Sacituzumab Tirumotecan Plus Pembrolizumab in PD-L1-Positive NSCLC

Key Takeaways

• Progression-free survival favored the combination on hazard ratio analysis at the prespecified interim review.
• The progression-free survival advantage was reported as broadly consistent across PD-L1 tumor proportion score subgroups.
• Grade 3 or higher treatment-emergent adverse events were more common with the combination, and the trial remains ongoing for final analysis.

In the interim phase 3 OptiTROP-Lung05 readout, median progression-free survival was not reached with the combination and was 5.7 months with pembrolizumab alone. The study enrolled patients with PD-L1-positive, locally advanced or metastatic NSCLC and no targetable genomic alterations. This first-line comparison paired sacituzumab tirumotecan with pembrolizumab against pembrolizumab alone in a randomized, open-label phase 3 trial. The findings came from a prespecified interim review rather than the completed trial analysis. Grade 3 or higher treatment-emergent adverse events were more common with the combination at this interim analysis.

OptiTROP-Lung05 was a randomized, open-label, phase 3 trial across 68 hospitals in China in locally advanced or metastatic NSCLC with PD-L1 tumor proportion score at least 1%. Eligible patients also had no targetable genomic alterations, and 741 were screened before 413 were randomly assigned. Patients were assigned 1:1 to sacituzumab tirumotecan plus pembrolizumab or pembrolizumab alone, with 208 and 205 patients allocated to the two groups. Sacituzumab tirumotecan was given at 4 mg/kg on days 1, 15, and 29 plus pembrolizumab 400 mg fixed dose on day 1, while the control group received pembrolizumab 400 mg fixed dose on day 1 alone. Both regimens were given intravenously every 6 weeks, and the primary endpoint was progression-free survival by blinded independent central review in the intention-to-treat population.

After a median follow-up of 10.5 months, the stratified hazard ratio for progression-free survival was 0.35, with a 95% confidence interval of 0.26 to 0.47. The p value was less than 0.0001, and the follow-up interquartile range was 8.7 to 12.5 months. Benefit was described as broadly consistent across PD-L1 tumor proportion score groups, with hazard ratios of 0.28 for TPS 1% to 49% and 0.47 for TPS 50% or greater. This pattern was seen across both lower and higher PD-L1 expression strata in the interim dataset. At this analysis, the efficacy findings were limited to progression-free survival outcomes.

Grade 3 or higher treatment-emergent adverse events occurred in 115 of 208 patients, or 55%, with the combination and 64 of 204, or 31%, with pembrolizumab alone. Recruitment was complete at the time of the interim analysis, but the trial remained ongoing. Investigators wrote that the regimen could have the potential to reshape first-line treatment, although that framing came before final analysis. Ongoing follow-up will determine how these interim findings compare with the trial's pending final results.