Clinical Summary: 

• Design/Population: The phase 3 EVOKE-03 trial compared first-line sacituzumab govitecan plus pembrolizumab with pembrolizumab alone in patients with untreated metastatic non-small cell lung cancer (NSCLC) with PD-L1 tumor proportion score of at least 50% and no EGFR, ALK, or ROS1 alterations.
• Key Outcomes: Sacituzumab govitecan plus pembrolizumab numerically prolonged progression-free survival (PFS) and produced a higher objective response rate compared with pembrolizumab alone, but the PFS difference did not meet the prespecified threshold for statistical significance. Overall survival (OS) was not improved at the interim analysis.
• Clinical Relevance: These findings do not support adding sacituzumab govitecan to first-line pembrolizumab for patients with PD-L1-high metastatic NSCLC based on the current analysis, as the increased response rate did not translate into a statistically significant PFS or OS benefit and was accompanied by substantially greater treatment-related toxicity.

Results from the phase 3 EVOKE-03/KEYNOTE D46 trial demonstrated that adding sacituzumab govitecan to pembrolizumab did not significantly improve progression-free survival (PFS) compared with pembrolizumab monotherapy in patients with previously untreated, PD-L1–high metastatic non-small cell lung cancer (NSCLC).

These results were presented in a plenary session at the World Conference on Lung Cancer by Giannis Mountzios, MD, MSc, PhD, Henry Dunant Hospital Center, Athens, Greece. 

In this open-label trial, 620 patients with untreated metastatic NSCLC, a PD-L1 tumor proportion score of at least 50%, and no EGFR, ALK, or ROS1 alterations were randomized to receive either sacituzumab govitecan plus pembrolizumab (n = 311) or pembrolizumab alone (n = 309).

Sacituzumab govitecan was administered at 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle, while pembrolizumab was administered at 200 mg intravenously on day 1 of each cycle. Randomization was stratified according to tumor histology, geographic region, and Eastern Cooperative Oncology Group performance status.

The dual primary end points were PFS by blinded independent central review and overall survival (OS). Secondary end points included objective response rate (ORR), duration of response, safety, and patient-reported outcomes.

At a median follow-up of 14.7 months, median PFS was numerically longer with sacituzumab govitecan plus pembrolizumab at 11.8 months compared with 7.7 months with pembrolizumab alone. However, the difference did not meet the study's threshold for statistical significance (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66 to 1.00; P = .0252).

At the interim OS analysis, median OS was 21.5 months with sacituzumab govitecan plus pembrolizumab and 22.8 months with pembrolizumab alone, and the OS end point did not meet statistical significance.

Despite the absence of a significant survival benefit, tumor responses were more frequent with the combination. Confirmed ORR was 56.6% with sacituzumab govitecan plus pembrolizumab compared with 43.7% with pembrolizumab monotherapy.

Treatment-related adverse events occurred in 93.2% of patients receiving sacituzumab govitecan plus pembrolizumab and 65.4% receiving pembrolizumab alone. Grade ≥3 treatment-related adverse events occurred in 55.7% and 16.5% of patients, respectively.

The most common treatment-related toxicities associated with the combination included anemia, alopecia, neutropenia, diarrhea, and nausea. No new or additional safety signals beyond the established profiles of the individual agents were identified.

The findings indicate that the higher response rate observed with sacituzumab govitecan plus pembrolizumab did not translate into a statistically significant PFS advantage over pembrolizumab alone in this biomarker-selected first-line population. Interim OS findings likewise did not demonstrate a survival benefit, while clinically significant treatment-related toxicity was substantially more frequent with the combination.

Source: 

Primary results from phase 3 EVOKE-03/KEYNOTE D46: Sacituzumab govitecan + pembrolizumab in PD-L1 TPS ≥50% metastatic NSCLC. Presented at the World Conference on Lung Cancer; September 12-15, 2026. Seoul, South Korea. Abstract PL02.06.