Triplet Therapy in RCC Falls Short in PFS, OS

The phase 3 LITESPARK-012 trial (NCT04736706) evaluating triplet regimens for the first-line treatment of advanced renal cell carcinoma (RCC) did not meet its primary end points of progression-free survival (PFS) or overall survival (OS). This randomized, open-label study investigated whether adding the HIF-2α inhibitor belzutifan (Welireg) or the CTLA-4 inhibitor quavonlimab to the standard pembrolizumab (Keytruda) and lenvatinib (Lenvima) doublet could improve clinical outcomes for patients with advanced clear-cell disease. According to a release from the manufacturers, neither triplet combination demonstrated a statistically significant benefit over the established doublet control.¹

Study Design

The trial design randomly assigned 1688 adults across 3 distinct arms to compare efficacy and safety.² Arm A evaluated a triplet of 120 mg of belzutifan daily with 400 mg of pembrolizumab every 6 weeks and 20 mg of lenvatinib daily. Arm B tested a coformulated regimen of 25 mg of quavonlimab and 400 mg of pembrolizumab every 6 weeks combined with 20 mg of lenvatinib daily. These experimental arms were measured against Arm C, the control group receiving the standard combination of 400 mg of pembrolizumab every 6 weeks and 20 mg of lenvatinib daily.²

The combination of pembrolizumab plus lenvatinib was previously investigated in RCC in the CLEAR/KEYNOTE-581 trial (NCT02811861) and is included as the control arm in LITESPARK-012, albeit with a modified dosing schedule for pembrolizumab.

Secondary end points, which compared both arm A and arm B against the control, focused on objective response rate (ORR) and duration of response (DOR) as determined by blinded independent central review using RECIST v1.1 criteria. ORR was defined as the proportion of patients achieving a best overall response of complete or partial response. DOR tracked the interval from the first documented response until disease progression or death. Investigators also monitored safety and tolerability, specifically tracking adverse events and the rate of study discontinuation resulting from such events.²

The study further explored patient-centric and pharmacokinetic data through several exploratory end points. Health-related quality of life and health utility were assessed using the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-5L instruments. Additionally, researchers performed pharmacokinetic analyses for belzutifan and quavonlimab alongside biomarker evaluations. These included blood and tumor sample analyses to investigate cellular components, circulating molecules, and germline genetic markers.

Reflecting on the findings, M. Catherine Pietanza, MD, vice president of global clinical development at Merck Research Laboratories, noted that “the study explored whether combining therapies with established activity could improve upon standards set by pembrolizumab-based regimens. While the regimens did not yield the hoped-for results, the data deepen the clinical understanding of advanced renal cell carcinoma and will help shape the next generation of treatment approaches for the oncology community.”¹

The sponsors and investigators plan to share the full results of an ongoing evaluation of the trial at a later date.

Despite the outcome of LITESPARK-012, the results do not impact other ongoing trials within the LITESPARK clinical program. Specifically, the FDA has accepted 2 supplemental new drug applications for review based on the separate phase 3 LITESPARK-011 (NCT04586231) trial.³ That study evaluates the combination of belzutifan and lenvatinib for certain previously treated patients with advanced disease. The FDA has set a Prescription Drug User Fee Act target action date of October 4, 2026, for that application.³

REFERENCES

1. Merck and Eisai Provide Update on Phase 3 LITESPARK-012 Trial Evaluating First-Line Combination Treatments for Certain Patients With Advanced Renal Cell Carcinoma (RCC). News release. Merck. April 21, 2026. Accessed April 21, 2026. https://tinyurl.com/hh4m7yse

2. Choueiri TK, Powles T, Voss MH, et al. LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Future Oncol. 2023;19(40):2631-2640. doi:10.2217/fon-2023-0283]

3. U.S. FDA has accepted for review two supplemental New Drug Applications for WELIREG plus LENVIMA in certain previously treated patients with advanced RCC. News release. Merck. February 28, 2026. Accessed April 21, 2026. https://tinyurl.com/yxsakjw2