Merck and Gilead discontinued the Phase 3 KEYNOTE-D46/EVOKE-03 trial after Trodelvy plus KEYTRUDA failed to achieve a statistically significant progression-free survival benefit in first-line metastatic NSCLC.
Written By: Disha Jadhao, BPharm
Reviewed By: Pharmacally Editorial Team
Merck and Gilead Sciences have discontinued the Phase 3 KEYNOTE-D46/EVOKE-03 study (NCT05609968) evaluating Trodelvy (sacituzumab govitecan-hziy) in combination with KEYTRUDA (pembrolizumab) as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 with a tumor proportion score (TPS) of at least 50%.
The decision followed a review by the study’s external Data Monitoring Committee (eDMC) of the pre-specified final analysis of progression-free survival (PFS) and an interim analysis of overall survival (OS).
Endpoints and Futility Assessment
The combination showed a numerical improvement in PFS compared with KEYTRUDA monotherapy but failed to achieve statistical significance on one of the study’s dual primary endpoints.
The eDMC also determined that the likelihood of achieving a statistically significant overall survival benefit at the planned final analysis was low, supporting a recommendation to discontinue the study. Regulatory authorities have been informed, and investigators will discuss treatment options with enrolled participants.
Trodelvy’s Mechanism and Rationale
Trodelvy is a Trop-2-directed antibody-drug conjugate (ADC) that delivers SN-38, a topoisomerase I inhibitor, directly to tumor cells. Trop-2 is highly expressed in many epithelial tumors, including most NSCLC cases, supporting its development across multiple solid tumor types.
Lung cancer remains the most commonly diagnosed cancer worldwide, with NSCLC accounting for approximately 80% to 85% of cases. Although immune checkpoint inhibitors have improved outcomes, many patients with metastatic disease eventually experience progression, highlighting the need for more effective treatment approaches.
Study Design and Patient Population
The global, open-label Phase 3 trial enrolled approximately 620 patients with previously untreated metastatic NSCLC lacking sensitizing EGFR, ALK, or ROS1 alterations.
Participants were randomized 1:1 to receive either Trodelvy plus KEYTRUDA or KEYTRUDA alone. Trodelvy was administered at 10 mg/kg intravenously on Days 1 and 8 of each 21-day cycle alongside KEYTRUDA 200 mg on Day 1.
The dual primary endpoints were PFS, assessed by blinded independent central review, and OS. Secondary endpoints included objective response rate, duration of response, patient-reported outcomes, and safety.
Safety Profile Remained Consistent
The safety profile of the combination was consistent with the established profiles of both therapies. No new safety signals were identified, indicating that efficacy rather than tolerability drove the study outcome.
Strategic Implications and Next Steps
The discontinuation applies only to KEYNOTE-D46/EVOKE-03, while other Trodelvy studies and Merck-sponsored programs remain unchanged.
For Gilead, the result represents a setback in efforts to expand Trodelvy beyond its approved breast cancer indications and into first-line metastatic NSCLC. The ADC remains approved in more than 60 countries for metastatic triple-negative breast cancer and in more than 50 countries for certain patients with HR-positive/HER2-negative metastatic breast cancer.
The outcome also highlights the challenge of improving on pembrolizumab monotherapy in patients with high PD-L1 expression, where the standard of care already delivers substantial clinical benefit. Despite this setback, Trodelvy continues to be evaluated across breast, gynecologic, and other solid tumor settings, while Merck continues to advance multiple KEYTRUDA-based combination studies in lung cancer.
Detailed results from KEYNOTE-D46/EVOKE-03 will be presented at a future medical meeting.
Reference
Merck and Gilead Provide Update on Phase 3 KEYNOTE-D46/EVOKE-03 Study – Merck.com
Gilead Sciences, Inc. – Merck and Gilead Provide Update on Phase 3 KEYNOTE-D46/EVOKE-03 Study