Sacituzumab Tirumotecan plus Pembrolizumab in PD-L1-Negative Advanced NSCLC

Key numbers

• 95% confidence interval
• 50.2% and 47.3% of the
• 95% CI

Background Pembrolizumab plus chemotherapy with a platinum-based agent and pemetrexed is a widely used standard first-line treatment option for patients with programmed death ligand 1 (PD-L1)-negative advanced nonsquamous non-small-cell lung cancer (NSCLC) without targetable genomic alterations, but outcomes remain suboptimal. Methods In this phase 3, open-label, randomized trial, we evaluated sacituzumab tirumotecan plus pembrolizumab in patients with previously untreated locally advanced or metastatic nonsquamous NSCLC without targetable genomic alterations and a PD-L1 tumor proportion score of less than 1%. Patients were randomly assigned in a 1:1 ratio to receive sacituzumab tirumotecan plus pembrolizumab or chemotherapy plus pembrolizumab. The primary end point was progression-free survival as assessed by blinded independent central review. Overall survival was a secondary end point. This report presents the results of the prespecified interim analysis. Results A total of 455 patients were randomly assigned to receive sacituzumab tirumotecan plus pembrolizumab (229 patients) or chemotherapy plus pembrolizumab (226 patients). After a median follow-up of 9.7 months, the median progression-free survival was significantly longer with sacituzumab tirumotecan plus pembrolizumab than with chemotherapy plus pembrolizumab (15.0 months vs. 5.7 months; hazard ratio for disease progression or death, 0.49; 95% confidence interval [CI], 0.36 to 0.65; P<0.001). An objective response occurred in 50.2% and 47.3% of the patients, respectively, and the median duration of response was 13.6 months and 6.8 months. Overall survival data were immature; the hazard ratio for death was 0.58 (95% CI, 0.38 to 0.88). Adverse events of grade 3 or higher that occurred after the start of treatment were reported in 47.6% of the patients assigned to receive sacituzumab tirumotecan plus pembrolizumab and in 60.6% of those assigned to receive chemotherapy plus pembrolizumab. Stomatitis was common with sacituzumab tirumotecan plus pembrolizumab, but the events were predominantly grade 1 or 2. Conclusions Among patients with PD-L1-negative advanced nonsquamous NSCLC without targetable genomic alterations, first-line treatment with sacituzumab tirumotecan plus pembrolizumab led to significantly longer progression-free survival than chemotherapy plus pembrolizumab. (Funded by Sichuan Kelun-Biotech Biopharmaceutical; OptiTROP-Lung06 ClinicalTrials.gov number, NCT06711900.).

Fei Zhou, Xiangjiao Meng, Qingqing Ding, Peng Zhang, Wenhua Liang, Sanxing Guo, Yan Yu, Wenxiu Yao, Yun Fan, Xingxiang Pu, Chunling Liu, Jiuwei Cui, Peng Chen, Hua Zhong, Yongsheng Wang, Zhangzhou Huang, Zhi Xu, Xiaorong Dong, Tienan Yi, Ying Hu, Qiming Wang, Bolin Chen, Hui Wang, Longhua Sun, Lang He, Wei Zheng, Yina Wang, Xiaochen Zhang, Yu Yao, Yongsheng Li, et al.

Leverage2 / 5

Reusable within one subfield (a technique, dataset, or protocol a few groups will adopt).

10% of this desk’s rubric

Magnitude3 / 5

Large gain: roughly 2x, or a clear new state of the art on a hard, unsaturated problem.

20% of this desk’s rubric

Evidence5 / 5

Definitive: phase 3 randomized evidence on hard endpoints, multi-lab replication, or community verification at scale.

32% of this desk’s rubric

Novelty3 / 5

A genuinely new approach to an open problem.

8% of this desk’s rubric

Trajectory2 / 5

Some room to improve with obvious engineering.

5% of this desk’s rubric

Stakes3 / 5

Meaningful benefit to many people within a few years.

25% of this desk’s rubric

• Citations0 (reference 20, via openalex, Oct 27, 2026, 06:17 UTC)

• Reviewed by heuristic-v10 on Oct 27, 2026, 06:17 UTC. Paper type: clinical.
• Categories: Journal Article
• TOP, No.3 in the Medicine edition of October 27, 2026.