The phase II KEYNOTE-B61 study is the largest clinical trial to date to investigate an immune checkpoint inhibitor (ICI) combination in patients with previously untreated non-clear-cell renal cell carcinoma (RCC) and is one of the largest to investigate any agent in this population. The results show that first-line treatment with pembrolizumab plus lenvatinib has promising antitumour activity, with 49% of patients having an objective response. Responses were durable, and although median duration of response was not reached, approximately 75% of responders remained in response for at least 12 months. Survival outcomes were also promising, with a 12-month progression-free survival (PFS) of 63% and a 12-month overall survival (OS) of 82%.

The activity of pembrolizumab plus lenvatinib was also generally consistent across subgroups, including by histological subtype, International Metastatic RCC Database Consortium risk category, and the presence or absence of sarcomatoid features. The findings are published by Prof. Laurence Albiges of Gustave Roussy, Paris-Saclay University in Villejuif, France, and colleagues on 11 July 2023 in The Lancet Oncology.

Non-clear-cell RCC accounts for approximately 25% of all RCC cases, encompassing various heterogenous histological subtypes, including papillary, chromophobe, and translocation RCC. Phase III clinical studies investigating treatments for advanced RCC have primarily been conducted in patients with clear cell histology due to its higher prevalence. The authors wrote in the background that therapeutics evaluated in patients with non-clear-cell RCC, such as mTOR inhibitors, tyrosine kinase inhibitors (TKIs), and ICIs, have either not notably improved outcomes or have not yet been established as standards of care and enrolment of these patients in clinical trials is strongly recommended.

In cohort B of the phase II KEYNOTE-427 study, pembrolizumab was shown to have promising antitumour activity in patients with previously untreated, advanced non-clear-cell RCC and a safety profile like that observed in other tumour types. Lenvatinib is a multitargeted TKI with immunomodulating activity approved for use in combination with the mTOR inhibitor everolimus for the treatment of advanced RCC following previous antiangiogenic therapy and in combination with pembrolizumab for the first-line treatment of advanced RCC. The approval of lenvatinib was based on the results of the phase III CLEAR/KEYNOTE-581/E7080-G000-307 study, in which the combination of pembrolizumab plus lenvatinib significantly prolonged PFS and OS compared with sunitinib in patients with previously untreated clear-cell RCC.

Based on the observed benefits of pembrolizumab plus lenvatinib in the CLEAR/KEYNOTE-581/E7080-G000-307 study, the KEYNOTE-B61 study investigators aimed to investigate the activity and safety of first-line treatment with pembrolizumab plus lenvatinib in patients with advanced non-clear-cell RCC. KEYNOTE-B61 is a single-arm, phase II study conducted at 48 hospitals and cancer centres in 14 countries. Adult patients (aged ≥18 years) with previously untreated stage IV non-clear-cell RCC and a Karnofsky performance status of 70% or higher were eligible for enrolment. All enroled patients received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (2 years) plus lenvatinib 20 mg orally once daily or until disease progression, unacceptable toxicity, or withdrawal; lenvatinib could be continued beyond 2 years.

The primary endpoint was the proportion of patients with a confirmed objective response as per adjusted RECIST v1.1 assessed by independent central review. Activity and safety were analysed in all patients who received at least one dose of study treatment. This study is no longer recruiting participants but is ongoing.

Between 23 February 2021 and 21 January 2022, 215 patients were screened of whom 158 were enroled and received treatment. Median age at baseline was 60 years, 112 of 158 patients (71%) were male, 46 (29%) were female, 128 (81%) were White, 12 (8%) were Asian, 3 (2%) were Black or African American, and 15 (9%) were missing data on race. As of data cut-off of 7 November 2022, median study follow-up was 14.9 months. A total, 78 of 158 patients (49%) had a confirmed objective response (95% confidence interval 41–57), including 9 patients (6%) with a confirmed complete response and 69 patients (44%) with a confirmed partial response.

Grade 3-4 treatment-related adverse events (TRAEs) occurred in 81 of 158 patients (51%), the most common of which were hypertension (23%), proteinuria (4%), and stomatitis (4%). Serious TRAEs occurred in 20% of patients. Eight patients (5%) died due to AEs, none of which was considered related to the treatment by the investigators (one each of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism).

The authors commented that heterogeneity of the non-clear-cell RCC population complicates interpretation of the findings; however, this cohort had relatively large proportions of patients with papillary and chromophobe RCC compared with other studies, as determined by both investigator assessment and post-hoc central pathology assessment, providing some insight into activity by histological subtype. Furthermore, although the translocation RCC group was small, which limits any conclusions that can be drawn, the historical data available about this histological subtype are scarce and the findings from this study provide some additional insights. Patients with collecting duct histology were excluded because it is considered an aggressive disease for which the preferred option of care is platinum-based chemotherapy.

The authors concluded that pembrolizumab plus lenvatinib showed durable antitumour activity in patients with previously untreated non-clear-cell RCC, including in patients with papillary and chromophobe histology, and had a safety profile consistent with that of other patient populations. These results support the use of pembrolizumab plus lenvatinib as a first-line treatment option for patients with advanced non-clear-cell RCC. The results further support the use of pembrolizumab plus lenvatinib for the first-line treatment of advanced RCC, regardless of histology.

The study was funded by Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai.


Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. The Lancet Oncology; Published online 11 July 2023. DOI: