Final results of a phase 2 trial of cabozantinib plus nivolumab (CaboNivo) in patients with non–clear cell renal cell carcinoma (nccRCC).

4521 Background: CaboNivo improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell RCC. (Choueiri NEJM 2021). We previously reported on 47 patients (pts) treated on a phase 2 trial of CaboNivo for nccRCC. We now present final results on all 60 pts accrued to the study. Methods: Pts had advanced nccRCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC (tRCC); Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy and slow accrual. Results: Of 60 pts, 53 were included in Cohort 1, of whom 16 had papillary RCC, 16 unclassified RCC with papillary features (UCPF), 8 FH-deficient, 8 unclassified without papillary features (UC), and 5 tRCC. In Cohort 1, 39 (74%) pts were previously untreated, and 14 (26%) pts had 1 prior line: 10 (19%) received prior VEGF-targeted therapy and 8 (15%) received prior mTOR-targeted therapy. For Cohort 1 (Table), the ORR was 43% (95% CI 30-58), including 88% in pts with FH-deficient RCC. Median PFS (mPFS) in Cohort 1 was 11 months (95% CI 8-14), median OS was 28 months (95% CI 21-37), and there were 43 deaths after a median follow-up of 50 months for survivors. 7 pts with chromophobe RCC were enrolled in Cohort 2 with 5 achieving stable disease (SD) but no objective responses observed. Adverse events were similar to the previously reported cohort and cabozantinib and nivolumab were discontinued for toxicity in 22 (42%) and 20 (38%) pts, respectively. Conclusions: Final results from this phase 2 trial in nccRCC confirm efficacy and acceptable safety of CaboNivo in pts with metastatic papillary, unclassified, or tRCC histologies with a particularly high ORR in FH-deficient RCC. These results justify CaboNivo as a standard first-line treatment option for these pts. In contrast, objective responses were not observed in chromophobe RCC. Clinical trial information: NCT03635892 . Cohort 1 outcomes. Outcome All Pts(n=53) 1 st -line(n=39) 2 nd -line(n=14) Papillary(n=16) UCPF(n=16) FH-def(n=8) UC(n=8) tRCC(n=5) ORR, %(95% CI) 43(30-58) 46(30-63) 36(13-65) 31(11-59) 38(15-65) 88(47-100) 50(16-84) 20(1-72) CR, n (%) 1 (2) 1 (3) 0 1 (6) 0 0 0 0 PR, n (%) 22 (42) 17 (44) 5 (36) 4 (25) 6 (38) 7 (88) 4 (50) 1 (20) SD, n (%) 27 (51) 19 (49) 8 (57) 10 (63) 10 (62) 1 (12) 2 (25) 4 (80) PD, n (%) 3 (6) 2 (5) 1 (7) 1 (6) 0 0 2 (25) 0 mPFS, mo.(95% CI) 11(8-14) 11(8-16) 14(5-23) 11(7-25) 10(5-13) 16(5-37) 8(1-34) 14(5-41) </