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

In the first-line treatment of PD-L1-negative advanced non-squamous non-small cell lung cancer (NSCLC), pembrolizumab combined with platinum/pemetrexed chemotherapy has been established as the standard regimen based on the KEYNOTE-189 study ^[2][5], but long-term patient benefit remains limited ^[2]. The combination of antibody-drug conjugates (ADC) with immunotherapy has clear biological rationale: ADCs can induce immunogenic cell death, activate dendritic cells, and promote T-cell infiltration, with potential synergy with immune checkpoint inhibitors ^[1]; meanwhile, transcriptomic and proteomic evidence shows that TROP2 overexpression is significantly associated with primary resistance to PD-L1 blockade therapy and poor prognosis ^[6], suggesting that TROP2-targeted ADCs may overcome this resistance mechanism.

This study (OptiTROP-Lung06, NCT06711900) randomly enrolled 455 patients with previously untreated, actionable driver gene mutation-negative, PD-L1 tumor proportion score <1% locally advanced or metastatic non-squamous NSCLC, who were assigned 1:1 to receive sacituzumab tirumotecan combined with pembrolizumab or chemotherapy combined with pembrolizumab. At a median follow-up of 9.7 months, the median progression-free survival (PFS) in the experimental group reached 15.0 months versus 5.7 months in the control group (hazard ratio 0.49, 95% CI 0.36-0.65, P<0.001); the objective response rates were similar between the two groups (50.2% vs 47.3%), but the duration of response was significantly longer in the experimental group (13.6 months vs 6.8 months). Overall survival (OS) data are still immature, with a hazard ratio of 0.58 (95% CI 0.38-0.88) suggesting a trend toward survival benefit. In terms of safety, the incidence of grade 3 or higher adverse events in the experimental group was 47.6%, lower than 60.6% in the control group; stomatitis was common but predominantly grade 1-2.

These results demonstrate an efficacy magnitude in a biomarker-negative population that surpasses the standard chemoimmunotherapy regimen: the median PFS of chemoimmunotherapy in KEYNOTE-189 was approximately 9 months ^[2][5], whereas PFS in the experimental group of this study doubled, and the hazard ratio of 0.49 outperformed prior dual immunotherapy plus chemotherapy ^[4] or anti-angiogenic therapy combined with immunochemotherapy ^[3] in similar populations. Notably, a phase III study (OptiTROP-Lung05) of the same TROP2 ADC, sacituzumab tirumotecan, is also underway in the PD-L1 high-expression (TPS≥50%) population, exploring its efficacy in combination with pembrolizumab versus immunotherapy alone ^[7][8], suggesting that this drug may achieve coverage of the entire population through biomarker stratification.

Limitations include that this was a prespecified interim analysis, OS is not yet mature, the follow-up duration was relatively short (9.7 months), and the open-label design enrolled only patients with non-squamous histology and no actionable driver genes. Long-term survival benefit, optimal treatment duration, and long-term management of characteristic toxicities (such as stomatitis) still need to be confirmed as subsequent data mature; currently, another maintenance therapy study (NCT06422143) is evaluating the strategy of pembrolizumab with or without sacituzumab tirumotecan maintenance ^[9], which may provide more evidence for clinical decision-making.