Sacituzumab Govitecan Combo Misses PFS End Point in PD-L1–High NSCLC

Updated results from the phase 3 KEYNOTE-D46/EVOKE-03 trial (NCT05609968) show that the combination of sacituzumab govitecan (Trodelvy) and pembrolizumab (Keytruda) did not demonstrate a statistically significant improvement in progression-free survival (PFS) compared with pembrolizumab alone in the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with high PD-L1 expression.¹

The data, presented at the 2026 World Conference on Lung Cancer (WCLC), follow the June 2026 announcement that the trial would be discontinued early after an external data monitoring committee determined that the combination was unlikely to demonstrate a statistically significant overall survival (OS) benefit at the planned final analysis.

Median PFS by blinded independent central review was 11.8 months with the combination vs 7.7 months with pembrolizumab monotherapy (HR, 0.81; 95% CI, 0.66-1.00; P =.0252). Although numerically longer, the improvement did not cross the prespecified threshold for statistical significance.

At interim analysis, there was also no statistically significant difference in OS, with a median OS of 21.5 months with sacituzumab govitecan plus pembrolizumab vs 22.8 months with pembrolizumab alone (HR, 1.07; 95% CI, 0.85-1.35; P =.7155).

"While the combination of sacituzumab govitecan 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 end point, and [OS] was not significantly improved at this interim analysis," Giannis Mountzios, MD, of the Henry Dunant Hospital Center in Athens, Greece, stated in a news release. "These findings provide important information as we continue to evaluate treatment strategies for patients with PD-L1-high metastatic NSCLC."

About the KEYNOTE-D46 Trial

EVOKE-03/KEYNOTE-D46 was an open-label, randomized phase 3 study that enrolled 620 patients with previously untreated metastatic NSCLC, PD-L1 tumor proportion score (TPS) of at least 50%, and no EGFR, ALK, or ROS1 alterations.²

Patients received sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 plus pembrolizumab at 200 mg intravenously on day 1 of each 21-day cycle, or pembrolizumab monotherapy. PFS by blinded independent central review and OS were the dual primary end points.

Response and Safety Findings

Despite the primary end points not being met, the combination produced a numerically higher confirmed objective response rate (ORR) than pembrolizumab alone, at 55.6% vs 43.7%, respectively. Disease control rates were 83.3% and 73.1%, while median duration of response was 21.4 months and 21.3 months, respectively.

Treatment-related adverse events (TRAEs) occurred in 93.2% of patients receiving the combination compared with 65.4% receiving pembrolizumab alone. Grade 3 or higher TRAEs occurred in 55.7% and 16.5% of patients, respectively. The most common TRAEs with the combination were 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 reported.

Clinical Context for Sacituzumab Govitecan

Sacituzumab govitecan is a Trop-2–directed antibody-drug conjugate (ADC) that links a humanized antibody targeting Trop-2 with SN-38, the active metabolite of irinotecan and a topoisomerase I inhibitor. Following binding to Trop-2–expressing cells, the ADC is internalized and SN-38 is released, resulting in DNA damage and cell death.

The agent has an established role in breast cancer, with FDA approvals in several metastatic triple-negative breast cancer (TNBC) and hormone receptor–positive, HER2-negative breast cancer settings. More recently, the FDA approved sacituzumab govitecan in combination with pembrolizumab for the first-line treatment of patients with PD-L1–positive, unresectable locally advanced or metastatic TNBC.³ Its investigation in NSCLC has centered in part on Trop-2 expression, which is prevalent in lung tumors, and the potential to pair the ADC's cytotoxic payload with immune checkpoint inhibition.

REFERENCES

1. Sacituzumab Govitecan Plus Pembrolizumab Does Not Meet Primary Endpoints in First-Line PD-L1-High Metastatic NSCLC. News release. International Association for the Study of Lung Cancer. September 13, 2026. Accessed September 15, 2026. https://tinyurl.com/3pz5k7re

2. Study of Pembrolizumab (MK-3475) Monotherapy Versus Sacituzumab Govitecan in Combination With Pembrolizumab for Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥50% (MK-3475-D46). ClinicalTrials.gov. Updated December 24, 2025. Accessed September 15, 2026. https://clinicaltrials.gov/study/NCT05609968

3. FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line treatment of triple-negative breast cancer. News release. US FDA. June 24, 2026. Accessed September 15, 2026. https://tinyurl.com/3n8bk44p