPION-Lung05 (n = 78) studies, Dato-DXd demonstrated a favorable efficacy and safety profile with confirmed ORR of 43% and median DOR of 7 months. The most common TEAE of special interest was stomatitis/mucositis, occurring in 69% of patients at any grade and 9% at grade 3 or more. No grade 4 or 5 cases of adjudicated drug-related ILD were reported.⁸⁷ These findings supported the approval of Dato-DXd at the recommended dose of 6 mg/kg every 3 weeks for the treatment of advanced/mNSCLC with EGFR mutations following prior EGFR-directed therapy and PBC. The antitumor activity of Dato-DXd in patients with EGFR-mutated mNSCLC previously treated with EGFR-directed therapy and platinum-based chemotherapy may reflect underlying tumor biology and resistance mechanisms.⁸⁸

TROP2, which can be upregulated in EGFR-TKI–resistant disease, promotes activation of the IGF2-IGF1R-AKT pathway and influences the tumor microenvironment, making it a biologically relevant therapeutic target.⁸⁹ By delivering a cytotoxic topoisomerase I inhibitor payload through TROP2-mediated internalization, Dato-DXd acts independently of EGFR signaling, offering a strategy to overcome resistance to EGFR-targeted therapies.⁸⁸

Review of Other TROP2-Directed ADCs in Clinical Development

Other TROP2-directed ADCs are currently being investigated in clinical trials for NSCLC. These include sacituzumab govitecan (SG), which is already FDA-approved for breast cancer, and sacituzumab tirumotecan (sac-TMT), which has received FDA breakthrough therapy designation for EGFR-mutated NSCLC.^90-94

Sacituzumab Govitecan

SG is a TROP2-directed ADC composed of an mAb conjugated to the cytotoxic topoisomerase I inhibitor SN-38 payload through a pH-sensitive hydrolyzable linker with a DAR of 7.6.^95,96 SN-38, the active metabolite of irinotecan, is approximately 20- to 136-fold more potent than its parent compound.⁹⁷ SG received FDA approval in 2020 for the treatment of previously treated, metastatic, triple-negative breast cancer, based on results from the phase 2/3 IMMU-132-01 basket trial (NCT01631552), making it the first-in-class anti-TROP2 ADC to gain approval.⁹³ In 2023, its indication was expanded to include hormone receptor–positive, HER2-negative, metastatic breast cancer.⁹⁴ However, in mNSCLC, the EVOKE-01 trial (NCT05089734) evaluating SG in the 2L setting after progression on ICI and PBC did not demonstrate a significant OS benefit over docetaxel.⁹⁸ Nevertheless, encouraging numerical trends in OS, especially in patients who did not initially respond to their last ICI-containing regimen, have prompted ongoing investigation into the potential role of SG in mNSCLC, including in the 1L setting.⁹⁸

EVOKE-01

The phase 3 EVOKE-01 trial compared the safety and efficacy of SG to docetaxel in patients with mNSCLC who experienced disease progression after PBC and ICI.^95,98 In the final analysis, the trial did not achieve significance for the primary end point of OS.⁹⁸ However, a numerical improvement in the OS favoring SG was observed with a 16% reduction in risk of death (HR, 0.84; 95% CI, 0.68-1.04), and this improvement was observed in both squamous and nonsquamous histology. Notably, a clinically meaningful difference in median OS of 3.5 months was seen with the use of SG in patients who were nonresponsive to prior ICI.⁹⁸ In the longer follow-up from EVOKE-01 (median, 23.5 months), SG maintained this numerical OS advantage over docetaxel (HR, 0.89; 95% CI, 0.74-1.07), including across key subgroups. SG also demonstrated a more favorable safety profile, including fewer TEAEs of grade 3 or more (68.6% vs 76.0%), lower rates of severe neutropenia (25.3% vs 36.8%), and fewer treatment-related discontinuations (7.4% vs 14.2%), indicating that it may be a more manageable long-term treatment option than docetaxel.⁹⁹

In NSCLC, circulating tumor DNA (ctDNA) analysis serves as a prognostic indicator that complements clinical efficacy assessment.¹⁰⁰ In the EVOKE-01 study, ctDNA was detected at baseline in over 90% of patients, with higher levels associated with worse OS. Patients with undetectable ctDNA had notably longer survival. Although not significant, median ctDNA reductions by cycle 2 were 59% with SG and 75% with docetaxel, with a reduction of at least 50% seen in 44% and 51% of patients, respectively. Early changes in ctDNA levels were prognostic, as patients with a reduction of at least 50% by cycle 2 had longer OS compared with those with less than 50% reduction.¹⁰⁰

In addition, in the post hoc analysis of the EVOKE-01 study, patients with BM had a median OS of 12.1 months with SG compared with 7.3 months with docetaxel (HR, 0.62; 95% CI, 0.34-1.13).¹⁰¹ Among patients with AGAs, median OS was not reached with SG, while it was 7 months with docetaxel (HR, 0.52; 95% CI, 0.22-1.23). These findings indicated a numerically longer OS with SG compared with docetaxel in both the BM and AGA subgroups.¹⁰¹ SG is currently under further investigation, including in the 1L setting in combination with ICI in the phase 2 EVOKE-02 trial (NCT05186974), with promising early results.⁹¹

Sacituzumab Tirumotecan

Sac-TMT is an investigational TROP2-targeting ADC featuring a novel linker conjugated to a belotecan-derived topoisomerase-I inhibitor, resulting in an average DAR of 7.4.¹⁰² The design leverages an irreversible but hydrolyzable sulfonylpyrimidine-CL2A-carbonate linker and aims to improve the balance between ADC stability in the bloodstream and efficient payload release within the target cells.^90,102

In the phase 2 expansion cohort of the phase 1/2 study (NCT04152499), sac-TMT given at 5 mg/kg every 2 weeks demonstrated positive activity with a manageable toxicity profile in patients with EGFR-mutated NSCLC compared with the EGFR–wild-type subgroup.¹⁰² In the overall population, ORR was 44% and median DOR was 9.3 months, with a 6-month DOR rate of 77%. In the EGFR–wild-type subgroup who had received a median of 2 prior lines of therapy, including ICI, ORR was 26%, median PFS was 5.3 months, and 9-month OS rate was 80.4%. For the subgroup of patients with TKI-resistant EGFR-mutated NSCLC, however, ORR was 60% and median PFS was 11.1 months with a 9-month PFS rate of 66.7%. TEAEs of at least grade 3 occurred in 67.4% of the patients, with neutropenia (32.6%) being the common event. Other AEs included stomatitis (9.3%), rash (7.0%), and decreased lymphocyte count (7.0%). There were no cases of neuropathy or ILD/pneumonitis attributed to sac-TMT.¹⁰² Encouraged by these results, the FDA granted breakthrough therapy designation to sac-TMT in December 2024 for the treatment of patients with advanced or metastatic, EGFR-mutated NSCLC after progression from TKI and PBC.⁹⁰

These early promising results led to further investigation of the role of sac-TMT with the latest data from the phase 2 OptiTROP-Lung03 trial (NCT05631262), where sac-TMT demonstrated significant clinical benefits compared with docetaxel in patients with previously treated EGFR-mutated NSCLC. ORR assessed by blinded independent central review (BICR) was 45.1% with sac-TMT compared with 15.6% with docetaxel.¹⁰³ PFS was also significantly improved, with a median of 6.9 months for sac-TMT versus 2.8 months for docetaxel (HR, 0.30; 95% CI, 0.20-0.46). Although the median OS was not reached in either group, sac-TMT showed a favorable trend with an HR of 0.49 (95% CI, 0.27-0.88). TEAEs of grade 3 or more were less common with sac-TMT than with docetaxel (56.0% vs 71.7%). Sac-TMT showed lower rates of neutropenia (42.9% vs 58.7%) and no cases of febrile neutropenia (0% vs 19.6% with docetaxel). While stomatitis and anemia were more frequent with sac-TMT than docetaxel, no cases of ILD were reported, supporting a favorable safety profile.¹⁰³

Advancements in Assessing TROP2 Expression

Identifying patients likely to benefit from TROP2–directed ADCs is essential, but traditional IHC methods for assessing TROP2 expression may not reliably predict treatment response. In analyses of archival tumor samples from patients treated with SG, although a high proportion (92%) showed moderate to strong TROP2 staining, a lack of correlation between IHC scores and best overall response, PFS, or OS suggests insufficient evidence for TROP2 expression as a reliable predictive biomarker.¹⁰⁴

Notably, emerging data from the OptiTROP-Lung03 study of sac-TMT suggest that higher TROP2 expression may be associated with numerically greater response rates.¹⁰³ In this study, TROP2 expression was retrospectively assessed by traditional IHC to categorize tumors as high versus low/medium. Nevertheless, clinical benefit was observed across all expression levels, highlighting that membrane-dominant TROP2 staining by IHC alone is insufficient as a predictive biomarker of sac-TMT response.^103,105

Emerging data highlight quantitative continuous scoring (QCS) for TROP2 and its potential role in predicting clinical response. QCS is a fully supervised computational pathology approach that precisely quantifies target expression (eg, TROP2) within tumor cells and across subcellular compartments.¹⁰⁶ For some ADCs that require receptor internalization for activation, expression alone may not be predictive of efficacy; rather, a marker of receptor trafficking would be expected to have greater predictive potential. Tissue samples from the biomarker-evaluable population in the TROPION-Lung01 study were assessed for TROP2 normalized membrane ratio (NMR) using QCS, which quantified membrane TROP2 relative to total TROP2 in both membrane and cytoplasm. In this exploratory analysis, TROP2 NMR positivity was more prevalent in patients with nonsquamous histology and was associated with higher objective ORR and longer PFS. Among patients treated with Dato-DXd, those who were TROP2 NMR–positive had an ORR of 32.7% versus 16.9% in NMR-negative patients, and PFS HRs were 0.57 versus 1.16, respectively.¹⁰⁶ These findings suggest that TROP2 NMR positivity may predict improved treatment outcomes, particularly in the non-AGA and nonsquamous advanced/mNSCLC population.

Additional ADC Targets in NSCLC and Current Clinical Data for ADCs in Development

The key findings and preliminary results from select clinical trials investigating ADCs in NSCLC discussed in this section are summarized in Table 2.

Review of Other HER2-Directed ADCs in Clinical Development

Beyond the approved T-DXd, several other HER2-directed ADCs are currently being evaluated in clinical trials for NSCLC. Trastuzumab rezetecan (SHR-A1811) is among the HER2-directed ADCs most advanced in their development, consisting of a humanized HER2-targeting mAb, a cleavable tetrapeptide linker, and a DNA topoisomerase I inhibitor.¹⁰⁷ In the multicenter, single-arm phase 2 HORIZON-Lung trial (NCT04818333), it demonstrated clinically meaningful efficacy and a manageable safety profile in patients with previously treated HER2-mutated NSCLC. Among 94 patients treated with trastuzumab rezetecan at a dose of 4.8 mg/kg every 3 weeks, the ORR was 74.5% (95% CI, 64.4%-82.9%). The median PFS was 11.5 months (95% CI, 9.7-15.2 months), with consistent benefit observed across baseline subgroups, including those with and without BM (median PFS, 11.3 vs 11.5 months, respectively). Median OS was not reached, although the 12-month OS rate was 88.2% (95% CI, 79.8%-93.3%). TEAEs of at least grade 3 were reported in 67% of patients, with hematologic toxicities being the most frequent. ILD occurred in 8.5% of patients, the majority of which were low-grade (grade ≤ 2).¹⁰⁷ Other HER2-directed ADCs in development for advanced HER2-positive mNSCLC include MRG002 (NCT05141786) and GQ1001 (NCT04450732).^108,109

HER3-Directed ADCs

HER3 (ERBB3) belongs to the ERBB/HER protein kinase family and is unique in that it lacks intrinsic tyrosine kinase activity.¹¹⁰ While not an oncoprotein itself, HER3 co-expresses and forms heterodimers with other receptor tyrosine kinases (eg, EGFR, HER2, and MET) to activate a downstream oncogenic signaling cascade via the PI3K/AKT/mTOR and Src kinase pathways. This activation of HER3 signaling leads to cell proliferation and blocks apoptosis, resulting in the promotion of cancer cell survival, proliferation, and progression.¹¹⁰

Elevated HER3 expression has been associated with poor survival in patients with solid tumors.¹¹⁰ In NSCLC, HER3 expression by IHC has been observed in 83% of the primary tumors.¹¹¹ HER3 expression can also drive resistance to targeted therapies in lung cancer by sustaining PI3K/AKT pathway activation, even in the presence of EGFR-targeted TKIs.^110-112 Thus, therapeutic inactivation of HER3 and its downstream signaling is an attractive target to overcome therapy resistance and improve clinical outcomes.¹¹⁰

Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is a novel, investigational ADC targeting HER3. It consists of a humanized mAb against HER3 (patritumab) linked covalently to a topoisomerase I inhibitor payload (MAAA-1181a, an exatecan derivative) through a tetrapeptide-based cleavable linker, with a DAR of 8.¹¹³ Following internalization, the ADC traffics to the lysosome, where upregulated lysosomal enzymes cleave the linker to liberate the cytotoxic payload. This payload then penetrates the nucleus, inducing cell death. Its ability to cross cell membranes also facilitates a bystander effect, allowing it to kill not only target cells but also neighboring tumor cells.¹¹³

HER3-DXd showed antitumor activity in EGFR-mutated NSCLC in the phase 2 HERTHENA-Lung01 trial (NCT04619004) that involved patients who were previously treated with an EGFR-targeted TKI and PBC.¹¹⁴ HER3-DXd was active both across diverse mechanisms of resistance to EGFR TKIs and a broad range of HER3 expression levels; the observed ORR was 29.8% (95% CI, 23.9%-36.2%), and the median DOR, PFS, and OS were 6.4, 5.5, and 11.9 months, respectively. Of note, efficacy was similar in the subgroup of patients with advanced EGFR-mutated NSCLC who experienced progression after at least 1 line of PBC and use of the third-generation EGFR TKI osimertinib.¹¹⁴

Based on the promising results of HERTHENA-Lung01 that demonstrated clinically meaningful efficacy and durable responses with HER3-DXd, the phase 3 HERTHENA-Lung02 trial (NCT05338970) was conducted. Eligible patients were those with advanced EGFR-mutated NSCLC who had received at least 1 line of an EGFR TKI, including a prior third-generation agent, and were randomly assigned to receive either HER3-DXd or PBC.¹¹⁵ The interim results of the HERTHENA-Lung02 trial demonstrated that HER3-DXd provided a significant improvement in PFS compared with PBC. HER3-DXd showed an HR of 0.77 (95% CI, 0.63-0.94) for PFS, with a median PFS of 5.8 months (95% CI, 5.5-6.8 months) versus 5.4 months (95% CI, 5.0-5.6 months) with PBC. Although the absolute difference in median PFS was modest, the HR indicates a clinically meaningful reduction in the risk of disease progression.¹¹⁶ HER3-DXd also resulted in a higher ORR of 35.2% (95% CI, 29.7%-40.9%) compared with 25.3% (95% CI, 20.4%-30.6%) with PBC, and a slightly longer median DOR (5.7 vs 5.4 months). In patients with baseline BM, IC PFS was 5.4 months with HER3-DXd compared with 4.2 months with PBC (HR, 0.75; 95% CI, 0.53-1.06), suggesting potential benefit in CNS disease, although this result was not statistically definitive.

TEAEs of at least grade 3 were more frequent in the HER3-DXd arm (73%) than in the PBC arm (57%), primarily due to a higher rate of severe thrombocytopenia (30% vs 7.9%). Additionally, ILD occurred in 5% of patients receiving HER3-DXd, including 2 fatal cases.¹¹⁶ Despite early indications of a potential benefit over chemotherapy in this treatment-resistant population, the Biologics License Application for accelerated approval in mNSCLC was voluntarily withdrawn on May 29, 2025, after the confirmatory trial failed to demonstrate a significant OS benefit.¹¹⁷

Additionally, in the all-comers NSCLC population that did not include EGFR alterations and who had progressed after PBC with or without ICI, HER3-DXd showed promising clinical activity. In the phase 1 trial (NCT03260491), the ORR was 28%, with a median DOR of 5.7 months and a median PFS of 5.4 months. Among patients with non-EGFR oncogenic alterations, ORR was 35% compared to 23% for those with non-AGA mNSCLC.¹¹⁸ The clinical response to HER3-DXd, however, was not associated with HER3 expression level.

MET-Directed ADCs in NSCLC

Because MET is highly expressed in NSCLC tumors and cell lines and functions as a biologically relevant oncogenic driver, it has emerged as a key target for novel therapeutic strategies. Studies using small interfering RNA–mediated MET downregulation have demonstrated significant reductions in NSCLC cell viability, further supporting its role as a potential therapeutic target.¹¹⁹ Collectively, these findings underscore the promise of MET inhibition and provide a strong rationale for continued development of MET-targeted therapies in NSCLC. In addition to the current approval of Teliso-V for MET-overexpressing NSCLC, multiple additional MET-directed agents are in clinical development. Those in early-stage investigation include MYTX-011, REGN5093-M114, and telisotuzumab adizutecan (Temab-A).

MYTX-011

Incorporating novel technology in the ADC design may increase drug delivery and exposure to target tumors and overcome the challenges arising from tumors with low levels of expression.¹²⁰ MYTX-01, a pH-dependent anti-MET ADC, has previously demonstrated higher tumor cell internalization and increased cytotoxicity in preclinical studies.¹²¹ Due to its pH-dependent binding and the resulting enhanced net internalization, MYTX-011 exhibited broad activity in vitro.¹²⁰ Following these findings, a first-in-human phase 1 study (NCT05652868) assessing the safety and efficacy of MYTX-011 in advanced NSCLC was undertaken. However, the study was terminated in December 2025 for business reasons.¹²²

REGN5093-M114

REGN5093-M114 is a novel biparatopic ADC that targets MET by binding 2 distinct epitopes on the receptor, and it is conjugated to a cytotoxic maytansine-derived payload (M114) via a protease-cleavable linker. In preclinical studies, REGN5093-M114 was evaluated for its ability to overcome MET-driven resistance to EGFR TKIs in EGFR-mutated NSCLC.¹²³ The ADC demonstrated significantly greater antitumor efficacy compared with both MET TKIs and the unconjugated antibody (REGN5093). Its activity was observed in MET-overexpressing, TKI-naive, EGFR-mutated NSCLC cells regardless of MET gene copy number, with cell-surface MET expression emerging as the strongest predictor of response.Additionally, REGN5093-M114 potentially reduced tumor growth in models of EGFR-mutated NSCLC that progressed following treatment with the combination of the third-generation EGFR TKI osimertinib and MET TKI savolitinib.¹²³

These findings suggest that REGN5093-M114 may offer a promising therapeutic strategy to overcome acquired resistance in MET-driven EGFR-mutated NSCLC. A study assessing the role of REGN5093-M114 as a monotherapy or in combination with cemiplimab in MET-overexpressing advanced NSCLC (NCT04982224) was launched. However, the sponsor terminated the study in November 2025.¹²⁴

Temab-A

Temab-A is an ADC composed of the MET-targeting mAb telisotuzumab linked to a novel topoisomerase I inhibitor payload.¹²⁵ In a phase 1 study of patients with advanced EGFR-mutated nonsquamous NSCLC, Temab-A demonstrated notable efficacy, with an ORR of 65% across all EGFR mutation subtypes and MET expression levels. Responses were observed regardless of TKI resistance mutations, and 54% of responders had a DOR of at least 6 months. Treatment was generally tolerable, with TEAEs of grade 3 or more occurring in 73% of patients, primarily hematologic (anemia 27%, neutropenia 22%).¹²⁵ Overall, Temab-A exhibits a manageable safety profile and promising clinical activity, supporting further investigation.

Bispecific ADCs

Bispecific ADCs demonstrate promising clinical activity in treating solid tumors. The most advanced bispecific ADC is izalontamab brengitecan (iza-bren; BL-B01D1), a first-in-class EGFR–HER3 bispecific ADC. Its safety and preliminary efficacy were evaluated in a phase 1a/b first-in-human trial in patients with locally advanced or metastatic solid cancers (NCT05194982). A total of 195 patients were enrolled, including 113 with NSCLC.¹²⁶ TEAEs of at least grade 3 were reported in 71% of patients, with neutropenia (47%) and anemia (39%) being the most common. Among 174 patients assessed for activity, with a median follow-up of 6.9 months, 34% (95% CI, 27%-42%) achieved an objective response. These findings indicate that iza-bren demonstrates preliminary activity in heavily pretreated advanced solid tumors with an acceptable safety profile. Based on safety and efficacy data from both phase 1a and 1b trials, a dose of 2.5 mg/kg administered on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose.¹²⁶ Other bispecific ADCs under development include AZD9592, targeting EGFR-MET (NCT05647122), and M1231, targeting EGFR-MUC1 (NCT04695847).^127,128

Other Emerging ADC Targets

There are other emerging targets in NSCLC and novel ADCs that are under investigation in early phases of clinical trials. Sigvotatug vedotin is an integrin-β⁶-directed ADC with encouraging antitumor activity in patients with previously treated NSCLC; the overall ORRs in a study of patients with NSCLC were 19.5% in all patients and 32.5% in patients with nonsquamous/taxane-naive disease, respectively.¹²⁹ Another target of interest includes AXL, a tyrosine kinase receptor that is frequently overexpressed in various solid and hematologic cancers and is associated with tumor progression and poor clinical outcomes. Additionally, AXL contributes to resistance against TKIs by enhancing its own signaling or by enabling cancer cells to switch oncogenic pathways. These characteristics position AXL as a compelling therapeutic target.

Mecbotamab vedotin (BA3011), a novel, conditionally active ADC, is currently in clinical development (NCT03425279). BA3011 selectively binds to AXL within the acidic tumor microenvironment, while its binding in healthy tissues is significantly reduced. In preclinical studies, BA3011 exhibited potent and durable antitumor activity against AXL-expressing cancer cells in human xenograft mouse models, highlighting its potential as a promising new treatment option targeting AXL.¹³⁰ Similarly, YL201 is a novel ADC targeting B7-H3, which also uses a tumor microenvironment-activated linker-payload system combined with a new topoisomerase 1 inhibitor connected through a protease-cleavable linker.¹²⁶ There are also multiple EGFR-targeting ADCs in development, including MRG003 and the dual-targeting EGFR-MUC1 ADC M1231, as mentioned earlier.¹³¹

ADC-Based Combination Strategies in Advanced NSCLC

ADC therapy in the 1L setting may offer an opportunity to assess its potential synergy with ICIs. See Table 3 for a summary of key findings and preliminary results from clinical trials investigating ADC-based combination strategies in NSCLC.^{91,92,132-144}

ADCs in Combination With ICIs

EVOKE-02

EVOKE-02 is an ongoing multicohort phase 2 trial evaluating SG combined with pembrolizumab either as a doublet or as a triplet with pembrolizumab and platinum in previously untreated patients with advanced/mNSCLC without AGAs. Initial results from 2 of the cohorts indicated the efficacy of SG/pembrolizumab/carboplatin triplet therapy in both the nonsquamous and squamous cohorts.⁹¹ Use of the triplet was associated with positive antitumor activity with an ORR of 45.1% (95% CI, 31.1%-59.7%) and 39% (95% CI, 24.2%-55.5%) in the nonsquamous and squamous cohorts, respectively. For patients with tumors that had a PD-L1 tumor proportion score (TPS) of at least 1%, the ORR was 41.7% (95% CI, 27.6%-56.8%), and the median PFS was 8.4 months (95% CI, 5.3-11.2 months).

These results demonstrated encouraging activity of SG in the 1L in combination with pembrolizumab/carboplatin in patients with mNSCLC without AGAs, and efficacy was seen across nonsquamous and squamous histologies and PD-L1 status. As expected from the SN-38 chemical moiety, the most common TEAEs of any grade were anemia, neutropenia, and diarrhea.⁹¹ These initial encouraging results and future investigation into the effect of SG combinations in NSCLC will further guide therapy in patients with advanced/mNSCLC without AGAs.

OptiTROP-Lung01

The recently updated results from the nonsquamous cohort of the phase 2 OptiTROP-Lung01 trial (NCT05351788) were presented, demonstrating promising activity of sac-TMT combined with the ICI tagitanlimab (anti–PD-L1, KL-A167) in the 1L treatment of non-AGA mNSCLC. After a median follow-up of 17.1 months, the ORR was 59.3%, with a median DOR of 16.5 months (95% CI, 11.7-22.1 months).⁹² Median PFS was 15.0 months (95% CI, 10.8-24.8 months), demonstrating durable benefit. Patients with PD-L1 TPS below 1% showed a confirmed ORR of 47.1% and mPFS of 12.4 months (95% CI, 7.6-15.4 months), indicating activity in this less responsive group. Those with PD-L1 TPS of at least 1% had improved outcomes, with ORR of 68.1% and mPFS of 17.8 months (95% CI, 14.5 months to NE), while patients with a TPS of at least 50% achieved the highest ORR of 77.8% and mPFS of 17.8 months (95% CI, 10.8 months to NE). These results highlight the consistent efficacy of sac-TMT plus tagitanlimab across PD-L1 levels, with greater benefit seen at higher expression. The most common TRAEs of at least grade 3 were neutropenia (45.7%), anemia (16.0%), and stomatitis (11.1%).⁹²

Other Trials

The phase 3 AVANZAR trial (NCT05687266) will compare Dato-DXd/durvalumab/carboplatin with pembrolizumab combined with histology-specific PBC in PD-L1–all-comer patients with advanced/mNSCLC.¹⁴⁰

Other early-stage trials evaluating ADCs in the frontline setting for patients without AGAs include the phase 3 TROPION-Lung07 trial (NCT05555732), which is limited to patients with PD-L1 TPS less than 50% and compares 3 arms: Dato-DXd/pembrolizumab/PBC triplet, Dato-DXd/pembrolizumab doublet, and pembrolizumab/chemotherapy (platinum or pemetrexed).¹³⁸ TROPION-Lung08 (NCT05215340) is currently recruiting patients for the comparison of Dato-DXd/pembrolizumab doublet versus pembrolizumab alone in patients with NSCLC having high PD-L1 expression.¹³⁹

The phase 2 NeoCOAST-2 platform trial (NCT05061550) is evaluating the efficacy and safety of the Dato-DXd/durvalumab/PBC combination in the neoadjuvant setting for patients with resectable NSCLC. Early results showed a pathological complete response (pCR) and a major pathological response of 34.1% and 65.9%, respectively.¹³² Overall pCR rates demonstrated positive activity across PD-L1 expression levels, with pCRs of 25%, 33%, and 41% in patients with PD-L1 TPS less than 1%, 1% to 49%, and at least 50%, respectively. TEAEs of at least grade 3 occurred in 24.1% of patients treated in the neoadjuvant setting and 4% of those treated in the adjuvant setting.¹³²

Additionally, TROPION-Lung10 (NCT06357533) is evaluating Dato-DXd given in the 1L in combination with rilvegostomig (an anti–PD-1/TIGIT bispecific antibody) in patients with advanced nonsquamous NSCLC with high PD-L1 expression and without AGAs.¹⁴¹ Of note, AVANZAR includes retrospective analyses of prospectively collected TROP2 NMR status as a biomarker end point, while TROPION-Lung10 will prospectively assess TROP2 NMR in its primary and key secondary analyses.^140,141 TROPION-Lung07 (NCT05555732) incorporates TROP2 NMR for PFS and OS subgroup analyses in the TROP2 NMR–positive populations as part of its efficacy end points.¹³⁸ Additionally, TROPION-Lung17 (NCT07291037) will be the first phase 3 trial to prospectively enroll only patients with TROP2 NMR–positive tumors, evaluating Dato-DXd versus docetaxel in previously treated advanced or metastatic nonsquamous NSCLC without AGAs.^136,137

ADCs in Combination With TKIs

The ORCHARD trial (NCT03944772) is a phase 2, biomarker-driven study in patients with advanced EGFR-mutated NSCLC who have progressed on 1L osimertinib.¹⁴⁴ It evaluates resistance-matched combination therapies, including targeted TKIs based on the mechanism of resistance and all-comer combinations such as Dato-DXd plus osimertinib, to explore strategies to overcome acquired resistance. Findings from ORCHARD suggest improved PFS with the combination compared with historical monotherapy, although higher rates of ILD are observed in the combination.¹⁴⁴

The phase 3 TROPION-Lung15 trial (NCT06417814) is evaluating the efficacy and safety of the Dato-DXd/osimertinib combination in the 2L setting after progression on frontline osimertinib,¹⁴³ and, similarly, the TROPION-Lung14 trial (NCT06350097) is evaluating this combination in the 1L setting for EGFR-mutated NSCLC.¹⁴² In addition, a phase 1 study (NCT04676477) is currently underway to assess the activity of HER3-DXd given in combination with osimertinib in patients with advanced EGFR-mutated NSCLC whose disease progressed on prior osimertinib.¹³³

Conclusions

There remains a significant unmet need for patients with advanced/mNSCLC, particularly those without actionable genomic alterations or whose disease progresses despite frontline therapies. ADCs have emerged as a groundbreaking therapeutic class, leveraging targeted delivery of cytotoxic agents to improve efficacy while minimizing off-target effects. ADCs directed at biomarkers such as TROP2, HER2, HER3, and MET have the potential to reshape the mNSCLC treatment landscape. TROP2-directed ADCs have demonstrated encouraging and increasingly broad activity in advanced/mNSCLC across molecular subgroups, including heavily pretreated patients and those with BM, with emerging evidence of benefit in both tumors without AGAs and selected AGA-driven populations, such as patients with EGFR-mutated disease. Concurrently, HER2-directed and HER3-directed ADCs continue to show particular promise in biomarker-defined subtypes, including HER2-mutated and EGFR-mutated NSCLC. These advancements underscore the expanding utility of ADCs across diverse molecular profiles and further support the evolution toward a more personalized, biomarker-informed ADC-based treatment paradigm.

Despite ongoing challenges, including limited therapeutic options in the 2L and later settings and recent setbacks in clinical trials for this patient population, the investigation of ADCs in earlier lines of therapy and in combination with IO represents a potential area of interest for future development. By targeting a broad spectrum of biomarkers and employing cutting-edge technologies, ADCs hold the potential to provide more effective, better-tolerated treatment options, addressing the significant unmet needs for patients with either AGA or non-AGA mNSCLC.

Authorship Affiliation

Department of Oncology, Stanford University (MD), Stanford, CA; Department of Medical Oncology, Yale School of Medicine (RSH), New Haven, CT; Department of Hematology Oncology, Georgetown University (SL), Washington, DC; Department of Oncology, University Hospital of Lausanne (SP), Lausanne, Switzerland; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute (JR), Boston, MA.

Source of Funding

This supplement was supported by AstraZeneca.

Author Disclosures

Dr Das reports participating in consultancies or paid advisory boards with AstraZeneca; Boehringer Ingelheim; Cellsight Technologies, Inc; EMD Serono; Genentech, Inc; Gilead Sciences, Inc; Jazz Pharmaceuticals, Inc; Johnson & Johnson; Lilly USA; Merck & Co, Inc; Merus; Natera, Inc; Novartis; Nuvation Bio Inc; OncoHost; RayzeBio, Inc; Regeneron Pharmaceuticals Inc; and Summit Therapeutics Inc.

Dr Herbst reports participating in consultancies or paid advisory boards with AstraZeneca; Amgen Inc; ArriVent BioPharma; Bristol Myers Squibb; Candel Therapeutics; Catalym; Checkpoint Therapeutics, Inc; Cybrexa Therapeutics; Genentech, Inc; Gilead Sciences, Inc; Johnson & Johnson; Lilly USA; Mediflix; Merck & Co, Inc; Neuvogen, Inc; NextCure, Inc; Normunity Inc; NovaBridge Biosciences; Novartis; Pfizer Inc; Regeneron Pharmaceuticals Inc; Roche; and Sanofi. He also holds stock ownership with Checkpoint Therapeutics, Inc; and Immunocore Holdings plc.

Dr Liu has participated in consultancies or paid advisory boards with AbbVie Inc; Amgen Inc; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Daiichi Sankyo, Inc; Genentech, Inc; Gilead Sciences, Inc; GSK plc; Guardant Health, Inc; Jazz Pharmaceuticals, Inc; Johnson & Johnson; Merck & Co, Inc; Merus; Natera, Inc; Novartis; Nuvalent; OSE Immunotherapeutics; Pfizer Inc; PharmaMar; Regeneron Pharmaceuticals Inc; Revolution Medicines, Inc; SystImmune, Inc; and Takeda Pharmaceutical Company Limited. He has also received grants from AbbVie Inc; Alkermes, AstraZeneca; Avenzo Therapeutics; BioNTech; Bristol Myers Squibb; Cogent Biosciences, Inc; Duality Biologics; Ellipses Pharma; Genentech, Inc; Gilead Sciences, Inc; MediLink Therapeutics; Merck & Co, Inc; Merus; Nuvalent; Nuvation Bio Inc; OSE Immunotherapeutics; Puma Biotechnology, Inc; Synthekine; and SystImmune, Inc.

Dr Peters reports consultancies or paid advisory boards with AbbVie Inc; Amgen Inc; Arcus Biosciences, Inc; AstraZeneca; Bayer; BeOne Medicines; BioNTech; Bicycle Therapeutics; Biocartis; BioInvent; Blueprint Medicines Corporation; Boehringer Ingelheim; Bristol Myers Squibb; Clovis Oncology; Daiichi Sankyo, Inc; Debiopharm; F-Star Therapeutics; Foundation Medicine, Inc; Genentech, Inc; Genmab; Genzyme; Gilead Sciences, Inc; GSK plc; HUTCHMED; Illumina, Inc; Incyte; Ipsen Pharma; iTeos Therapeutics Inc; Johnson & Johnson; Lilly USA; Merck Sharp & Dohme Federal Credit Union; Merck Serono; Novartis; Novocure; Nuvalent; Nuvation Bio Inc; Nykode Therapeutics; Oncoinvent; Pfizer Inc; PharmaMar; Promontory Therapeutics; Qlucore; Regeneron Pharmaceuticals Inc; Sanofi; Takeda Pharmaceutical Company Limited; and Zymeworks Inc. She has also received lecture fees for speaking at the invitation of a commercial sponsor from AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Foundation Medicine, Inc; Genentech, Inc; GSK plc; Illumina, Inc; Ipsen Pharma; Lilly USA; Merck Sharp & Dohme Federal Credit Union; Novartis; Pfizer Inc; Sanofi; and Takeda Pharmaceutical Company Limited. Dr Peters has received grants from Amgen Inc; Arcus Biosciences, Inc; AstraZeneca; BeOne Medicines; Boehringer Ingelheim; Bristol Myers Squibb; Genentech, Inc; GSK plc; iTeos Therapeutics Inc; Lilly USA; Merck Sharp & Dohme Federal Credit Union; Mirati Therapeutics, Inc; Pfizer Inc; PharmaMar; and Promontory Therapeutics.

Dr Rotow has participated in consultancies or paid advisory boards with Amgen Inc; AstraZeneca; BioAtla Inc; BlossomHill Therapeutics, Inc; Boehringer Ingelheim; Bristol Myers Squibb; Catalyst Pharmaceuticals, Inc; Daiichi Sankyo, Inc; G1 Therapeutics, Inc; Genentech, Inc; Guardant Health, Inc; Jazz Pharmaceuticals, Inc; Johnson & Johnson; Merus; Novocure; Nuvalent; Nuvation Bio Inc; Pfizer Inc; Regeneron Pharmaceuticals Inc; Sanofi; Summit Therapeutics Inc; and Takeda Pharmaceutical Company Limited. She has also received lecture fees for speaking at the invitation of a commercial sponsor for AstraZeneca; Daiichi Sankyo, Inc; and Pfizer Inc, as well as had contracts for institutional research for AbbVie Inc; Altor BioSciences Corp; AstraZeneca; Bicycle Therapeutics; BioAtla Inc; Black Diamond Therapeutics; BlossomHill Therapeutics, Inc; Blueprint Medicines Corporation; Bristol Myers Squibb; Duality Biologics; Enliven Therapeutics; EpimAb Biotherapeutics; ImmunityBio, Inc; Loxo Oncology, Inc; ORIC Pharmaceuticals, Inc; RedCloudBio Co, Ltd; Regeneron Pharmaceuticals Inc; Summit Therapeutics Inc; and Synthekine.

Authorship Information

Concept and design (RSH, SP, JR); analysis and interpretation of data (MD, RSH, SL, SP); drafting of the manuscript (RSH, SL, SP); critical revision of the manuscript for important intellectual content (MD, RSH, SL, SP, JR); supervision (MD, RSH, JR).

Acknowledgments

AstraZeneca was given the opportunity to review the content for medical accuracy. Under the direction of the authors, medical writing support and editorial assistance were provided by MJH Life Sciences^®. The authors thank Nikunj Patel, PharmD, RAC, for scientific, logistical, and editorial support.

Address Correspondence To

Stephen V. Liu, MD.

3800 Reservoir Rd NW, LCCC Pod A

Washington, DC, 20007

Stephen.v.liu@gunet.georgetown.edu

REFERENCES

1. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10-45. doi:10.3322/caac.21871

2. All cancer sites combined recent trends in SEER age-adjusted incidence rates, 2000-2022. National Cancer Institute Surveillance, Epidemiology, and End Results Program. April 16, 2025. Accessed June 27, 2025. https://seer.cancer.gov/statistics-network/explorer/

3. Simeone JC, Nordstrom BL, Patel K, Klein AB. Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting. Future Oncol. 2019;15(30):3491-3502. doi:10.2217/fon-2019-0348

4. Hardtstock F, Myers D, Li T, et al. Real-world treatment and survival of patients with advanced non-small cell lung cancer: a German retrospective data analysis. BMC Cancer. 2020;20(1):260. doi:10.1186/s12885-020-06738-z

5. Liu L, Bai H, Wang C, et al. Efficacy and safety of first-line immunotherapy combinations for advanced NSCLC: a systematic review and network meta-analysis. J Thorac Oncol. 2021;16(7):1099-1117. doi:10.1016/j.jtho.2021.03.016

6. Leighl NB. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, second-, and third-line. Curr Oncol. 2012;19(suppl 1):S52-S58. doi:10.3747/co.19.1114

7. Auclin E, Benitez-Montanez J, Tagliamento M, et al. Second-line treatment outcomes after progression from first-line chemotherapy plus immunotherapy in patients with advanced non-small cell lung cancer. Lung Cancer. 2023;178:116-122. doi:10.1016/j.lungcan.2023.02.002

8. Marschner N, Zacharias S, Lordick F, et al. Association of disease progression with health-related quality of life among adults with breast, lung, pancreatic, and colorectal cancer. JAMA Netw Open. 2020;3(3):e200643. doi:10.1001/jamanetworkopen.2020.0643

9. Lee ATM, Nagasaka M. CheckMate-722: the rise and fall of nivolumab with chemotherapy in TKI-refractory EGFR-mutant NSCLC. Lung Cancer (Auckl). 2023;14:41-46. doi:10.2147/LCTT.S408886

10. Thomas A, Teicher BA, Hassan R. Antibody-drug conjugates for cancer therapy. Lancet Oncol. 2016;17(6):e254-e262. doi:10.1016/S1470-2045(16)30030-4

11. Peters S, Paz-Ares L, Herbst RS, Reck M. Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects. J Immunother Cancer. 2022;10(7):e004863. doi:10.1136/jitc-2022-004863

12. Dragnev KH, Redman MW, Reckamp KL, et al. PRAGMATICA-LUNG (SWOG S2302): a prospective, randomized study of ramucirumab plus pembrolizumab versus standard of care for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer. J Clin Oncol. 2025;43(suppl 17):LBA8671. doi:10.1200/JCO.2025.43.17_suppl.LBA8671

13. Attili I, Corvaja C, Spitaleri G, et al. Post-progression analysis of EGFR-mutant NSCLC following osimertinib therapy in real-world settings. Cancers (Basel). 2024;16(14):2589. doi:10.3390/ cancers16142589

14. Wang K, Leyba A, Hsu R. Addressing the unmet need in NSCLC progression with advances in second-line therapeutics. Explor Target Antitumor Ther. 2024;5(6):1297-1320. doi:10.37349/ etat.2024.00277

15. Okuno T, Isobe T, Tsubata Y. Current pharmacologic treatment of brain metastasis in non-small cell lung cancer. Clin Exp Metastasis. 2024;41(5):549-565. doi:10.1007/ s10585-024-10276-4

16. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511-1521. doi:10.1093/neuonc/nox077

17. Waqar SN, Samson PP, Robinson CG, et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. 2018;19(4):e373-e379. doi:10.1016/j.cllc.2018.01.007

18. Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698-2705. doi:10.1002/cncr.10541

19. Rangachari D, Yamaguchi N, VanderLaan PA, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108-111. doi:10.1016/j.lungcan.2015.01.020

20. Zhao W, Zhou W, Rong L, et al. Epidermal growth factor receptor mutations and brain metastases in non-small cell lung cancer. Front Oncol. 2022;12:912505. doi:10.3389/ fonc.2022.912505

21. Kahraman S, Karakaya S, Kaplan MA, et al. Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases. Sci Rep. 2024;14(1):5820. doi:10.1038/s41598-024-56046-w

22. Weiss JM, Stinchcombe TE. Second-line therapy for advanced NSCLC. Oncologist. 2013;18(8):947-953. doi:10.1634/theoncologist.2013-0096

23. Non-Small Cell Lung Cancer Treatment (PDQ)–Health Professional Version. National Cancer Institute. Accessed May 12, 2024. https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq

24. Tabchi S, Kassouf E, Florescu M, Tehfe M, Blais N. Factors influencing treatment selection and survival in advanced lung cancer. Curr Oncol. 2017;24(2):e115-e122. doi:10.3747/co.24.3355

25. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 5.2024. Accessed April 23, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

26. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742. doi:10.1056/NEJMoa1000678

27. Garon EB, Visseren-Grul C, Rizzo MT, Puri T, Chenji S, Reck M. Clinical outcomes of ramucirumab plus docetaxel in the treatment of patients with non-small cell lung cancer after immunotherapy: a systematic literature review. Front Oncol. 2023;13:1247879. doi:10.3389/ fonc.2023.1247879

28. Goldschmidt JH, Tseng WY, Wang Y, et al. Treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum-based chemotherapy and immunotherapy. Drugs Real World Outcomes. 2024;11(3):425-439. doi:10.1007/s40801-024-00440-3

29. Divan HA, Bittoni MA, Krishna A, Carbone DP. Real-world treatment patterns and outcomes of patients with metastatic nonsquamous non-small cell lung cancer after progression on standard-of-care therapy in the United States. Lung Cancer. 2023;179:107177. doi:10.1016/j. lungcan.2023.107177

30. Leal TA, Dasgupta A, Latremouille-Viau D, et al. Real-world treatment patterns and clinical outcomes after platinum-doublet chemotherapy and immunotherapy in metastatic non-small cell lung cancer: a multiregional chart review in the United States, Europe, and Japan. JCO Glob Oncol. 2024;10:e2300483. doi:10.1200/go.23.00483

31. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi:10.1016/S0140- 6736(14)60845-X

32. Matsuzawa R, Morise M, Ito K, et al. Efficacy and safety of second-line therapy of docetaxel plus ramucirumab after first-line platinum-based chemotherapy plus immune checkpoint inhibitors in non-small cell lung cancer (SCORPION): a multicenter, open-label, single-arm, phase 2 trial. EClinicalMedicine. 2023;66:102303. doi:10.1016/j. eclinm.2023.102303

33. Nakamura A, Yamaguchi O, Mori K, et al. Multicentre real-world data of ramucirumab plus docetaxel after combined platinum-based chemotherapy with programmed death-1 blockade in advanced non-small cell lung cancer: NEJ051 (REACTIVE study). Eur J Cancer. 2023;184:62-72. doi:10.1016/j.ejca.2023.01.025

34. Neal J, Pavlakis N, Kim SW, et al. CONTACT-01: a randomized phase III trial of atezolizumab + cabozantinib versus docetaxel for metastatic non-small cell lung cancer after a checkpoint inhibitor and chemotherapy. J Clin Oncol. 2024;42(20):2393-2403. doi:10.1200/jco.23.02166

35. Leighl NB, Paz-Ares L, Rodriguez- Abreu D, et al. 65O Phase III LEAP-008 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic non-small cell lung cancer (NSCLC) that progressed on a PD-(L)1 inhibitor and platinum-containing chemotherapy. Immunooncol Technol. 2023;20(suppl):100537. doi:10.1016/j.iotech.2023.100537

36. Borghaei H, de Marinis F, Dumoulin D, et al; SAPPHIRE Investigators. SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2024;35(1):66-76. doi:10.1016/j.annonc.2023.10.004

37. Decary S, Berne PF, Nicolazzi C, et al. Preclinical activity of SAR408701: a novel anti-CEACAM5- maytansinoid antibody-drug conjugate for the treatment of CEACAM5-positive epithelial tumors. Clin Cancer Res. 2020;26(24):6589-6599. doi:10.1158/1078-0432.CCR-19-4051

38. Sanofi announces end of program evaluating tusamitamab ravtansine after a 2L NSCLC phase 3 trial did not meet a primary end point. Press release. Sanofi. December 21, 2023. Accessed April 18, 2024. https://www.sanofi.com/en/media-room/press-releas es/2023/2023-12-21-06-30-00-2799759

39. Johnson ML, Chadjaa M, Yoruk S, Besse B. Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy. J Clin Oncol. 2020;38(suppl 15):TPS9625. doi:10.1200/JCO.2020.38.15_suppl.TPS9625

40. Yu X, Ji X, Su C. HER2-altered non-small cell lung cancer: biology, clinicopathologic features, and emerging therapies. Front Oncol. 2022;12:860313. doi:10.3389/fonc.2022.860313

41. Uzunparmak B, Haymaker C, Raso G, et al. HER2-low expression in patients with advanced or metastatic solid tumors. Ann Oncol. 2023;34(11):1035-1046. doi:10.1016/j. annonc.2023.08.005

42. Takenaka M, Hanagiri T, Shinohara S, et al. The prognostic significance of HER2 overexpression in non-small cell lung cancer. Anticancer Res. 2011;31(12):4631-4636.

43. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/ NEJMoa2112431

44. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. 2023;41(31):4852-4863. doi:10.1200/jco.23.01361

45. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 16, 2022. Accessed June 28, 2025. https://www. fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung

46. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed October 11, 2024. https:// www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

47. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024;25(4):439-454. doi:10.1016/S1470- 2045(24)00064-0

48. Lazaratos AM, Petrecca K, Guiot MC, Jerzak KJ, Dankner M. CNS activity of trastuzumab deruxtecan in HER2-expressing non-small-cell lung cancer. Lancet Oncol. 2024;25(7):e282. doi:10.1016/S1470-2045(24)00261-4

49. A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for unresectable, locally advanced/ metastatic non-small cell lung cancer with HER2 mutations. ClinicalTrials.gov. Updated April 3, 2026. Accessed June 16, 2026. https:// clinicaltrials.gov/study/NCT05048797?term=NCT05048797&viewType=Card&rank=1

50. Liang H, Wang M. MET oncogene in non-small cell lung cancer: mechanism of MET dysregulation and agents targeting the HGF/c-Met axis. Onco Targets Ther. 2020;13:2491- 2510. doi:10.2147/OTT.S231257

51. Noriega-Guerra H, Freitas VM. Extracellular matrix influencing HGF/c-MET signaling pathway: impact on cancer progression. Int J Mol Sci. 2018;19(11):3300. doi:10.3390/ijms19113300

52. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109(7):863-867. doi:10.1172/JCI15418

53. Araghi M, Mannani R, Heidarnejad Maleki A, et al. Recent advances in non-small cell lung cancer targeted therapy; an update review. Cancer Cell Int. 2023;23(1):162. doi:10.1186/ s12935-023-02990-y

54. Sakamoto M, Patil T. MET alterations in advanced non-small cell lung cancer. Lung Cancer. 2023;178:254-268. doi:10.1016/j.lungcan.2023.02.018

55. Criscitiello C, Morganti S, Curigliano G. Antibody-drug conjugates in solid tumors: a look into novel targets. J Hematol Oncol. 2021;14(1):20. doi:10.1186/s13045-021-01035-z

56. Kujtan L, Subramanian J. Telisotuzumab vedotin with erlotinib in the treatment of non-small cell lung cancer: a well MET combination? Transl Lung Cancer Res. 2023;12(8):1826-1829. doi:10.21037/tlcr-23-288

57. Camidge DR, Morgensztern D, Heist RS, et al. Phase I study of 2- or 3-week dosing of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, monotherapy in patients with advanced non-small cell lung carcinoma. Clin Cancer Res. 2021;27(21):5781-5792. doi:10.1158/1078-0432.CCR-21-0765

58. Goldman JW, Lu S, Bar J, et al. LUMINOSITY, a phase 2 study of telisotuzumab vedotin in patients with c-Met protein–overexpressing non-squamous EGFR-wildtype advanced NSCLC: efficacy outcomes by prior therapy. J Clin Oncol. 2025;43(suppl 16):8618. doi:10.1200/ JCO.2025.43.16_suppl.8618

59. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression. FDA. May 14, 2025. Accessed June 28, 2025. https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression

60. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: primary analysis of the LUMINOSITY trial. J Clin Oncol. 2024;42(suppl 16):103. doi:10.1200/ JCO.2024.42.16_suppl.103

61. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl 16):9016. doi:10.1200/JCO.2022.40.16_suppl.9016

62. Goldman JW, Horinouchi H, Cho BC, et al. Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl 16):9013. doi:10.1200/JCO.2022.40.16_suppl.9013

63. Lu S, Goldman JW, Tanizaki J, et al. A phase 3 global study of telisotuzumab vedotin versus docetaxel in previously treated patients with c-Met overexpressing, EGFR wildtype, locally advanced/metastatic nonsquamous NSCLC (TeliMET NSCLC-01). J Clin Oncol. 2024;42(suppl 16):TPS8656. doi:10.1200/JCO.2024.42.16_suppl.TPS8656

64. Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015;6(3-4):84-105. doi:10.18632/ genesandcancer.40

65. Lipinski M, Parks DR, Rouse RV, Herzenberg LA. Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci U S A. 1981;78(8):5147-5150. doi:10.1073/pnas.78.8.5147

66. Lenárt S, Lenárt P, Šmarda J, Remšík J, Souček K, Beneš P. Trop2: jack of all trades, master of none. Cancers (Basel). 2020;12(11):3328. doi:10.3390/cancers12113328

67. McDougall ARA, Tolcos M, Hooper SB, Cole TJ, Wallace MJ. Trop2: from development to disease. Dev Dyn. 2015;244(2):99-109. doi:10.1002/dvdy.24242

68. Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem. 2011;59(7):701-710. doi:10.1369/0022155411410430

69. Dum D, Taherpour N, Menz A, et al. Trophoblast cell surface antigen 2 expression in human tumors: a tissue microarray study on 18,563 tumors. Pathobiology. 2022;89(4):245-258. doi:10.1159/000522206

70. Inamura K, Yokouchi Y, Kobayashi M, et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget. 2017;8(17):28725-28735. doi:10.18632/oncotarget.15647

71. Mito R, Matsubara E, Komohara Y, et al. Clinical impact of TROP2 in non-small lung cancers and its correlation with abnormal p53 nuclear accumulation. Pathol Int. 2020;70(5):287-294. doi:10.1111/pin.12911

72. Omori S, Muramatsu K, Kawata T, et al. Trophoblast cell-surface antigen 2 expression in lung cancer patients and the effects of anti-cancer treatments. J Cancer Res Clin Oncol. 2022;148(9):2455-2463. doi:10.1007/s00432-021-03784-3

73. Jiang A, Gao X, Zhang D, Zhang L, Lu H. Expression and clinical significance of the Trop-2 gene in advanced non-small cell lung carcinoma. Oncol Lett. 2013;6(2):375-380. doi:10.3892/ ol.2013.1368

74. Ambrogi F, Fornili M, Boracchi P, et al. Trop-2 is a determinant of breast cancer survival. PLoS One. 2014;9(5):e96993. doi:10.1371/journal.pone.0096993

75. Bessede A, Peyraud F, Besse B, et al. TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2024;30(4):779-785. doi:10.1158/1078-0432.CCR-23-2566

76. Meric-Bernstam F, Spira AI, Lisberg AE, et al. TROPION-PanTumor01: dose analysis of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd, DS-1062) for the treatment (Tx) of advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9058. doi:10.1200/JCO.2021.39.15_suppl.9058

77. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329-2340. doi:10.1158/1535-7163.MCT-21-0206

78. Fu Y, Ho M. DNA damaging agent-based antibody-drug conjugates for cancer therapy. Antib Ther. 2018;1(2):33-43. doi:10.1093/abt/tby007

79. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed July 2, 2025. https://www.fda. gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast

80. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed July 2, 2025. https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer

81. Ahn MJ, Lisberg A, Paz-Ares L, et al. LBA12 datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01. Ann Oncol. 2023;34(suppl 2):S1305-S1306. doi:10.1016/j.annonc.2023.10.061

82. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. 2025;43(3):260-272. doi:10.1200/jco-24-01544

83. Sands J, Lisberg A, Okamoto I, et al. Datopotamab deruxtecan vs docetaxel in patients with non-small cell lung cancer: final overall survival from TROPION-Lung01. J Thorac Oncol. 2024;19(10):S24. doi: 10.1016/j.jtho.2024.09.048

84. Sands J, Ahn MJ, Lisberg A, et al. Datopotamab deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: results from the phase II TROPION-Lung05 study. J Clin Oncol. 2025;43(10):1254-1265. doi:10.1200/jco-24-01349

85. Lisberg A, Ahn MJ, Kitazono S, et al. Intracranial efficacy of datopotamab deruxtecan in patients with previously treated advanced/metastatic non-small cell lung cancer with actionable genomic alterations: Results from TROPION-Lung05. J Clin Oncol. 2024;42(16; suppl):8593. doi:10.1200/JCO.2024.42.16_suppl.8593

86. Pons-Tostivint E, Okamoto I, Ahn M, et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients with advanced/metastatic NSCLC in TROPION-Lung01. Abstract presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer 2025; September 6-9, 2025; Barcelona, Spain.

87. Ahn MJ, Sands J, Lisberg A, et al. Efficacy and safety of datopotamab deruxtecan in patients with previously-treated EGFR-mutated advanced non-small cell lung cancer: a pooled analysis of TROPION-Lung01 and TROPION-Lung05. Ann Oncol. 2024;35(4; suppl):S1630-S1631. doi: 10.1016/j.annonc.2024.10.656

88. Datroway. Prescribing Information. Daiichi Sankyo. 2026. https://daiichisankyo.us/ prescribing-information-portlet/getPIContent?productName=Datroway&inline=true

89. Sun X, Jia L, Wang T, et al. Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment. J Cancer. 2021;12(17):5310-5319. doi:10.7150/jca.57711

90. FDA grants breakthrough therapy designation to sacituzumab tirumotecan (sac-TMT) for the treatment of certain patients with previously treated advanced or metastatic nonsquamous non-small cell lung cancer with EGFR mutations. News release. Merck. December 3, 2024. Accessed July 2, 2025. https://www.merck.com/news/fda-grants-breakthrough-therapy-designation-to-sacituzumab-tirumotecan-sac-tmt-for-the-treatment-of-certain-patients-with-previously-treated-advanced-or-metastatic-nonsquamous-non-small-cell-lung-ca/

91. Gray JE, Neal J, Patel J, Liu S, Girard N. Sacituzumab govitecan + pembrolizumab + carboplatin in 1L metastatic non-small cell lung cancer: the EVOKE-02 study. Abstract presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer 2024; September 7-10, 2024; San Diego, CA.

92. Fang W, Wang Q, Cheng Y, et al. Sacituzumab tirumotecan (sac-TMT) in combination with tagitanlimab (anti-PD-L1) in first-line (1L) advanced non-small-cell lung cancer (NSCLC): non-squamous cohort from the phase II OptiTROP-Lung01 study. J Clin Oncol. 2025;43(suppl 16):8529. doi:10.1200/JCO.2025.43.16_suppl.8529

93. FDA approved new therapy for triple negative breast cancer that has spread, not responded to other treatments. Press release. FDA. April 22, 2020. Accessed June 15, 2026. https:// wayback.archive-it.org/7993/20201226154049/https:/www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-triple-negative-breast-cancer-has-spread-not-responded-other-treatments

94. FDA approved sacituzumab govitecan-hziy for HR-positive breast cancer. Press release. FDA. February 3, 2023. Accessed June 15, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sacituzumab-govitecan-hziy-hr-positive-breast-cancer

95. Garassino MC, Reznick D, Liu SY, et al. EVOKE-01: a phase 3 study of sacituzumab govitecan (SG) versus docetaxel in patients with non–small cell lung cancer (NSCLC) progressing on or after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2022;40(suppl 16):TPS9149. doi:10.1200/JCO.2022.40.16_suppl.TPS9149

96. Kopp A, Hofsess S, Cardillo TM, Govindan SV, Donnell J, Thurber GM. Antibody-drug conjugate sacituzumab govitecan drives efficient tissue penetration and rapid intracellular drug release. Mol Cancer Ther. 2023;22(1):102-111. doi:10.1158/1535- 7163.MCT-22-0375

97. Goldenberg DM, Stein R, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48):28989-29006. doi:10.18632/ oncotarget.25615

98. Paz-Ares LG, Juan-Vidal O, Mountzios GS, et al. Sacituzumab govitecan (SG) vs docetaxel (doc) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC) previously treated with platinum (PT)-based chemotherapy (chemo) and PD(L)-1inhibitors (IO): primary results from the phase 3 EVOKE-01 study. J Clin Oncol. 2024;42(suppl 17):LBA8500. doi:10.1200/ JCO.2024.42.17_suppl.LBA8500

99. Reinmuth N, Garassino MC, Juan-Vidal O, et al. Longer follow-up for survival and safety from the EVOKE-01 trial of sacituzumab govitecan (SG) vs docetaxel in patients (pts) with metastatic non-small cell lung cancer (mNSCLC). J Clin Oncol. 2025;43(suppl 16):8599. doi:10.1200/ JCO.2025.43.16_suppl.8599

100. Felip E, Kuo P, Garrido P, et al. Exploratory ctDNA analyses for the EVOKE-1 study in metastatic non-small cell lung cancer (mNSCLC). J Clin Oncol. 2025;43(suppl 16):8522. doi:10.1200/JCO.2025.43.16_suppl.8522

101. Felip E, Garrido P, Rodriguez-Abreu D, et al. 13P: brain metastases and actionable genetic alterations with sacituzumab govitecan versus docetaxel in metastatic non-small cell lung cancer: subgroups of the phase III EVOKE-01 trial. J Thorac Oncol. 2025;20(3):S17-S18. doi:10.1016/ S1556-0864(25)00208-4

102. Fang W, Cheng Y, Chen Z, et al. SKB264 (TROP2-ADC) for the treatment of patients with advanced NSCLC: efficacy and safety data from a phase 2 study. Abstract presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 9114.

103. Zhang L, Fang W, Li X, et al. Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated non-small cell lung cancer (NSCLC): results from the randomized OptiTROP-Lung03 study. J Clin Oncol. 2025;43(suppl 16):8507. doi:10.1200/ JCO.2025.43.16_suppl.8507

104. Heist RS, Guarino MJ, Masters G, et al. Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol. 2017;35(24):2790- 2797. doi:10.1200/JCO.2016.72.1894

105. Shimizu T, Sands J, Yoh K, et al. First-in-human, phase I dose-escalation and dose-expansion study of trophoblast cell-surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan in non–small-cell lung cancer: TROPION-PanTumor01. J Clin Oncol. 2023;41(29):4678-4687. doi:10.1200/jco.23.00059

106. Garassino MC, Sands J, Paz-Ares L, Lisberg AE, Johnson ML. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01. Abstract presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer 2024; September 7-10, 2024; San Diego, CA. Abstract PL02.11.

107. Lu S, Li Z, Wang Y, Sun Y. CT009 - SHR-A1811, a HER2-directed antibody-drug conjugate (ADC), in advanced HER2-mutant non-small cell lung cancer (NSCLC): updated phase 2 results from HORIZON-Lung. Abstract presented at: American Association for Cancer Research 2025; April 27, 2025; Chicago, IL. Abstract CT009.

108. A study of MRG002 in the treatment of patients with HER2-mutated unresectable/ metastatic non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated December 2, 2021. Accessed June 12, 2026. https://clinicaltrials.gov/study/NCT05141786

109. Safety of GQ1001 in adult patients with HER2-positive advanced solid tumors ClinicalTrials. gov. Updated December 5, 2023. Accessed June 12, 2026. https://clinicaltrials.gov/study/ NCT04450732

110. Lyu H, Han A, Polsdofer E, Liu S, Liu B. Understanding the biology of HER3 receptor as a therapeutic target in human cancer. Acta Pharm Sin B. 2018;8(4):503-510. doi:10.1016/j. apsb.2018.05.010

111. Scharpenseel H, Hanssen A, Loges S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep. 2019;9(1):7406. doi:10.1038/s41598-019-43678-6

112. Yonesaka K. HER2-/HER3-targeting antibody-drug conjugates for treating lung and colorectal cancers resistant to EGFR inhibitors. Cancers (Basel). 2021;13(5):1047. doi:10.3390/cancers13051047

113. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3- DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov. 2022;12(1):74-89. doi:10.1158/2159-8290.CD-21-0715

114. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/ JCO.23.01476

115. Halmos B, Yu HA, Wu Y, Nishio M, Reck M. HERTHENA-Lung02: a randomized phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor. Abstract presented at: American Association for Cancer Research Annual Meeting 2023; April 14-19, 2023; Orlando, FL. Abstract CT066/24.

116. Mok TSK, Yu HA, Lim SM, et al. Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: the phase 3 HERTHENA-Lung02 study. J Clin Oncol. 2025;43(suppl 16):8506. doi:10.1200/ JCO.2025.43.16_suppl.8506

117. Patritumab deruxtecan biologics license application for patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer voluntarily withdrawn. News release. Merck. May 29, 2025. Accessed July 2, 2025. https://www. merck.com/news/patritumab-deruxtecan-biologics-license-application-for-patients-with-previously-treated-locally-advanced-or-metastatic-egfr-mutated-non-small-cell-lung-cancer-voluntarily-withdrawn/

118. Steuer CE, Hayashi H, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 9017.

119. Ma PC, Jagadeeswaran R, Jagadeesh S, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 2005;65(4):1479-1488. doi:10.1158/0008-5472.CAN-04-2650

120. Gera N, Fitzgerald KM, Ramesh V, et al. MYTX-011: a pH-dependent anti-c-MET antibody-drug conjugate designed for enhanced payload delivery to c-MET-expressing tumor cells. Mol Cancer Ther. 2024;23(9):1282-1293. doi:10.1158/1535-7163.MCT-23-0784

121. Spira AI, Johnson ML, Blumenschein GR, et al. Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):TPS9147. doi:10.1200/JCO.2023.41.16_suppl. TPS9147

122. Clinical study of antibody-drug conjugate MYTX-011 in subjects with non-small cell lung cancer. ClinicalTrials.gov. Updated December 16, 2025. Accessed June 12, 2026. https:// clinicaltrials.gov/study/NCT05652868

123. Oh SY, Lee YW, Lee EJ, et al. Preclinical study of a biparatopic METxMET antibody-drug conjugate, REGN5093-M114, overcomes MET-driven acquired resistance to EGFR TKIs in EGFR-mutant NSCLC. Clin Cancer Res. 2023;29(1):221-232. doi:10.1158/1078-0432.ccr-22-2180

124. Study of REGN5093-M114 (METxMET antibody-drug conjugate) in adult patients with mesenchymal epithelial transition factor (MET) overexpressing advanced cancer. ClinicalTrials. gov. Updated November 3, 2025. Accessed June 12, 2026. https://clinicaltrials.gov/study/ NCT04982224

125. Camidge DR, Raimbourg J, Lee YG, et al. Telisotuzumab adizutecan (ABBV-400; Temab-A), a c-Met protein–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced EGFR-mutated (MT) non-squamous (NSQ) non-small cell lung cancer (NSCLC): results from a phase 1 study. J Clin Oncol. 2025;43(suppl 16):8512. doi:10.1200/JCO.2025.43.16_suppl.8512

126. Ma Y, Huang Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study. Lancet Oncol. 2024;25(7):901-911. doi:10.1016/ S1470-2045(24)00159-1

127. First in human study of AZD9592 in solid tumors (EGRET). ClinicalTrials.gov. Updated June 11, 2026. Accessed June 12, 2026. https://clinicaltrials.gov/study/NCT05647122

128. M1231 in participants with solid tumors. ClinicalTrials.gov. Updated July 7, 2023. Accessed June 12, 2026. https://clinicaltrials.gov/study/NCT04695847

129. Peters S, Hollebecque A, Sehgal K, et al. Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: updated phase 1 results (SGNB6A-001). J Clin Oncol. 2024;42(suppl 16):8521. doi:10.1200/JCO.2024.42.16_suppl.8521

130. Chang HW, Wang J, Liu H, et al. Preclinical development of mecbotamab vedotin (BA3011), a novel, AXL-specific conditional active biologic antibody-drug conjugate. Antib Ther. 2025;8(2):145-156. doi:10.1093/abt/tbaf006

131. Hsu R, Benjamin DJ. A narrative review of antibody-drug conjugates in EGFR-mutated non-small cell lung cancer. Front Oncol. 2023;13:1252652. doi:10.3389/fonc.2023.1252652

132. Cascone T, Florian G, Bonanno L, et al. Neocoast-2: efficacy and safety of neoadjuvant durvalumab (D) + novel anticancer agents + CT and adjuvant D ± novel agents in resectable NSCLC. J Thorac Oncol. 2024;19(10):S1-S2. doi: 10.1016/j.jtho.2024.09.013

133. Janne PA, Mostillo J, Shrestha P, Zhang R, Fan PD, Cantero F. Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with advanced EGFR-mutated NSCLC. J Clin Oncol. 2022;40(suppl 16):TPS3161. doi:10.1200/ JCO.2022.40.16_suppl.TPS3161

134. Levy BP, Paz-Ares LG, Su WC, et al. Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt_CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC): subgroup analysis from TROPION-Lung02. J Clin Oncol. 2024;42(16 suppl):8617. doi: 10.1200/JCO.2024.42.16_suppl.8617

135. Papadopoulos KP, Bruno D, Kitazono S, et al. OA05.06 Datopotamab deruxtecan (Dato- DXd) + durvalumab ± carboplatin in advanced/mNSCLC: initial results from phase 1b TROPION-Lung04. J Thorac Oncol. 2023;18(suppl 11):S55. doi:10.1016/j.jtho.2023.09.043

136. Phase III study of datopotamab deruxtecan versus docetaxel in previously treated TROP2- positive advanced or metastatic non-squamous NSCLC without actionable genomic alterations (TROPION-Lung17). ClinicalTrials.gov. Updated March 20, 2026. Accessed April 3, 2026. https:// clinicaltrials.gov/study/NCT07291037

137. TROPION-Lung17 TROP2 biomarker directed phase 3 trial of DATROWAY® initiated in patients with previously treated advanced nonsquamous non-small cell lung cancer. Press release. Business Wire. January 13, 2026. Accessed April 3, 2026. https://www.businesswire. com/news/home/20260112719100/en/TROPION-Lung17-TROP2-Biomarker-Directed-Phase- 3-Trial-of-DATROWAY-Initiated-in-Patients-with-Previously-Treated-Advanced-Nonsquamous-Non- Small-Cell-Lung-Cancer

138. Datopotamab deruxtecan (Dato-DXd) and pembrolizumab with or without platinum chemotherapy in 1L non-small cell lung cancer (TROPION-Lung07). ClinicalTrials.gov. Updated March 25, 2026. Accessed June 9, 2026. https://clinicaltrials.gov/study/NCT05555732

139. Study of Dato-DXd plus pembrolizumab vs pembrolizumab alone in the first-line treatment of subjects with advanced or metastatic NSCLC without actionable genomic alterations (TROPION-Lung08). ClinicalTrials.gov. Updated May 13, 2026. Accessed June 9, 2026. https://clinicaltrials. gov/study/NCT05215340

140. Phase III, open-label, first-line study of Dato-DXd in combination with durvalumab and carboplatin for advanced NSCLC without actionable genomic alterations (AVANZAR). ClinicalTrials. gov. Updated April 22, 2026. Accessed June 9, 2026. https://clinicaltrials.gov/study/ NCT05687266

141. Phase III, open-label, study of first-line Dato-DXd in combination with rilvegostomig for advanced non-squamous NSCLC with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations (TROPION-Lung10). ClinicalTrials.gov. Updated May 18, 2026. Accessed June 9, 2026. https://clinicaltrials.gov/study/NCT06357533

142. Phase III, open-label study of first-line osimertinib with or without datopotamab deruxtecan for EGFRm locally advanced or metastatic non-small cell lung cancer (TROPION-Lung14). ClinicalTrials.gov. Updated May 6, 2026. Accessed June 9, 2026. https://clinicaltrials.gov/study/ NCT06350097

143. A study to investigate the efficacy and safety of Dato-DXd with or without osimertinib compared with platinum based doublet chemotherapy in participants with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (TROPION-Lung15). ClinicalTrials.gov. Updated May 14, 2026. Accessed June 9, 2026. https://clinicaltrials.gov/study/NCT06417814

144. Phase 2 platform study in patients with advanced non-small lung cancer who progressed on first-line osimertinib therapy (ORCHARD). ClinicalTrials.gov. Updated January 30, 2025. Accessed June 9, 2026. https://clinicaltrials.gov/study/NCT03944772