Is TROP2 ADC ready for EGFR-TKI-resistant NSCLC?

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have transformed the first-line treatment landscape for advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance still remains inevitable, a major unmet clinical need for this patient population (1). Following EGFR-TKI failure, platinum-pemetrexed doublet chemotherapy has long been the standard second-line regimen, with a median progression-free survival (PFS) of only four to five months and a limited overall survival (OS) benefit associated with substantial toxicities (2).

Antibody-drug conjugates (ADCs), novel agents which combine targeted monoclonal antibodies with cytotoxic payloads, have emerged as a new treatment option for EGFR-mutated NSCLC. Trophoblast cell-surface antigen 2 (TROP2) is highly expressed in EGFR-TKI-resistant NSCLC cells, and preclinical data confirm that EGFR mutations enhance the internalization and tumoricidal activity of TROP2-directed ADCs, providing a strong biological rationale for their use in this setting (3).

The OptiTROP-Lung04 trial, published online at NEJM.org on October 19, 2025, is a phase III trial conducted in China comparing a TROP2 ADC head-to-head with platinum-based chemotherapy in EGFR-TKI-resistant EGFR-mutated NSCLC (4). While the trial establishes a promising standard of care for this population with its significant PFS benefit, it also raises critical clinical questions regarding patient selection, toxicity management, and the future development of TROP2 ADCs.

Trial design and key findings

OptiTROP-Lung04, a multicenter, open-label, randomized phase III trial conducted across 66 sites in China, enrolled 376 patients with locally advanced (IIIB–IIIC) ineligible for curative therapy or metastatic non-squamous NSCLC who progressed on EGFR-TKIs. Patients were randomized 1:1 to receive single-agent sacituzumab tirumotecan (sac-TMT) or pemetrexed plus platinum chemotherapy, with PFS assessed by blinded independent central review (BICR) as the primary endpoint, and OS as the hierarchically tested key secondary endpoint. The enrolled population was highly representative of real-world clinical practice: 94.7% of patients had received prior third-generation EGFR-TKIs, over 60% had 3 or more metastatic sites, and nearly 20% had baseline brain metastases.

After a median follow-up of 18.9 months, sac-TMT improved median PFS to 8.3 versus 4.3 months with chemotherapy, corresponding to a 51% reduction in the risk of disease progression or death [hazard ratio (HR) 0.49, 95% confidence interval (CI): 0.39–0.62, P<0.0001]. The 12-month PFS rate was 32.3% with sac-TMT, compared to 7.9% with chemotherapy, a magnitude of benefit rarely observed in the second-line setting of advanced lung cancer. The median PFS of 4.3 months in the platinum pemetrexed control arm is consistent with historical data from post-osimertinib trials such as MARIPOSA-2 (5). However, cross-trial comparisons should be interpreted cautiously due to differences in patient eligibility, prior treatment lines, and geographic practice patterns. This contextualizes the magnitude of PFS improvement with sac-TMT rather than suggesting an unusually poor control performance.

The preplanned interim analysis showed a median OS not reached in the sac-TMT arm versus 17.4 months with chemotherapy, with a 40% reduction in the risk of death (HR 0.60, 95% CI: 0.44–0.82, P=0.001) that crossed the prespecified statistical significance boundary. The 18-month OS rates were 65.8% and 48.0% in the experimental and control arms, respectively, demonstrating a survival benefit trend. At the time of interim analysis, OS data were still immature with only 35.6% maturity, and median OS in the sac-TMT arm had not been reached. Therefore, the observed OS benefit should be regarded as preliminary; definite conclusions regarding long-term OS advantage cannot be drawn until mature follow-up data become available.

Although crossover was not permitted, subsequent ADCs were used in 1.4% of patients in the sac-TMT group and in 19.6% of those in the chemotherapy group. In a supplementary analysis in which data were censored at the start of subsequent ADC treatment, the hazard ratio for death remained favorable (HR 0.56; 95% CI: 0.41–0.77), supporting that the interim OS signal is not solely explained by post-progression sequencing.

However, the OS event maturity was only 35.6% at this interim analysis, median OS in the experimental arm is not yet reached. Notably, any post-progression use of sac-TMT in the chemotherapy arm would be expected to dilute OS differences, which provides additional context for the interim hazard ratio. Therefore, no definitive conclusion of a long-term OS benefit can be drawn at this time, and mature follow-up data are required to validate this signal. In prespecified OS subgroup analyses, the hazard ratio for death among patients with brain metastases was 0.65 (95% CI: 0.32–1.30), although confidence intervals were wide and not adjusted for multiplicity.

Additional efficacy endpoints further support the clinical value of sac-TMT: the objective response rate (ORR) was 60.6% with the ADC versus 43.1% with chemotherapy, and the median duration of response (DOR) was 8.3 months.

Balancing efficacy and safety

The overall safety profile of sac-TMT is clinically manageable; however, its unique toxicity spectrum presents important management challenges. Overall, the incidence of grade 3 or higher treatment-related adverse events (TRAEs) was similar between the sac-TMT and chemotherapy groups (58.0% vs. 53.8%), but the rate of treatment-related serious adverse events was lower with the ADC (9.0% vs. 17.6%). No treatment-related deaths or permanent treatment discontinuations due to TRAEs occurred in the sac-TMT arm.

Clinical tolerability and clinical manageability are two distinct concepts; clinical manageability does not equate to a low incidence of adverse events, and patient quality of life must be a core consideration throughout treatment decision-making. Although patients on sac-TMT showed a higher grade 3 or higher neutropenia than chemotherapy, febrile neutropenia occurred in only 0.5% of patients on Sac-TMT compared with 2.7% with chemotherapy. Grade 3 or higher anemia and thrombocytopenia were less frequent with the ADC, which may reduce the need for blood product transfusions and supportive care.

However, sac-TMT presents a distinct toxicity profile compared to chemotherapy, most notably stomatitis, which occurred in 64.4% of patients. While most cases were grade 1–2, grade 3 stomatitis was reported in 4.8% of patients, and dose modifications were required in 10.1% of patients due to this event. Even with symptomatic intervention, recurrent mucosal injury directly impairs oral intake, nutritional status, and daily functioning, which can be particularly challenging in patients with pre-existing oral disease or malnutrition. Ocular surface toxicities were also reported in 9.6% of patients, all mild to moderate, but requiring long-term supportive care that adds to patient treatment burden. These adverse events should be aggressively monitored during treatment to prevent complications.

Given the distinct and impactful toxicity profile of TROP2 ADCs, it should be emphasized the critical importance of shared decision-making, detailed informed consent, and integration of patient preferences when selecting between ADCs and alternative therapies with differing toxicity burdens. This ensures that treatment decisions align not only with clinical efficacy but also with individual patient quality of life priorities, particularly for toxicities such as stomatitis that can significantly impair daily functioning.

ADC is not indicated for all patients

The significant PFS benefit and OS trend demonstrated in the interim analysis of OptiTROP-Lung04 does reinforces sac-TMT as a potential treatment option for select patients with EGFR-TKI-resistant NSCLC. This trial highlights the importance of precision medicine in the management of EGFR-TKI resistant NSCLC. The decision to use ADC therapy must be guided by the patient’s underlying resistance mechanism and biomarker profile, to optimize patients outcomes.

Notably, OptiTROP-Lung04 was ‘biomarker-light’: eligibility was defined by EGFR genotype and clinical criteria rather than a prespecified TROP2 expression threshold. This may reduce testing friction in practice, but it also sharpens the key unanswered question—whether EGFR-context biology and ADC uptake dynamics, rather than surface expression alone, best predict benefit. How to sequence a TROP2 ADC alongside resistance-directed strategies and other emerging options remains to be defined.

Advances in next-generation sequencing (NGS) have unraveled the molecular mechanisms behind EGFR-TKI resistance, with distinct resistance subtypes corresponding to vastly different optimal therapeutic strategies (6).

For patients with high PD-L1 expression after progression to TKI, immunotherapy-based combination regimens such as ivonescimab plus chemotherapy, and sintilimab-containing combination regimen investigated in the ORIENT-31 trial are new options (7,8). Targeted therapy remains the treatment of choice for those with mesenchymal-epithelial transition factor (c MET) amplification, occurring in 5–10% of EGFR-TKI-resistant cases; for these patients, the combination of a MET inhibitor plus EGFR-TKI delivers a median PFS of 7.3–9.1 months with a non-overlapping toxicity profile (9). For patients with acquired human epidermal growth factor receptor 2 (HER2) mutations, HER2-directed ADCs such as trastuzumab deruxtecan (T-DXd) and SHR-A1811 have demonstrated antitumor activity (10,11). Thus, the treatment approach after EGFR-TKI failure is dependent on comprehensive NGS and biomarker testing to determine the resistance mechanism. In practice, post-EGFR-TKI decisions should integrate resistance profiling and competing treatment priorities; how best to sequence a TROP2 ADC alongside other options remains to be defined.

Advantages and challenges of ADC combination therapy

The success of single-agent sac-TMT provided the basis for exploring ADC-based combination strategies to further improving efficacy and address acquired resistance. However, the inherent toxicity profile of sac-TMT, particularly hematologic and mucosal toxicities, represents a major barrier to the clinical translation of combination regimens.

Mechanistically, combinations of ADCs with EGFR-TKIs, immunotherapy, antiangiogenic agents, or chemotherapy have theoretical synergistic antitumor effects. However, available clinical data consistently demonstrate that combination ADC therapy is accompanied by a critical challenge of cumulative toxicity, even with improved efficacy. The phase II ORCHARD trial investigated osimertinib plus the TROP2 ADC datopotamab deruxtecan (Dato-DXd) in EGFR-TKI-resistant NSCLC, and while the 6 mg/kg dose group achieved a median PFS of 11.7 months, the incidence of grade 3 or higher TRAEs was 56%, with over half of patients requiring dose reduction (12). While no mature data exist for sac-TMT plus EGFR-TKIs, the 39.9% incidence of grade 3 or higher neutropenia with single-agent sac-TMT suggests a high risk of cumulative myelosuppression with this combination, necessitating strict dose modification and prophylactic supportive care.

For ADC plus immunotherapy combinations, the phase I OptiTROP-Lung01 trial showed that sac-TMT plus a PD-L1 inhibitor achieved an ORR of 59.3% and median PFS of 15.0 months in first-line driver-negative NSCLC, but grade 3 or higher TRAEs increased to 60.5%, with a 45.7% incidence of neutropenia and 11.1% incidence of grade 3 or higher stomatitis (13). Immune-related adverse events may have a synergistic effect with the mucosal and hematologic toxicities of ADCs, further increasing the risk of severe adverse events. Combinations of sac-TMT with chemotherapy have shown only marginal improvements in ORR alongside substantial increases in severe hematologic toxicity, limiting their use to patients with excellent performance status.

In summary, while sac-TMT-based combination therapy has broad exploratory potential, cumulative toxicity is an unavoidable bottleneck. Future research must prioritize the balance of efficacy and toxicity, through optimized dosing schedules, patient selection, and proactive toxicity management, to maximize synergistic efficacy without compromising patient tolerability.

Unmet needs in predictive biomarkers for ADC efficacy

Within the broader global landscape of TROP2-directed ADC development, Dato-Dxd provides a critical benchmark for defining the relative positioning of sac-TMT in EGFR-TKI-resistant NSCLC. The phase III TROPION-Lung01 trial (n=605) established the superiority of Dato-DXd over docetaxel in previously treated advanced NSCLC, with a pre-specified subgroup analysis of 119 EGFR-mutant patients demonstrating a confirmed ORR of 42.9% and median PFS of 5.6 months (14). The phase II TROPION-Lung05 study further validated these findings in a dedicated cohort of 78 EGFR-TKI-pretreated patients (71.5% of whom had received ≥3 lines of prior therapy), reporting a consistent ORR of 43.6%, median PFS of 5.8 months, and median DOR of 7.0 months (15).

These data confirm a clear class effect of TROP2-directed ADCs in EGFR-TKI-resistant NSCLC, with both agents demonstrating superior efficacy to standard chemotherapy. From a precision medicine perspective, cross-agent comparisons highlight a critical and underrecognized challenge in TROP2 ADC development: predictive biomarkers are agent-specific, not class-wide. The most significant advance in this field comes from the TROPION-Lung01 trial, which demonstrated that a novel quantitative normalized membrane ratio (NMR) TROP2 scoring system—rather than conventional semi-quantitative immunohistochemistry (IHC) H-scoring—could robustly stratify Dato-DXd responders (16). Patients with high TROP2 NMR scores had a 62% reduction in the risk of disease progression or death compared to docetaxel (HR 0.38, 95% CI: 0.25–0.58), while those with low NMR scores derived no statistically significant PFS benefit (HR 0.82, 95% CI: 0.54–1.24). In contrast, traditional IHC H-scores showed no correlation with Dato-DXd efficacy across any threshold.

Notably, this NMR biomarker has not been validated for sac-TMT. Subgroup analyses of the phase II OptiTROP-Lung03 and phase III OptiTROP-Lung04 trials found no significant association between conventional TROP2 IHC expression and Sac-TMT efficacy (17), and no quantitative NMR data have been reported for this agent to date. This discrepancy may be explained by differences in antibody binding epitopes and internalization kinetics: Dato-DXd binds to a distinct extracellular domain of TROP2 compared to sac-TMT, and its efficacy appears more dependent on cell surface TROP2 density, while sac-TMT may benefit from enhanced internalization driven by EGFR mutation signaling, as suggested by preclinical data. These findings underscore the urgent need for agent-specific predictive biomarkers and standardized global TROP2 detection assays, rather than a one-size-fits-all approach, to optimize patient selection for TROP2 ADC therapy.

Conclusion and future perspectives

The OptiTROP-Lung04 trial is a landmark study in the treatment of EGFR-TKI-resistant NSCLC, showing the role of sac-TMT in improving PFS compared with platinum-based chemotherapy, supporting a potential option for patients without actionable resistance driver mutations. Longer follow-up is needed to ascertain its OS benefit and multinational phase III trials may be conducted to validate its efficacy in a global and more diverse population.

The clinical challenges of managing its characteristic mucosal toxicities, the need for precision patient stratification based on resistance mechanisms, the risk of cumulative toxicity with combination therapies, and the lack of validated predictive biomarkers are all core issues that must be addressed in clinical practice. Guidelines on how to manage common adverse events should likewise be formulated to guide both clinicians and patients while on this treatment.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0334/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0334/coif). R.N.V. reports lecture honoraria: Astra Zeneca, Pfizer, MSD (all outside the scope of this editorial). A.C.T. reports consulting or advisor role in Amgen, AstraZeneca, Bayer, and Pfizer; all outside the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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