Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus pembrolizumab (P) as first-line treatment for PD-L1–positive advanced non-small cell lung cancer (NSCLC): Results from the randomized phase 3 OptiTROP-Lung05 study.

8506 Background: Pembrolizumab has been the standard first-line treatment for PD-L1 positive advanced NSCLC. Sac-TMT, a TROP2-directed antibody-drug conjugate with a unique bifunctional linker, and PD-1/L1 inhibitors demonstrate complementary mechanisms that enhance antitumor activity in the first-line treatment of NSCLC ( Hong et al., Nat Med, 2025 ). Here, we report the results from the planned interim analysis for PFS in this phase 3 OptiTROP-Lung05 study (NCT06448312). Methods: Eligible patients (pts) had treatment-naïve, locally advanced or metastatic NSCLC without EGFR/ ALK alterations and positive PD-L1 expression (defined as TPS ≥1%, 22C3 assay). Pts were stratified by PD-L1 (TPS 1-49% vs ≥ 50%), histology (squamous vs non-squamous) and ECOG (0 vs 1) and then randomized (1:1) to receive sac-TMT 4 mg/kg Q2W plus P 400 mg Q6W or P 400 mg Q6W. The primary endpoint was PFS per RECIST 1.1 assessed by blinded independent central review (BICR), and the key secondary endpoint was OS. Results: A total of 413 pts (median age 65 yrs; 84.5% ECOG 1; 40.0% squamous; 40.0% PD-L1 TPS ≥ 50%) were randomized to receive sac-TMT + P (n = 208) or P (n = 205). As of Sep 29, 2025, the median follow-up was 10.5 months. PFS by BICR was significantly longer in the sac-TMT + P group than the P group (median, not reached vs 5.7 months; HR, 0.35; 95% CI, 0.26-0.47; p < 0.0001). The data for OS were not mature, and a favorable trend was observed in the sac-TMT + P group (HR, 0.55; 95% CI, 0.36-0.85). The BICR-assessed ORR was 70.2% in the sac-TMT + P group versus 42.0% in the P group. In the pre-specified PD-L1 subgroups, the HRs for PFS in pts with TPS 1-49% and TPS ≥ 50% were 0.28 (95% CI, 0.19-0.41) and 0.47 (95% CI, 0.29-0.77). In the pre-specified histology subgroups, the HRs for PFS in pts with non-squamous and squamous were 0.28 (95% CI, 0.18-0.43) and 0.44 (95% CI, 0.29-0.66). Grade ≥ 3 TEAEs were 55.3% in the sac-TMT + P group and 31.4% in the P group. Most common grade ≥3 TEAEs of special interest for sac-TMT were neutrophil count decreased (17.3%), anemia (9.1%), and stomatitis (5.3%). TEAEs led to discontinuation of sac-TMT/ pembrolizumab in 3.8%/5.3% of pts in the sac-TMT + P group while discontinuation of pembrolizumab occurred in 4.9% of pts in the P group. Conclusions: To our knowledge, this is the first phase 3 study to demonstrate the significant PFS benefit of an antibody-drug conjugate plus pembrolizumab in the first-line treatment of PD-L1 positive advanced NSCLC compared to pembrolizumab. The safety profile of sac-TMT + P was generally manageable and consistent with the safety profile of the components. No new safety signals were seen. These results from phase 3 OptiTROP-Lung05 study support sac-TMT + P as a potential new treatment option for this population. Clinical trial information: NCT06448312 .