The current standard of care (SoC) for advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) and no actionable driver mutations is first-line monotherapy with an immune checkpoint inhibitor (ICI).

Despite use of ICI-based frontline treatment, “more than half of our patients with metastatic NSCLC do not respond to first-line treatment with pembrolizumab monotherapy, including those with high programmed death ligand 1 (PD-L1) expression,” said Giannis Mountzios, MD, MSc, PhD, Director of the 4th Oncology Clinic and Clinical Studies Clinic at the Henry Dunant Hospital Center, Athens.

During the 2026 World Conference on Lung Cancer, Dr. Mountzios shared the primary results from the phase III EVOKE-03/KEYNOTE D46 trial, comparing sacituzumab govitecan-pembrolizumab combination therapy with pembrolizumab monotherapy in patients with metastatic NSCLC who had not received any systemic treatments in the metastatic setting and had PD-L1 TPS ≥ 50%, and had no actionable alterations in EGFR, ALK, or ROS1.

Presidential Symposium 1

Sacituzumab Govitecan-Pembrolizumab Combination in PD-L1-High NSCLC

Registered WCLC 2026 attendees can watch Presidential Symposium 1 with on-demand access to session recordings via the virtual platform. WATCH NOW

In EVOKE-03, 620 patients were randomized 1:1 to receive either the combination or pembrolizumab alone. The study design split the α value between the coprimary endpoints of progression-free survival (PFS) and overall survival (OS).

Discussant Ji-Youn Han, MD, PhD, from the National Cancer Center in Goyang, Republic of Korea, credited the strong statistical design of the study, noting that use of coprimary PFS and OS endpoints precludes overinterpretation of a PFS-alone benefit in the absence of OS benefit.

Dr. Mountzios said that at a median follow-up of 14.8 and 14.4 months for the combination and pembrolizumab-alone arms, there was no statistically significant difference in PFS between the arms, despite a numerically longer PFS in patients who received the combination (median PFS, 11.8 vs 7.7 months; hazard ratio, 0.81; p=0.0252, and 18-month estimated PFS rates of 36% vs 29.9%). Additionally, sacituzumab govitecan plus pembrolizumab did not improve OS. Median OS was 21.5 months with the combination, compared with 22.8 months with pembrolizumab alone (hazard ratio, 1.07; p=0.7155), he said.

The secondary endpoints of overall response rate (ORR) and disease control rate (DCR) were higher in patients who received the combination than in those who received pembrolizumab monotherapy. The difference in confirmed ORR was around 12% (55.6% vs 43.7%); DCRs were 83.3% and 73.1%. The median duration of response was similar between treatment arms.

Dr. Han contextualized the negative OS findings, pointing out that “pembrolizumab monotherapy has already set a high bar in PD-L1-high metastatic NSCLC.”

He summarized negative OS findings from clinical trials—KEYNOTE-598, LEAP-007, KEYVIBE-003, SKUSCRAPER-01, and CEHM-IO—that evaluated add-on strategies to improve upon the OS benefit with pembrolizumab alone, without success, despite prolonging PFS and/or increasing ORRs.

“The recurring lesson is simple: ORR and PFS are increased [with add-on strategies], but OS is not,” Dr. Han said, adding that the add-on approaches appear to delay progression in patients who eventually progress on pembrolizumab therapy, but the combination therapy does not convert these short-term responses into longer overall survival.

Dr. Han also discussed potential explanations for lack of OS benefit, despite the PFS advantage in EVOKE-003.

Post hoc analysis of OS in the subset of patients enrolled in East Asia, representing more than a third of the entire cohort, indicated improved OS with the combination approach versus pembrolizumab alone; median OS was not reached in the combination arm, compared with 27.9 months in the pembrolizumab-alone arm. Similarly, patients in China also showed an OS benefit, representing half of the East Asian population in the study.

Dr. Han said these post hoc findings from non-prespecified strata are hypothesis-generating and can inform future study designs, including stratification by geographical region to enable comparisons of prespecified subgroups. Subgroup analyses also suggested a numerical trend in improved PFS with the combination, over pembrolizumab alone, in patients with nonsquamous histology.