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.

8507 Background: Sac-TMT (MK-2870/SKB264), a novel TROP2 ADC developed to conjugate a belotecan-derivative topoisomerase I inhibitor, has shown encouraging antitumor activity in EGFRm NSCLC pts in phase Ⅰ trial (Fang et al . AACR 2024). Here, we report the results from a multicenter, randomized, controlled study comparing sac-TMT with docetaxel in previously treated EGFRm NSCLC pts (OptiTROP-Lung03, NCT05631262). Methods: Pts with advanced EGFRm NSCLC who had progressed after EGFR TKI and platinum-based chemotherapy were randomized (2:1) to receive sac-TMT 5 mg/kg Q2W or docetaxel 75 mg/m 2 . Pts with verified progression on docetaxel could be crossed over to receive sac-TMT if eligible. Hierarchical fixed-sequence testing was employed for efficacy endpoints, including ORR (primary) and PFS, assessed by blinded independent review committee (BIRC), followed by OS. Pre-specified OS interim analysis was conducted alongside final PFS analysis, with the level at one-sided alpha of 1.23% determined by alpha spending function. The crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: A total of 137 pts (median age 56 yrs; 43.8% male; 82.5% ECOG PS 1; 93.4% prior 3 rd EGFR TKI) were randomized to receive sac-TMT (n=91) or docetaxel (n=46). At a median follow-up of 12.2 mo (data cutoff: Dec 31, 2024), 25.3% of pts (sac-TMT) vs 4.3% (docetaxel) remained on treatment. The study met its primary and key secondary endpoints. Sac-TMT achieved statistically significant clinical outcomes compared to docetaxel: confirmed ORR (BIRC: 45.1% vs 15.6%, 1-sided p=0.0004; investigator [INV]: 34.1% vs 8.7%), PFS (BIRC: median 6.9 vs 2.8 mo, HR 0.30 [95% CI: 0.20, 0.46], 1-sided p<0.0001; INV: median 7.9 vs 2.8 mo, HR 0.23 [95% CI: 0.15, 0.36]), and OS (median not reached [NR] for both groups, HR 0.49 [95% CI: 0.27, 0.88], 1-sided p=0.007), with 36.4% of pts in docetaxel group crossed over to receive sac-TMT. The RPSFT model adjusted median OS was 9.3 mo for docetaxel and NR for sac-TMT (HR for OS 0.36 [95% CI: 0.20, 0.66]). Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 56.0% of pts in sac-TMT group vs 71.7% in docetaxel group, and treatment-related SAEs were 16.5% vs 41.3%. Most common (≥ 10%) grade ≥ 3 TRAEs (sac-TMT vs docetaxel) were neutrophil count decreased (42.9% vs 58.7%), WBC count decreased (25.3% vs 52.2%), stomatitis (16.5% vs 2.2%), anemia (12.1% vs 4.3%) and febrile neutropenia (0% vs 19.6%). No cases of ILD were reported in sac-TMT group. Conclusions: Sac-TMT demonstrated improved ORR, PFS and OS compared to docetaxel, with manageable safety profile in pts with previously treated advanced EGFRm NSCLC. These results highlight significant survival benefits and suggest that sac-TMT could emerge as a new standard of care for this population. Clinical trial information: NCT05631262 .