Combination Therapy Fails to Meet Primary Endpoint in Metastatic NSCLC Study

In a Phase 3 clinical trial, the combination of sacituzumab govitecan (SG) and pembrolizumab did not meet the primary endpoint of statistically significant improvement in progression-free survival (PFS) for patients with metastatic non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of 50% or greater. The results were presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).

The study, known as EVOKE-03/KEYNOTE-D46, enrolled 620 patients who were previously untreated for metastatic NSCLC and had a PD-L1 TPS of at least 50%. Participants were randomly assigned to receive either SG plus pembrolizumab or pembrolizumab alone. The median PFS by blinded independent central review was 11.8 months for the combination group compared to 7.7 months for the pembrolizumab-only group. While the combination showed a numerically longer PFS, the difference did not reach statistical significance.

At the interim analysis, median overall survival was 21.5 months for the SG plus pembrolizumab group and 22.8 months for the pembrolizumab-only group. Overall survival also did not meet statistical significance at this stage.

The confirmed objective response rate was higher with the combination therapy, at 55.6%, compared to 43.7% for pembrolizumab alone. The disease control rate was 83.3% for the combination and 73.1% for pembrolizumab. The median duration of response was 21.4 months for the combination and 21.3 months for pembrolizumab.

Treatment-related adverse events occurred in 93.2% of patients receiving the combination, with 55.7% experiencing grade 3 or higher events. The most common treatment-related adverse events 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.

Dr. Giannis Mountzios, from the Henry Dunant Hospital Center in Athens, Greece, commented, "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 the statistical significance for its primary PFS endpoint. These findings provide important information as we continue to evaluate treatment strategies for patients with PD-L1-high metastatic NSCLC."

The EVOKE-03/KEYNOTE-D46 trial is an open-label Phase 3 study designed to evaluate the efficacy and safety of sacituzumab govitecan plus pembrolizumab compared to pembrolizumab alone in patients with untreated PD-L1-high metastatic NSCLC. The primary endpoints were PFS by blinded independent central review and overall survival.

The International Association for the Study of Lung Cancer (IASLC) is the world's largest organization dedicated solely to the study of lung cancer and other thoracic malignancies. The IASLC hosts the WCLC, which attracts nearly 7,000 researchers, physicians, and specialists from over 100 countries. The conference aims to increase awareness, collaboration, and understanding of lung cancer and to help participants implement the latest developments globally.