RAHWAY, N.J. and FOSTER CITY, Calif., June 8, 2026
Merck (NYSE: MRK) and Gilead Sciences (Nasdaq: GILD) announced the discontinuation of the Phase 3 KEYNOTE-D46/EVOKE-03 study evaluating Trodelvy (sacituzumab govitecan-hziy) in combination with KEYTRUDA (pembrolizumab) versus KEYTRUDA monotherapy in previously untreated PD-L1 high metastatic non-small cell lung cancer (NSCLC). The decision followed a recommendation from the independent Data Monitoring Committee (DMC) after review of the final progression-free survival (PFS) analysis and interim overall survival (OS) data, which indicated that the study was unlikely to meet its primary endpoints at final analysis despite ongoing safety monitoring showing no new concerns
Study Discontinuation Decision and Data Review
The external Data Monitoring Committee (eDMC) concluded that continuing the trial was unlikely to change the overall outcome, leading to the recommendation to stop the study early. While investigators observed a numerical improvement in progression-free survival (PFS) in the combination arm, the benefit did not achieve statistical significance, weakening the clinical justification for continuation. Additionally, the probability of achieving meaningful improvement in overall survival (OS) at final analysis was assessed as low based on current trends. The companies confirmed that regulatory authorities have been informed and that investigators will communicate with enrolled patients regarding treatment continuation decisions. Importantly, Merck and Gilead emphasized that there are no changes to other ongoing clinical trials involving either Trodelvy or KEYTRUDA, indicating that the decision is limited to this specific combination in this indication and does not impact broader development programs.
Clinical Results and Efficacy Findings
The Phase 3 KEYNOTE-D46/EVOKE-03 study enrolled approximately 620 patients with previously untreated metastatic NSCLC whose tumors expressed PD-L1 TPS ≥50% and lacked EGFR, ALK, or ROS1 alterations. Patients were randomized to receive either Trodelvy plus KEYTRUDA or KEYTRUDA alone, with dual primary endpoints of PFS and OS. Despite the biological rationale for combining a Trop-2 directed antibody-drug conjugate (ADC) with PD-1 blockade, the observed efficacy signal was insufficient to demonstrate a statistically robust advantage over standard immunotherapy. The data suggest that while combination strategies remain scientifically attractive in oncology, tumor biology in high PD-L1 NSCLC may already be maximally responsive to checkpoint inhibition alone in many patients, limiting incremental benefit from adding cytotoxic payload delivery approaches such as SN-38-based ADC therapy.
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Safety Profile and Clinical Tolerability
From a safety perspective, the combination of Trodelvy and KEYTRUDA demonstrated a profile consistent with known risks of each agent, without emergence of unexpected toxicities or new safety signals. Reported adverse events aligned with established class effects of ADC therapy and immune checkpoint inhibition, including manageable hematologic and gastrointestinal events typical of Trodelvy and immune-related effects associated with pembrolizumab. Investigators confirmed that the safety data did not contribute to the decision to discontinue the study; instead, the decision was driven purely by lack of sufficient efficacy benefit. This reinforces a key theme in modern oncology development: acceptable safety alone is not sufficient for continuation when survival benefit is uncertain or unlikely, particularly in competitive frontline NSCLC treatment landscapes where single-agent immunotherapy already delivers durable responses in a subset of patients.
Implications for NSCLC Treatment and Pipeline Strategy
The outcome of KEYNOTE-D46/EVOKE-03 highlights the continued challenge of improving first-line outcomes in metastatic non-small cell lung cancer (mNSCLC), a disease where fewer than 10% of patients survive beyond five years despite advances in immunotherapy. While KEYTRUDA remains a cornerstone therapy, the failure of this combination to demonstrate superiority underscores the difficulty of enhancing efficacy in high PD-L1 populations. For Gilead, the result provides important directional insight for Trodelvy’s role beyond breast cancer, particularly in lung cancer settings where combination strategies must demonstrate clear survival advantage. Both companies reaffirmed ongoing commitment to broader oncology pipelines, including continued exploration of Trop-2 ADC combinations, biomarker-driven strategies, and alternative tumor types, suggesting a shift toward more selective patient stratification and rational combination design rather than broad immunotherapy pairing approaches.
Source: Gilead Sciences press release
