Medically 3D illustration showing a tumor in right kidney, x-ray style: ©peterschreiber.media – stock.adobe.com
Frontline pembrolizumab (Keytruda)/lenvatinib (Lenvima) continued to produce durable antitumor activity and delivered 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 complete responses in 10.1% of patients and partial responses in 40.5%.
The study treatment yielded an ORR of 53.8% in patients with papillary disease (n = 93), 31.0% in those with chromophobe histology (n = 29), and 66.7% in those with translocations (n = 6). Additionally, 50.0% and 77.8% of patients with unclassified (n = 20) and other histology (n = 9), respectively, experienced a response.
Any reduction in tumor burden occurred in 88.6% of all patients. Moreover, tumor burden reductions were observed in 91.4% of those with papillary disease, 75.9% of those with chromophobe histology, 95.0% of those with unclassified disease, 100% of those with translocations, and 88.9% of those with other histologies.
The median duration of response (DOR) was 23.5 months (range, 1.5+ to 40.2+). T he median progression-free survival (PFS) was 17.9 months (95% CI, 15.0-21.1) across the overall population, which included a PFS rate of 39% at 24 months and 26% at 36 months. Additionally, the median PFS was 17.7 months (95% CI, 13.5–21.1) in the papillary subgroup and 11.3 months (95% CI, 6.7–29.0) in the chromophobe subgroup; in each respective group, the 24-month PFS rate was 35% and 44%, and the 36-month rate was 22% and 27%.
Across the overall population, the study treatment produced a median overall survival (OS) of 41.5 months (95% CI, 32.8–not reached [NR]), with OS rates of 67% and 54% at 24 months and 36 months, respectively. The median OS was 37.5 months (95% CI, 27.1–NR) in the papillary subgroup and NR (95% CI, 21.7–NR) in the chromophobe subgroup; the OS rates in each group were 65% vs 69% at 24 months, and the rates were 50% and 62% at 36 months.
Laurence Albiges, MD, PhD
“After a minimum of 3 years of follow-up, pembrolizumab plus lenvatinib continued to show durable antitumor activity and promising survival outcomes in the first-line setting for [patients with] advanced [non–clear cell] RCC,” lead study author Laurence Albiges, MD, PhD, said in the presentation.1 “As of now, this is one of our standards of care to treat patients, including papillary, chromophobe, or different histologies than nonclear cell [RCC]. We’re excited that this has changed the paradigm for our patients.”
Albiges is head of the Department of Medical Oncology at Institut Gustave Roussy, Villejuif, France.
In KEYNOTE-B61 trial (NCT04704219), 158 patients were assigned to receive pembrolizumab at 400 mg intravenously every 6 weeks for a maximum of 18 cycles plus lenvatinib at 20 mg orally once daily. The trial’s primary end point was ORR per RECIST v1.1 criteria. The trial’s secondary end points included DOR, PFS, OS, and safety.
Patients aged 18 years and older with histologically confirmed stage IV non–clear cell RCC, measurable disease per RECIST v1.1 guidelines, a Karnofsky performance status of 70% or higher, and no prior therapy for advanced disease were eligible for enrollment on the trial. Having adequately controlled blood pressure with or without antihypertensive medications as well as adequate organ function were additional requirements for study entry.2
The median patient age was 60.0 years (range, 24–87). The most common histology was papillary (58.9%), followed by chromophobe (18.4%), unclassified (12.7%), other (5.7%), translocated (3.8%), and medullary (0.6%). Additionally, 12.0% of patients had sarcomatoid features, and 63.3% had an intermediate or poor International Metastatic RCC Database Consortium risk.
Investigators administered any subsequent therapy to 38.6% of the study population. The most common types of subsequent treatment included any VEGF or VEGFR inhibitor (35.4%), any mTOR inhibitor (8.9%), and any PD-(L)1 inhibitor (6.3%).
Any-grade adverse effects (AEs) affected 99.4% of patients, and 77.2% experienced grade 3 to 5 toxicities. Additionally, 31.0% of AEs resulted in treatment discontinuation, 48.1% had serious AEs, and 6.3% had AEs leading to death. Any-grade and grade 3 or higher treatment-emergent AEs (TEAEs) affected 96.2% and 60.1% of patients, respectively, and any-grade and grade 3 or higher immune-mediated AEs occurred in 58.9% and 10.1%. T he most common TEAEs included hypertension (57.6%), diarrhea (50.0%), hypothyroidism (41.1%), proteinuria (34.2%), fatigue (31.0%), and palmar-plantar erythrodysesthesia syndrome (30.4%). Other TEAEs included nausea (25.3%), decreased weight (22.8%), asthenia (22.2%), arthralgia (19.6%), stomatitis (19.6%), mucosal inflammation (15.2%), and pruritus (15.2%).