First-line lenvatinib plus pembrolizumab treatment across non-clear cell renal cell carcinomas: Results of the phase 2 KEYNOTE-B61 study.

4518 Background: Lenvatinib (lenva) + pembrolizumab (pembro) is a first-line treatment for advanced clear cell renal cell carcinoma (RCC). Initial results of the single-arm, phase 2 KEYNOTE-B61 (NCT04704219) study showed antitumor activity of lenva + pembro in patients (pts) with advanced non-clear cell RCC who had opportunity for ≥24 wk of follow-up (n=82). We report results from the complete cohort of pts enrolled in KEYNOTE-B61 (N=158) with extended follow-up. Methods: Adults with previously untreated advanced non-clear cell RCC and measurable disease per RECIST v1.1 received lenva 20 mg PO QD + pembro 400 mg IV Q6W for up to 18 cycles (~2 y). The primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DOR, DCR, and PFS per RECIST v1.1 by BICR; OS; and safety. Histology was assessed by investigator (assessment by central review is planned). Results: Of 158 treated pts, 93 (59%), 29 (18%), and 21 (13%) had papillary, chromophobe, and unclassified histology, respectively. Additionally, 6 pts (4%) had translocation and 9 (6%) had other histology. 70 pts (44%) had IMDC favorable risk and 88 (56%) had intermediate/poor risk. Median follow-up was 14.9 mo (range 8.7-19.7). ORR was 49% (95% CI, 41-57; 9 CRs [6%]; 69 PRs [44%]). DCR was 82% (95% CI, 75-88). Median DOR was not reached (NR; range, 1.5+ to 15.3+ mo). By Kaplan-Meier estimate, 75% of responders had a response for ≥12 mo. ORR and DCR by histology are shown in the table. For the IMDC favorable risk group, ORR was 51% (95% CI, 39-64) and DCR was 87% (95% CI, 77-94). For the IMDC intermediate/poor risk group, ORR was 48% (95% CI, 37-59) and DCR was 78% (95% CI, 68-86). In all pts, median PFS and OS were 17.9 mo (95% CI, 13.5-NR) and NR (95% CI, NR-NR), respectively; 12-mo rates were 63% and 82%. Treatment-related AEs (TRAEs) occurred in 149 pts (94%) and were consistent with results from other studies. The most common (≥30%) TRAEs were hypertension (n=90; 57%), diarrhea (n=69; 44%), and hypothyroidism (n=58; 37%). Grade 3-4 TRAEs occurred in 81 pts (51%). Overall, 17 pts (11%) discontinued pembro, 14 (9%) discontinued lenva, and 5 (3%) discontinued both drugs because of TRAEs. No deaths occurred because of TRAEs. Conclusions: In pts with advanced non-clear cell RCC enrolled in KEYNOTE-B61, lenva + pembro showed antitumor activity with no new safety signals. These data support the use of lenva + pembro as first-line treatment for pts with non-clear cell RCC, regardless of histology. Clinical trial information: NCT04704219 . [Table: see text]