Scituzumab Thyrumotecan vs Platinum Chemotherapy in EGFR-Mutated NSCLC: OptiTROP-Lung04 Trial

In this study, the authors present the results of OptiTROP-Lung04 (NCT05870319), a phase III, multicenter, randomized clinical trial that compared sacituzumab tirumotecan (Sac-TMT), an anti-TROP2 antibody-drug conjugate (ADC), with platinum-based chemotherapy in patients with EGFR-activating mutation non-small cell lung cancer (NSCLC) (EGFRm) after progression to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The study demonstrated that Sac-TMT provided statistically and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) compared to chemotherapy, with a manageable safety profile. The results were presented at ESMO 2025.

Sac-TMT is an anti-TROP2 ADC developed with an innovative linker that conjugates a belotcan derivative (topoisomerase I inhibitor). Previous studies have shown survival benefit with Sac-TMT compared to docetaxel in patients with EGFRnPC after failure of EGFR-TKI and platinum-based chemotherapy. OptiTROP-Lung04 evaluated its efficacy and safety compared to standard treatment in a larger and more homogeneous cohort.

In the present study, 376 patients (median age 59.5 years; 39.6% male; 79.3% ECOG PS 1; 94.7% previously treated with third-generation EGFR-TKI) were randomized 1:1 to Sac-TMT 5 mg/kg every 2 weeks (n=188) or chemotherapy with pemetrexed 500 mg/m² + carboplatin AUC5 or cisplatin 75 mg/m² every 3 weeks for 4 cycles, followed by maintenance with pemetrexed (n=188). The primary outcome was PFS assessed by an independent committee (BIRC), and the hierarchical secondary was OS.

After a median follow-up of 18.9 months, 21.3% of the patients in the Sac-TMT group versus 1.6% in the chemotherapy group remained on treatment. Sac-TMT demonstrated significant PFS benefit (8.3 vs 4.3 months; HR 0.49; 95%CI 0.39–0.62; p<0.0001) and prolonged OS, not yet reached in the experimental group (NR vs 17.4 months; HR 0.60; 95%CI 0.44–0.82; p=0.0006). After adjusting for subsequent ADC therapies, adjusted OS maintained an advantage (HR 0.56; 95%CI 0.41–0.77; p=0.0002). The objective response rate (ORR) was 60.6% with Sac-TMT and 43.1% with chemotherapy, with a median duration of response (DOR) of 8.3 vs 4.2 months, respectively.

Grade ≥3 treatment-related adverse events occurred in 49.5% and 52.2% of patients in the Sac-TMT and chemotherapy groups, respectively. Serious adverse events related to Sac-TMT were less frequent (7.4% vs 17.0%), and there were no cases of drug-related pneumonitis/pulmonary interstitiopathy in either group. In conclusion, the study presents Sac-TMT as the first anti-TROP2 ADC to demonstrate statistically and clinically significant improvements in PFS and OS compared to platinum-based chemotherapy in EGFRm NSCLC after EGFR-TKIs failure, with favorable safety and absence of new signs of toxicity. These results position the Sac-TMT as a potential new standard of care for this patient population.

References

1. Li Zhang, Wen Feng Fang, Lin Wu 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. ESMO 2025