Dr Giannis Mountzios - EVOKE-03/KEYNOTE D46Combination treatment with sacituzumab govitecan (SG) and pembrolizumab has resulted in a numerically longer progression-free survival (PFS) compared with pembrolizumab alone in patients with previously untreated metastatic nonsmall-cell lung cancer (NSCLC), but the difference did not reach statistical significance, according to the phase III EVOKE-03/KEYNOTE D46 study.
“Although SG plus pembrolizumab demonstrated numerically longer PFS vs pembrolizumab monotherapy at PFS primary analysis, the study did not meet its primary endpoint because the difference was not statistically significant,” said study co-author and presenter Dr Giannis Mountzios, Henry Dunant Hospital Center, Athens, Greece, at WCLC 2026.
The median PFS by blinded independent central review was 11.8 months in the SG plus pembrolizumab group compared with 7.7 months in the pembrolizumab monotherapy group (hazard ratio [HR], 0.81, 95 percent confidence interval [CI], 0.66‒1.00; p=0.0252). The PFS rates were 48.3 vs 36.9 months at 12 months and 36.0 vs 29.9 months at 18 months, respectively.
At the interim analysis, the median overall survival (OS) was 21.5 months with the combination therapy vs 22.8 months with monotherapy (HR, 1.07, 95 percent CI, 0.85‒1.35; p=0.7155).
For the secondary efficacy endpoints, the confirmed objective response rate was higher with SG plus pembrolizumab than with pembrolizumab monotherapy (55.6 percent vs 43.7 percent; ~12-percent difference). The disease control rate was 83.3 percent vs 73.1 percent, respectively, and the median duration of response was similar between the two groups (21.4 vs 21.3 months, respectively).
“While the combination of SG and pembrolizumab produced a numerically longer PFS and a higher response rate, EVOKE-03/KEYNOTE-D46 did not meet statistical significance for its primary PFS endpoint, and OS was not significantly improved at this interim analysis,” said Mountzios.
“These findings provide important information as we continue to evaluate treatment strategies for patients with PD-L1-high metastatic NSCLC,” he added. [https://www.iaslc.org/iaslc-news/press-release/sacituzumab-govitecan-plus-pembrolizumab-does-not-meet-primary-endpoints]
Safety outcomes
In terms of safety, treatment-emergent adverse events (TEAEs) occurred in 98.4 percent of patients in the SG plus pembrolizumab group and in 95.1 percent of those in the pembrolizumab monotherapy group. Grade ≥3 TEAEs occurred in 73.6 percent and 45.0 percent of participants, respectively.
The most common TEAE in the combination group was anaemia (n=44), followed by alopecia (n=41), neutropenia (n=40), diarrhoea (n=32), and nausea (n=30). Other recorded AEs included fatigue, leukopenia, decreased appetite, rash, increased alanine aminotransferase, and pruritis.
“The safety profile of SG plus pembrolizumab was consistent with the known profiles of each agent, and no new or additional toxicities were observed with the combination,” Mountzios said.
The open-label phase III EVOKE-03/KEYNOTE-D46 study included a total of 620 patients with untreated metastatic NSCLC, PD-L1 TPS ≥50 percent, and no EGFR, ALK, or ROS1 alterations. Participants were randomly allocated 1:1 to receive SG at 10 mg/kg intravenously (IV) on days 1 and 8 plus pembrolizumab 200 mg IV on day 1 of each 21-day cycle or pembrolizumab alone.
“SG is [a] Trop-2‒directed antibody-drug conjugate with a Topo-1 payload being investigated for metastatic NSCLC in the first-line setting,” Mountzios said. [J Thorac Oncol 2026;21:103509]
“Despite advances with immunotherapy, >50 percent of patients with metastatic NSCLC do not respond to first-line pembrolizumab monotherapy,” he added. [Cancers (Basel) 2024;16:744]