Treatment with sacituzumab tirumotecan yielded significant improvements in both progression-free survival (PFS) and overall survival (OS) compared to platinum-based chemotherapy among patients with EGFR-mutant non–small cell lung cancer (NSCLC) who have progressed on prior EGFR tyrosine kinase inhibitor (TKI) and chemotherapy. 

These results from the phase 3 OptiTROP-Lung04 trial were presented at the 2025 ESMO Congress, representing the first final PFS and preplanned interim OS analyses of this study.

Sacituzumab tirumotecan is a next-generation TROP2-directed antibody-drug conjugate developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor.

This randomized, open-label global trial randomized 376 patients in a 1:1 ratio to receive either sacituzumab tirumotecan (5 mg/kg every 2 weeks) or chemotherapy with pemetrexed plus carboplatin or cisplatin (4 cycles, followed by pemetrexed maintenance). The study population had a median age of 59.5 years, with nearly all patients (94.7%) previously exposed to a third-generation EGFR-TKI.

At a median follow-up of 18.9 months, sacituzumab tirumotecan significantly improved PFS, with a median PFS of 8.3 months compared to 4.3 months with chemotherapy (hazard ratio [HR], 0.49; 95% CI, 0.39 to 0.62; P <.0001). The 12-month PFS rate was 32.3% and 7.9% for chemotherapy, respectively.

The preplanned interim overall survival (OS) analysis also favored sacituzumab tirumotecan, with median OS not reached (95% CI, 21.5 to not estimable) vs 17.4 months (95% CI, 15.7 to 20.4) for chemotherapy (HR, 0.60; 95% CI, 0.44 to 0.82; P = .0006). After censoring for subsequent antibody-drug conjugate therapy, the adjusted OS HR improved to 0.56 (P = .0002). The objective response rates were 60.6% vs 43.1% and median duration of response was 8.3 vs 4.2 months, respectively.

Treatment was generally well tolerated. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 49.5% of patients receiving sacituzumab tirumotecan and 52.2% with chemotherapy, while serious TRAEs were lower with the antibody-drug conjugate (7.4% vs 17%). Notably, no drug-related interstitial lung disease or pneumonitis was reported.

The trial investigators concluded that these findings establish sacituzumab tirumotecan as the first TROP2 antibody-drug conjugate to achieve statistically significant and clinically meaningful benefits in both PFS and OS over platinum-based chemotherapy in this heavily pretreated EGFR-mutant NSCLC population. The results position sacituzumab tirumotecan as a potential new standard of care for patients with EGFR-TKI–resistant disease.

Source:

Zhang L, Fang WF, Wu L, et al. Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase III OptiTROP-Lung04 study. Presented at the 2025 ESMO Congress; October 17-21, 2025. Berlin, Germany. LBA5