Application of pembrolizumab combined with lenvatinib/lenvatinib (Lenvima) in nccRCC

First-line pembrolizumab/lenvatinib continues to produce durable anti-tumor activity and encouraging survival outcomes in patients with advanced non-clear cell renal cell carcinoma (RCC), according to data presented at the 2025 Kidney Cancer Research Summit. Among all evaluable patients who received pembrolizumab/lenvatinib (n=152), the overall response rate (ORR) was 50.6% (95% CI, 42.6%-58.7%), the disease control rate was 82.3% (95% CI, 75.4%-87.9%), and the clinical benefit rate was 71.5% (95% CI-63.8%-78.4%). Data showed that 10.1% of patients had complete remission and 40.5% had partial remission.

The ORR of the study treatment was 53.8% in patients with papillary lesions (n=93), 31.0% in patients with chromophobe histology (n=29), and 66.7% in patients with translocations (n=6). In addition, 50.0% and 77.8% of patients with unclassified (n=20) and other histology (n=9) experienced responses, respectively. Tumor burden was reduced in 88.6% of patients. Additionally, tumor burden was reduced in 91.4% of patients with papillary lesions, 75.9% of patients with chromophobe histology, 95.0% of patients with unclassified disease, 100% of patients with displacement, and 88.9% of patients with other histologies.

The median duration of response (DOR) was 23.5 months (range, 1.5+ to 40.2+). The median progression-free survival (PFS) of the overall population was 17.9 months (95% CI, 15.0-21.1), with the 24-month and 36-month PFS rates of 39% and 26%, respectively. In addition, the median progression-free survival in the nipple subgroup was 17.7 months (95% CI, 13.5-21.1), and the chromophobe subgroup group was 11.3 months (95% CI, 6.7-29.0); in each group, the 24-month PFS rates were 35% and 44%, respectively, and the 36-month progression-free survival rates were 22% and 27%, respectively.

Across the entire population, the median overall survival (OS) with study treatment was 41.5 months (95% CI, 32.8 - not reached [NR]), with 24-month and 36-month OS rates of 67% and 54%, respectively. The median OS of the nipple subgroup was 37.5 months (95% CI, 27.1-NR), and that of the chromophobe subgroup was 37.5 months (95% CI, 27.1-NR).The NR was 21.7-NR; the OS rates in each group were 65% and 69% at 24 months, and 50% and 62% at 36 months, respectively.

After at least 3 years of follow-up, pembrolizumab combined with lenvatinib continues to show durable antitumor activity and promising survival outcomes in the first-line treatment of patients with advanced [non-clear cell] RCC. As of now, this is one of the standards for treating patients with papillary, chromophobe cellor histology that is different from opaque cell[RCC].

In the KEYNOTE-B61 trial (NCT04704219), 158 patients were assigned to receive 400 mg of pembrolizumab intravenously every 6 weeks for up to 18 cycles, plus 20 mg of lenvatinib orally once daily. The primary endpoint of the trial is ORR according to RECIST v1.1 criteria. Secondary endpoints of the trial include DOR, PFS, OS and safety.

Patients 18 years of age and older with histologically confirmed stage IV non-clear cell renal cell carcinoma, measurable disease according to RECIST v1.1 guidelines, a Karnofsky performance status of 70% or greater, and no prior treatment for advanced disease are eligible to participate in the trial. Adequate blood pressure control and normal organ function, with or without antihypertensive medications, were additional requirements for study entry.

The median age of patients was60.0 years (range, 24-87 years). The most common histology was papillary (58.9%), followed by chromophobe (18.4%), unclassified (12.7%), other (5.7%), displaced (3.8%), and medullary (0.6%). Additionally, 12.0% of patients had sarcomatoid features and 63.3% had intermediate or poor International Metastatic Renal Cell Carcinoma Database Consortium risk.

Researchers treated38.6% of the study population with any subsequent treatment. The most common types of subsequent therapy included any VEGF or VEGFR inhibitor (35.4%), any mTOR inhibitor (8.9%), and any PD-(L)1 inhibitor (6.3%).

Adverse reactions (AEs) of any grade occurred in 99.4% of patients, and grade 3 to 5 toxicities occurred in 77.2% of patients. In addition, 31.0% of adverse events led to treatment interruption, 48.1% had serious adverse events, and 6.3% had adverse events leading to death. Treatment-emergent adverse events (TEAEs) of any grade and grade 3 or higher affected 96.2% and 60.1% of patients, respectively, and 58.9% and 10.1% of patients experienced immune-mediated adverse events of any grade, grade 3 or higher. The most common TEAEs include hypertension, diarrhea, hypothyroidism, proteinuria, fatigue, and palmoplantar dysesthesia syndrome. Other TEAEs included nausea (25.3%), weight loss (22.8%), fatigue (22.2%), arthralgia (19.6%), stomatitis (19.6%), mucosal inflammation (15.2%), and pruritus (15.2%).

Reference materials:https://www.targetedonc.com/view/pembrolizumab-plus-lenvatinib-delivers-in-nccrcc