Phase 3 Trial of Sacituzumab Govitecan Plus Pembrolizumab Stopped Early in First-Line mNSCLC

Merck and Gilead Sciences announced on June 8, 2026, the discontinuation of the Phase 3 KEYNOTE-D46/EVOKE-03 trial (NCT05609968), which was evaluating sacituzumab govitecan-hziy (Trodelvy) in combination with pembrolizumab (Keytruda) vs pembrolizumab monotherapy as first-line treatment for patients with metastatic non–small cell lung cancer (mNSCLC) whose tumors expressed PD-L1 with a tumor proportion score (TPS) ≥50%. The decision followed a recommendation from the external data monitoring committee (eDMC) based on results from the prespecified final analysis of progression-free survival (PFS) and an interim analysis of overall survival (OS).¹

Although a numerical improvement in PFS was observed in the combination arm, it did not reach statistical significance. The eDMC further determined that achieving statistically significant OS at the planned final analysis was unlikely. The safety profile of sacituzumab govitecan in combination with pembrolizumab was consistent with the known profile of each individual agent, and no new safety signals were identified. Full data from the study will be submitted for presentation at a future medical meeting.

Trial Design and Patient Population

KEYNOTE-D46/EVOKE-03 was a global, open-label, randomized phase 3 trial sponsored by Merck. Approximately 620 patients were enrolled at study sites worldwide. Eligible patients had previously untreated mNSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR, ALK, or ROS1 genomic alterations.

Patients were randomized 1:1 to receive either sacituzumab govitecan (10 mg/kg intravenously on days 1 and 8 of a 21-day cycle) plus pembrolizumab (200 mg IV on day 1 of each 21-day cycle), or pembrolizumab monotherapy (200 mg IV on day 1 of each 21-day cycle). Pembrolizumab was administered for up to 35 cycles; sacituzumab govitecan was continued until disease progression, death, unacceptable toxicity, or another discontinuation criterion was met.

The dual primary end points were PFS by blinded independent central review (BICR) per RECIST v1.1 and OS. Secondary end points included objective response rate (ORR), duration of response (DOR), patient-reported outcomes, and safety.

Clinical Context

Lung cancer remains one of the most common malignancies worldwide. According to data from the International Agency for Research on Cancer (IARC), approximately 2.5 million new lung cancer cases were reported globally in 2022.² NSCLC accounts for approximately 80% to 85% of all lung cancers, and nearly half of patients with NSCLC are diagnosed only after distant metastasis has occurred, when treatment options are more limited. The 5-year survival rate for metastatic NSCLC remains below 10%.

Pembrolizumab monotherapy is a standard first-line option for patients with mNSCLC and PD-L1 TPS ≥50% based on data from the KEYNOTE-024 trial, which demonstrated a significant PFS and OS benefit over platinum-based chemotherapy in this biomarker-selected population.³ Despite this advance, a substantial proportion of patients do not achieve durable responses, and new treatment combinations continue to be investigated.

Sacituzumab govitecan is a first-in-class TROP2–directed antibody-drug conjugate (ADC) that delivers SN-38, a topoisomerase I inhibitor, via a proprietary hydrolyzable linker. TROP2 is highly expressed across multiple tumor types, including in more than 90% of breast and lung cancers.¹ The agent is currently approved in more than 60 countries for second-line or later metastatic triple-negative breast cancer (TNBC) and in more than 50 countries for certain patients with pretreated hormone receptor (HR)–positive/HER2-negative metastatic breast cancer. The hypothesis underlying KEYNOTE-D46/EVOKE-03 was that combining TROP2–directed cytotoxic activity with checkpoint inhibition could improve outcomes beyond pembrolizumab alone.

Implications for Practice and Future Development

The negative result from KEYNOTE-D46/EVOKE-03 adds to a growing body of evidence highlighting the complexity of combining ADCs with immune checkpoint inhibitors in first-line lung cancer. The combination did not improve upon what is already an effective single-agent regimen in PD-L1–high mNSCLC.

No changes to ongoing sacituzumab govitecan or pembrolizumab studies are planned as a result of this discontinuation, according to the joint announcement. Sacituzumab govitecan continues to be evaluated in multiple phase 3 trials across tumor types with high TROP2 expression, including earlier lines of treatment for TNBC and HR-positive/HER2-negative breast cancer, as well as in small cell lung cancer and gynecologic cancers. Regulatory authorities have been informed of the trial discontinuation, and investigators are being notified. Patients enrolled in the study are being advised to consult with their treating physicians regarding ongoing care.

Selected Safety Considerations

The known safety profile of sacituzumab govitecan includes a boxed warning for severe, life-threatening, or fatal neutropenia and severe diarrhea. Grade 3–4 neutropenia was observed in approximately 49% of patients in pivotal breast cancer trials, and grade 3 to 4 diarrhea occurred in approximately 11%. Clinicians should also note that patients homozygous for the UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia.

Pembrolizumab carries risks of severe and fatal immune-mediated adverse reactions affecting any organ system, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic reactions, among others. Clinicians are advised to monitor patients closely and initiate appropriate management promptly.

REFERENCES

1. Merck and Gilead Provide Update on Phase 3 KEYNOTE-D46/EVOKE-03 Study. News release. Merck. June 8, 2026. Accessed June 10, 2026. https://tinyurl.com/ytud3vvu

2. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4. PMID: 38572751.

3. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8. PMID: 27718847.