1Pembrolizumab plus lenvatinib for previously untreated advanced non–clear cell renal cell carcinoma: 3-year follow-up of the phase 2 KEYNOTE-B61 study

Abstract Background First-line pembrolizumab plus lenvatinib showed durable responses in participants with advanced non–clear cell renal cell carcinoma (nccRCC) in the single-arm, phase 2 KEYNOTE-B61 study (NCT04704219). Responses were observed across subtypes including papillary, chromophobe, and unclassified histologies. We present results from KEYNOTE-B61 with approximately 18 months of additional follow-up from the previous analysis. Methods Adults with previously untreated, advanced nccRCC and measurable disease per RECIST v1.1 received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (approximately 2 years) plus lenvatinib 20 mg by mouth once daily until intolerable toxicity, progressive disease, or participant withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Histologic subtypes were determined by investigator assessment and retrospectively reviewed by central pathology. Results Overall, 158 participants received pembrolizumab plus lenvatinib. Median study follow-up (time from first dose to the data cutoff date of January 27, 2025) was 41.6 months (range, 35.4-46.4). Of 158 participants, 93 (58.9%) had papillary, 29 (18.4%) had chromophobe, and 20 (12.7%) had unclassified histologies, and 16 (10.1%) had translocation (n = 6), medullary (n = 1), or other (n = 9) histologic subtypes. As of the data cutoff date, 121 of 158 participants (76.6%) had discontinued treatment, most commonly due to disease progression (n = 81, 51.3%). A total of 61 of 158 participants (38.6%) received subsequent anticancer therapy, most commonly cabozantinib (n = 38, 24.1%). In all participants, ORR was 50.6% (n = 80; 95% CI, 42.6-58.7), with 16 complete responses and 64 partial responses. ORR was generally consistent across histologic subtypes, including chromophobe (33.3%) and papillary (52.9%). Median DOR was 23.5 months (range, 1.5+ to 40.2+); 34.6% of responders remained in response for ≥36 months per Kaplan-Meier estimates. In all participants, median PFS was 17.9 months (95% CI, 15.0-21.1); the 24- and 36-month PFS rates were 39.2% and 26.4%, respectively. Median OS was 41.5 months (95% CI, 32.8 to not reached [NR]); the 24- and 36-month OS rates were 66.5% and 53.7%, respectively. Based on histologic subtype, median PFS was 18.2 months (95% CI, 15.0-21.0) for participants with papillary nccRCC and 11.3 months (95% CI, 6.7-29.0) for participants with chromophobe nccRCC (table). Median OS was 37.5 months (95% CI, 27.1-NR) and NR (95% CI, 21.7-NR) for papillary and chromophobe histology, respectively. Grade 3 or 4 treatment-related adverse events occurred in 95 participants (60.1%) and most commonly included (≥5%) hypertension (25.9%), proteinuria (7.6%), diarrhea (6.3%), and weight decreased (6.3%). No deaths due to treatment-related adverse events occurred. Table. Conclusions After a minimum of 3 years of follow-up, pembrolizumab plus lenvatinib continued to demonstrate durable responses and promising survival outcomes in the first-line setting for advanced nccRCC. With additional follow-up, 3 additional complete responses from the previous data cutoff were observed. No new safety signals have been reported with extended follow-up. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for patients with nccRCC regardless of histology.