Sacituzumab govitecan combination misses progression-free survival endpoint in metastatic NSCLC

Sacituzumab govitecan (SG) plus pembrolizumab did not demonstrate a statistically significant improvement in progression-free survival compared with pembrolizumab alone as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) and PD-L1 tumor proportion score (TPS) of 50% or greater, according to primary results from the Phase 3 EVOKE-03/KEYNOTE-D46 trial presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).

In the study, median progression-free survival (PFS) by blinded independent central review was 11.8 months with SG plus pembrolizumab compared with 7.7 months with pembrolizumab alone (HR, 0.81; 95% CI, 0.66-1.00; P=0.0252). Although PFS was numerically longer with the combination, the result did not meet the prespecified threshold for statistical significance. At the interim analysis, median overall survival was 21.5 months with SG plus pembrolizumab and 22.8 months with pembrolizumab alone (HR, 1.07; 95% CI, 0.85-1.35; P=0.7155).

While the combination of sacituzumab govitecan and pembrolizumab produced a numerically longer progression-free survival and a higher response rate, EVOKE-03/KEYNOTE-D46 did not meet statistical significance for its primary PFS endpoint, and overall survival was not significantly improved at this interim analysis. These findings provide important information as we continue to evaluate treatment strategies for patients with PD-L1-high metastatic NSCLC.”

Giannis Mountzios, M.D., of the Henry Dunant Hospital Center, Athens, Greece

EVOKE-03/KEYNOTE-D46 is an open-label Phase 3 study that enrolled 620 patients with previously untreated metastatic NSCLC, PD-L1 TPS of at least 50%, and no EGFR, ALK or ROS1 alterations. Participants were randomized to receive SG at 10 mg/kg intravenously on days 1 and 8 plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle, or pembrolizumab alone. The dual primary endpoints were PFS by blinded independent central review and overall survival.

The confirmed objective response rate was higher with SG plus pembrolizumab than with pembrolizumab alone. The abstract reports an objective response rate of 55.6% for the combination and 43.7% for pembrolizumab alone. The disease control rate reported in the study table was 83.3% versus 73.1%, respectively, and median duration of response was 21.4 months versus 21.3 months.

Treatment-related adverse events occurred in 93.2% of patients receiving SG plus pembrolizumab and 65.4% of those receiving pembrolizumab alone. Grade 3 or higher treatment-related adverse events occurred in 55.7% and 16.5% of patients, respectively. The most common treatment-related adverse events in the combination arm included anemia, alopecia, neutropenia, diarrhea and nausea. The safety profile was consistent with the known profiles of the individual agents, with no new or additional toxicities observed with the combination.

Dr. Mountzios concluded that, despite a numerical improvement in PFS and a higher response rate, SG plus pembrolizumab did not meet statistical significance for PFS compared with pembrolizumab monotherapy in patients with untreated PD-L1-high metastatic NSCLC Overall survival also did not meet statistical significance at the interim analysis.