KEYMAKER-U03 Substudy 03B: Evaluating Pembrolizumab and Targeted Therapy Combinations in Advanced Clear Cell RCC

A phase I/II trial evaluating combination therapies for previously treated advanced clear cell renal cell carcinoma (ccRCC) suggests that the combination of lenvatinib and belzutifan demonstrated promising antitumor activity with a manageable safety profile. The findings are presented by Laurence Albiges, MD, PhD, of Gustave Roussy, at the 2025 ASCO Genitourinary Cancers Symposium.

The KEYMAKER-U03 Substudy 03B aimed to explore targeted therapy–based regimens in patients with locally advanced or metastatic ccRCC who had experienced disease progression during prior treatment with  programmed cell death ligand 1 (PD-L1) inhibitors and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (VEGF-TKIs). Patients were randomly assigned to one of three treatment arms: pembrolizumab plus belzutifan (Arm B4), lenvatinib plus belzutifan (Arm B5), or pembrolizumab plus lenvatinib, which served as the reference arm. The trial’s primary endpoints included safety and objective response rate (ORR) based on RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints included duration of response, clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS).

Among 199 enrolled patients, median follow-up ranged from 16.6 to 19.4 months across treatment arms. The lenvatinib + belzutifan combination (Arm B5) exhibited the highest ORR at 47%, compared with 40% in the pembrolizumab + lenvatinib reference arm and 19% in the pembrolizumab + belzutifan arm. The CBR, which includes complete response, partial response, and stable disease lasting six months or longer, was highest in the lenvatinib + belzutifan arm at 59%, followed by pembrolizumab + lenvatinib at 58% and pembrolizumab + belzutifan at 32%.

In terms of disease progression, the median PFS was 12.5 months in the lenvatinib + belzutifan arm, compared with 9.4 months in the pembrolizumab + lenvatinib arm and 5.4 months in the pembrolizumab + belzutifan arm. At 12 months, the OS rate was 80% for lenvatinib + belzutifan, 82% for pembrolizumab + lenvatinib, and 68% for pembrolizumab + belzutifan. Although the median OS was not reached in the pembrolizumab + lenvatinib arm, the lenvatinib + belzutifan combination demonstrated an OS of 32.3 months, suggesting durable survival benefits in this heavily pretreated population.

Treatment-related adverse events (TRAEs) were consistent with known profiles of the individual drugs. Grade 3-5 TRAEs occurred in 60% of patients in the lenvatinib + belzutifan arm, 49% in the pembrolizumab + lenvatinib arm, and 42% in the pembrolizumab + belzutifan arm. Notably, two patients in the lenvatinib + belzutifan arm experienced fatal TRAEs (cerebral hemorrhage and intracranial hemorrhage), and one patient in the pembrolizumab + lenvatinib arm died of esophageal perforation.

Clinical Implications

The findings from KEYMAKER-U03 Substudy 03B suggest that the lenvatinib + belzutifan combination holds significant promise for patients with previously treated ccRCC, demonstrating the highest response rates and longest PFS among the studied regimens. The study’s investigators noted that these results support further evaluation of this combination, particularly in the ongoing LITESPARK-011 trial, which is specifically investigating lenvatinib and belzutifan in advanced RCC.

Although pembrolizumab + belzutifan showed lower efficacy, the pembrolizumab + lenvatinib arm remained a strong reference treatment option. However, the lenvatinib + belzutifan combination may emerge as an alternative regimen for patients previously treated with immune checkpoint inhibitors and VEGF-TKIs.

Longer follow-up and further studies are needed to assess long-term survival benefits, tolerability, and potential biomarkers that could guide treatment selection in advanced ccRCC.