KEYNOTE-D46 Trial Is Discontinued With Sacituzumab Govitecan Plus Pembrolizumab in PD-L1–High NSCLC

The phase 3 KEYNOTE-D46/EVOKE-03 trial (NCT05609968) has been discontinued following a recommendation from the external Data Monitoring Committee (EDMC). The trial, which had been evaluating the combination of sacituzumab govitecan-hziy (Trodelvy) and pembrolizumab (Keytruda) vs pembrolizumab monotherapy in patients with treatment-naive metastatic non–small cell lung cancer (NSCLC), whose tumors expressed PD-L1 with a tumor proportion score (TPS) of 50% or greater, was discontinued because of data from the prespecified final analysis of progression-free survival (PFS) and interim analysis of overall survival (OS).¹

What did the data monitoring committee find?

The combination failed to deliver a statistically significant improvement in progression-free survival (PFS) vs single-agent pembrolizumab, although numerical benefit was seen. Moreover, the EDMC determined that the likelihood of the combination resulting in a statistically significant OS advantage vs pembrolizumab alone at the planned final analysis was low.

The adverse effects seen with the combination mirrored the profiles of the individual agents, and no new safety signals were reported with the combination. The data will be presented at an upcoming scientific meeting.

How was the KEYNOTE-D46/EVOKE-03 trial designed?

The KEYNOTE-D46/EVOKE-03 study is a global, open-label, randomized phase 3 trial that was designed to compare the efficacy and safety of sacituzumab govitecan plus pembrolizumab with pembrolizumab alone.^1,2 The target population consisted of 620 patients with previously untreated metastatic NSCLC whose tumors express PD-L1 with a TPS of 50% or greater, without sensitizing EGFR, ALK, or ROS1 alterations.

Specific eligibility criteria included a histologically or cytologically confirmed diagnosis of metastatic NSCLC; confirmation that EGFR, ALK1, or ROS1-directed therapy is not suitable for primary therapy; availability of centrally tested tumor tissue demonstrating the presence of PD-L1 TPS of at least 50% on tumor cells via immunohistochemistry (IHC); and life expectancy of at least 3 months.

Patients were randomly assigned 1:1 to receive either intravenous (IV) sacituzumab govitecan at 10 mg/kg on days 1 and 8 of a 21-day cycle plus IV pembrolizumab at 200 mg on day 1 of a 21-day cycle, or IV pembrolizumab at 200 mg alone on day 1 of a 21-day cycle. Pembrolizumab was given for a maximum of 35 cycles, and sacituzumab govitecan was continued until disease progression, death, unacceptable toxicity, or another treatment discontinuation criterion was met.

The dual primary end points of the study are blinded independent central review–assessed PFS according to RECIST 1.1 criteria and OS. Secondary end points include objective response rate, duration of response, patient-reported outcomes, and safety.

What happens next for patients and investigators following the trial closure?

The company has alerted regulatory authorities and will give notice to study investigators of the decision. Patients included in the study are being advised to discuss treatment with their physician.

References

1. Merck and Gilead provide update on phase 3 KEYNOTE-D46/EVOKE-03 study. News release. Merck. June 8, 2026. Accessed June 9, 2026. https://www.merck.com/news/merck-and-gilead-provide-update-on-phase-3-keynote-d46-evoke-03-study/
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 June 9, 2026. https://clinicaltrials.gov/study/NCT05609968