Sacituzumab tirumotecan and the expanding role of TROP2-directed therapy in epidermal growth factor receptor-mutant non-small cell lung cancer

Introduction

A recent study by Fang et al. demonstrated that the TROP2-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) improved objective response rate (ORR) and progression-free survival (PFS) compared with docetaxel in patients with heavily pretreated epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) (1). This is the first randomized clinical trial to show superiority of a TROP2-targeting ADC over docetaxel in this patient population and could change the treatment paradigm in this setting.

Current therapeutic landscape

The treatment landscape for patients with EGFR-mutant NSCLC is rapidly evolving. Until recently, the standard of care for first-line therapy was osimertinib (2). Results from the MARIPOSA-1 and FLAURA-2 studies have now expanded first-line options to include amivantamab plus lazertinib and osimertinib plus chemotherapy (3,4). Second-line therapies depend on prior treatment but may include amivantamab plus a platinum doublet or platinum doublet alone (5). Immunotherapy, with or without vascular endothelial growth factor (VEGF)-targeting agents, has been explored with mixed results and only modest benefit in EGFR-mutant patients (6). Subsequent therapies have historically been limited, and guidelines for sequencing are lacking. Docetaxel with or without ramucirumab has been the traditional option after progression on tyrosine kinase inhibitor (TKI) therapy and chemotherapy, but this regimen is poorly tolerated and has limited efficacy (7). More recently, there has been growing interest in ADCs for this patient population, which have shown promising efficacy and encouraging tolerability.

TROP2-directed ADCs in EGFR-mutant NSCLC

TROP2 has emerged as a promising therapeutic target in NSCLC (8). TROP2-directed ADCs such as sacituzumab govitecan (SG) and datopotamab deruxtecan (dato-DXd) have been evaluated in heavily pretreated metastatic NSCLC. The EVOKE-01 study reported an ORR of 14% with SG and a median PFS of 4.2 months (9). Similarly, the TROPION-Lung01 trial evaluating dato-DXd showed an ORR of 26.4% and median PFS of 4.4 months (10). Of interest, subgroup analyses from TROPION-Lung01 showed that patients with targetable alterations derived greater benefit, with a median PFS of 5.7 vs. 2.6 months [hazard ratio (HR) =0.35] and median overall survival (OS) of 15.6 vs. 9.8 months (HR =0.65). The overall ORR was 26.4 % with dato-DXd compared with 12.8% for docetaxel, with durable responses and consistent benefit across actionable and non-actionable subsets.

Clinical activity of sac-TMT

The OptiTROP-Lung03 study was an open-label randomized clinical trial enrolling Chinese patients with previously treated EGFR-mutant NSCLC (1). Patients were randomized 2:1 to receive sac-TMT (5 mg/kg on days 1 and 15 of a 4-week cycle) or docetaxel (75 mg/m² every 3 weeks). Conducted across 48 centers in China, the trial’s primary endpoint was blinded ORR, with key secondary endpoints including investigator-assessed ORR, disease control rate (DCR), PFS, and OS. Crossover from docetaxel to sac-TMT upon progression was allowed.

Efficacy results mirrored those of a pooled analysis of dato-DXd in EGFR-mutant NSCLC (11). In the OptiTROP-Lung03 trial, ORR was 45% with sac-TMT vs. 16% with docetaxel and median PFS was 6.9 months. Clinical benefit was observed across subgroups, including patients with brain metastases. These are comparable to the HER3-targeting ADC patritumab deruxtecan (HER3-DXd), which showed a similar median PFS of 5.5 months on the HERTHENA-Lung02 trial (12).

Preclinical data suggest that EGFR-mutant TKI-resistant cells exhibit increased TROP2-mediated internalization of sac-TMT which could explain the activity of this agent in this patient population (13). To that end, TROP2 normalized membrane ratio (NMR) is an emerging biomarker developed through quantitative image analysis to measure membrane-specific TROP2 expression. Unlike categorical scoring, it provides a continuous, normalized measure of TROP2 density on tumor cell membranes, improving correlation with ADC internalization potential. Analyses from TROPION-Lung01 demonstrated that high TROP2 NMR was associated with greater response and longer PFS with dato-DXd, though these findings remain exploratory and require prospective validation (14).

Safety profile and comparison with other ADCs

Overall, grade ≥3 treatment-related adverse events (TRAEs) were significantly lower with sac-TMT than with docetaxel (56% vs. 72%) (13). The most common adverse events (AEs) with sac-TMT included cytopenias and stomatitis. Grade ≥3 neutropenia occurred in 43% of patients with sac-TMT compared to 59% with docetaxel, and grade ≥3 leukopenia in 35% vs. 52%, respectively. Stomatitis was seen in 16% of sac-TMT patients. Importantly, febrile neutropenia was not observed with sac-TMT, compared with 20% of patients receiving docetaxel. In contrast to other ADCs, ocular toxicity was rare (2%) and no interstitial lung disease (ILD) events were reported. By comparison, ocular toxicity rates were 9% with SG and 23% with dato-DXd, while ILD occurred in 2% and 6% of patients, respectively (9,10). No treatment discontinuations due to AEs occurred in the sac-TMT arm, although 32% required dose reductions.

Limitations and future directions

Several limitations restrict generalizability to Western populations. As the study was conducted exclusively in China and the vast majority of patients were Asian. Moreover, ORR as a surrogate for OS in the context of ADCs remains uncertain. Thus, larger global phase III trials with more diverse populations and mature survival data are required to validate these findings and establish sac-TMT’s role beyond China. An ongoing phase III trial (MK-2870-004; NCT06074588) is currently randomizing sac-TMT against investigator’s-choice chemotherapy (docetaxel or pemetrexed) in patients with advanced NSCLC harboring EGFR mutations or other actionable genomic alterations (15). Given that dato-DXd is already approved in the U.S. for patients with EGFR-mutant NSCLC after platinum-based chemotherapy, determining the optimal sequencing of ADCs targeting TROP2 will be an important next step.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Shanghai Chest. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2025-aw-6/coif). A.E.L. serves as an unpaid editorial board member of Shanghai Chest from April 2024 to June 2026. M.A.V. has served as a consultant for AstraZeneca, Medscape, OncoHost, MJH Life Sciences, and Elevance Health. M.A.V. has also participated in the speaker’s bureau for OncoHost. A.E.L. has received institutional research funding from Daiichi Sankyo, Calithera Biosciences, AstraZeneca, Dracen Pharmaceuticals, WindMIL, eFFECTOR Therapeutics, Duality Biologics, Seagen (Pfizer), and BioNTech. A.E.L. has served as a compensated consultant or advisory board member for AstraZeneca, Bristol Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals, Novocure, Pfizer, MorphoSys, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen Oncology, Sanofi, G1 Therapeutics, Molecular Axiom, Amgen, IQVIA, Bayer, Daiichi Sankyo, Gilead Sciences, AbbVie, and Whitehawk Therapeutics. A.E.L. has received travel support from Duality Biologics and BioNTech. A.E.L.’s spouse is employed by Boston Scientific and holds stock, and A.E.L. holds stock in Paralos Bioscience. The other author has 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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