Pembrolizumab-Based Combinations Miss the Mark in Frontline ccRCC

The triplet regimen of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) and belzutifan (Welireg), as well as a regimen of coformulated pembrolizumab and quavonlimab (MK-1308A) combined with lenvatinib, did not improve progression-free survival (PFS) or overall survival (OS) vs pembrolizumab plus lenvatinib in patients with treatment-naive, advanced clear cell renal cell carcinoma (ccRCC), missing the dual primary end points of the phase 3 LITESPARK-012 trial (NCT04736706).¹

Data from the prespecified interim analysis of LITESPARK-012 also showed that the safety profiles of the combinations were consistent with those observed in previously reported studies of the individual agents.

“With the LITESPARK-012 trial, we explored whether combining therapies with established activity could improve upon well-established standards set by [pembrolizumab]-based regimens, reflecting our commitment to continuously explore ways to improve outcomes for the kidney cancer community,” M. Catherine Pietanza, MD, the vice president of global clinical development at Merck Research Laboratories, stated in a news release. “While these regimens did not demonstrate the results we hoped, the data deepen our understanding of advanced RCC and will help shape the next generation of treatment approaches.”

How was LITESPARK-012 designed?

LITESPARK-012 was an open-label, randomized study that enrolled adult patients with advanced ccRCC who had not received prior systemic therapy for advanced disease.² Patients were also required to have adequately controlled blood pressure with or without antihypertensive medications and adequate organ function; those receiving bone resorptive therapy must have therapy initiated at least 2 weeks prior to random assignment.

Patients were randomly assigned to receive pembrolizumab plus belzutifan and lenvatinib; pembrolizumab/quavonlimab plus lenvatinib; or pembrolizumab plus lenvatinib. Pembrolizumab was administered at 400 mg every 6 weeks for up to 18 administrations; belzutifan and lenvatinib were given orally once daily until disease progression or discontinuation at 120 mg and 20 mg, respectively. The combination of pembrolizumab/quavonlimab consisted of 400 mg of pembrolizumab and 25 mg of quavonlimab, given once every 6 weeks.

The primary end points were PFS and OS. Secondary end points included objective response rate and duration of response per RECIST 1.1 criteria per blinded independent central review, as well as safety.

What are the next steps for LITESPARK-012?

Results from the LITESPARK-012 trial do not affect other ongoing studies from the LITESPARK clinical program, including those conducted jointly with Eisai, according to Merck.¹ A full evaluation of the data from LITESPARK-012 is ongoing, and Merck and Eisai plan to work with investigators to share the results with the scientific community.

“While we are disappointed that LITESPARK-012 did not meet its primary end points, the findings reinforce the central role of [pembrolizumab] plus [lenvatinib] in the first-line treatment of patients with advanced RCC,” Corina Dutcus, MD, the senior vice president and oncology global clinical development lead at Eisai Inc, added in the news release.¹ “Findings from trials such as this play an important role in shaping health care providers’ perspectives as the treatment paradigm for advanced RCC continues to evolve. We are committed to advancing the care of people living with this disease, and we are grateful to the patients, caregivers, and investigators whose participation and dedication made this research possible.”

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. Updated April 21, 2026. https://www.merck.com/news/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/
2. A study of pembrolizumab (MK-3475) in combination with belzutifan (MK-6482) and lenvatinib (MK-7902), or pembrolizumab/​quavonlimab (MK-1308A) in combination with lenvatinib, versus pembrolizumab and lenvatinib, for treatment of advanced clear cell renal cell carcinoma (MK-6482-012). ClinicalTrials.gov. Updated November 18, 2024. Accessed April 21, 2026. https://clinicaltrials.gov/study/NCT04736706