Lenvatinib Plus Pembro Remains Frontline Standard in RCC

Adding either belzutifan (Welireg) or the investigational anti–CTLA-4 antibody quavonlimab to first-line pembrolizumab (Keytruda) plus lenvatinib (Lenvima) did not improve progression-free survival (PFS) or overall survival (OS) in patients with advanced clear cell renal cell carcinoma (ccRCC), according to results from the phase 3 LITESPARK-012 trial (NCT04736706) presented at the 2026 European Society for Medical Oncology (ESMO) Congress.¹

At a median of 43.6 months (range, 31.8-57.4) from randomization to data cutoff, median PFS by blinded independent central review (BICR) was 20.8 months (95% CI, 17.9-23.7) with pembrolizumab, lenvatinib, and belzutifan vs 23.7 months (95% CI, 20.7-26.6) with pembrolizumab plus lenvatinib (HR, 1.08; 95% CI, 0.93-1.26; 1-sided P = .8408). The 12-, 24-, and 36-month PFS rates were 66.3%, 45.3%, and 34.7% vs 69.1%, 49.6%, and 36.7%, respectively. PFS results were similar across subgroups, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable (HR, 0.86), intermediate (HR, 1.19), and poor (HR, 1.04) risk.¹

Median OS was 52.0 months (95% CI, 48.0-not reached) with the belzutifan triplet and not reached with the doublet (HR, 1.04; 95% CI, 0.87-1.25; 1-sided P = .6622), with 36-month OS rates of 64.5% and 66.3%.¹

Quavonlimab/pembrolizumab (MK-1308A) plus lenvatinib was tested first in patients with IMDC intermediate- or poor-risk disease. In this group, median PFS was 20.5 months (95% CI, 16.6-23.5) vs 23.5 months (95% CI, 20.6-26.3) with the control regimen (HR, 1.12; 95% CI, 0.94-1.33; 1-sided P = .8954), and median OS was 39.1 vs 46.2 months (HR, 1.17; 95% CI, 0.96-1.42; 1-sided P = .9419). Because this hypothesis was not met, no alpha was allocated to the intention-to-treat analyses, in which the PFS HR was 1.07 (95% CI, 0.92-1.25) and the OS HR was 1.12 (95% CI, 0.94-1.35; nominal 1-sided P = .8955). In the PFS subgroups, results favored the control arm in men (HR, 1.23; 95% CI, 1.03-1.46) but not women (HR, 0.76; 95% CI, 0.56-1.03).¹

The objective response rate (ORR) by BICR was 69.1% with the belzutifan triplet and 69.0% with the quavonlimab regimen vs 76.3% with pembrolizumab plus lenvatinib, with complete responses in 19.1%, 14.8%, and 14.8%. Median duration of response was 26.4, 26.3, and 27.7 months, respectively. In intermediate- or poor-risk disease, the ORR was 66.9% with quavonlimab/pembrolizumab plus lenvatinib vs 75.5% with the doublet.¹

“Neither addition of the HIF-2α inhibitor belzutifan nor the CTLA-4 inhibitor quavonlimab to pembrolizumab plus lenvatinib improved efficacy in participants with previously untreated advanced ccRCC,” said lead author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School in Boston, Massachusetts. “Efficacy and safety of standard-of-care pembrolizumab plus lenvatinib were consistent with prior reports, and this regimen was reinforced as a standard of care in front-line advanced ccRCC.”

Safety of Belzutifan and Quavonlimab Combinations in ccRCC

Grade 3 or higher adverse events (AEs) occurred in 87.2%, 88.7%, and 84.8% of patients in the belzutifan, quavonlimab, and control arms, respectively. AEs led to discontinuation of any study drug in 51.6%, 51.4%, and 36.2% and to death in 7.6%, 9.5%, and 7.8%. Grade 3 or higher treatment-related AEs occurred in 77.5%, 78.3%, and 69.1%.¹

Grade 3 to 5 anemia (23.4% vs 4.1% vs 3.7%) and hypoxia (13.5% vs 0.2% vs 0.4%) were more frequent with belzutifan. Immune-mediated hyperthyroidism (21.7%) and adrenal insufficiency (12.2%) were most common with quavonlimab, and no new safety signals emerged for the coformulation. Hepatotoxicity associated with lenvatinib occurred in 55.9%, 50.4%, and 43.8% of patients, hypertension in 54.5%, 58.8%, and 68.1%, and cardiac dysfunction in 11.9%, 6.5%, and 6.7%.¹

Higher discontinuation rates reduced exposure in the experimental arms. Median duration of pembrolizumab was 14.1 months with the triplet vs 21.2 months with the doublet, and quavonlimab/pembrolizumab was given for a median of 11.8 months. Median lenvatinib duration was 18.1, 15.2, and 22.2 months, respectively, and median belzutifan duration was 18.6 months.¹

LITESPARK-012 Trial Design and Eligibility

Between April 2021 and June 2023, the open-label trial randomly assigned 1688 adults with untreated stage IV ccRCC, a Karnofsky performance status of at least 70%, and measurable disease to pembrolizumab 400 mg every 6 weeks plus lenvatinib 20 mg daily and belzutifan 120 mg daily (n = 560), quavonlimab/pembrolizumab 25 mg/400 mg every 6 weeks plus lenvatinib (n = 562), or pembrolizumab plus lenvatinib (n = 566). Antibody therapy continued for up to 18 cycles. Randomization was stratified by IMDC risk, region, and sarcomatoid features.¹

PFS by BICR per RECIST 1.1 and OS were dual primary end points, and secondary end points included ORR, duration of response, and safety. One-sided type I error was controlled at 2.5% within each comparison.¹

REFERENCE

1. Choueiri TK, Powles TB, Voss MH, et al. First-line pembrolizumab plus lenvatinib plus belzutifan or MK-1308A plus lenvatinib in advanced RCC: randomized open-label phase 3 LITESPARK-012 study. Presented at: ESMO Congress 2026; October 2026; Madrid, Spain. Abstract 3586O.