Efficacy and safety of nivolumab plus ipilimumab (Nivo/Ipi) in patients with metastatic variant histology renal cell carcinoma.

558 Background: Nivo/ipi is a standard of care first-line (1L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC) but its role in patients with metastatic variant histology RCC (vhRCC) has not been fully defined. Methods: We report a single-institution experience with nivo/ipi to treat 55 patients with metastatic vhRCC between Nov. 2017 and Feb. 2024 at MD Anderson Cancer Center. Tumor response was measured by blinded radiologists using RECIST v1.1. Descriptive statistics and the Kaplan-Meier method were used. Results: Twenty-five (45.5%) patients had papillary histology (pRCC), 12 (21.8%) patients had chromophobe (chRCC), and 18 (32.7%) patients had unclassified RCC (uRCC) (Table). Fifty-two (94.5%) patients received nivo/ipi in 1L. Sarcomatoid features (SF) were found in 20 (36.4%) cases. Overall response rate (ORR) was 48% (12/25) for pRCC, 25% (3/12) for chRCC, 27.8% (5/18) for uRCC, and 55% (11/20) across histologies with SF. Median progression-free survival (PFS) was 10.6 mo [95% CI: 2.8 – 22.8] in pRCC, 3.6 mo [95% CI: 0.9 – NE] in chRCC, and 3 mo [95% CI: 2.1 – 7] in uRCC. Six-month PFS milestone was 56% [95% CI: 36.3 – 75.7], 41.7% [95% CI: 21.7 – 56.1], and 47.2% [95% CI: 35.3– 59.1] in pRCC, chRCC and uRCC, respectively. Median overall survival (OS) was 36.7 mo [95% CI: 11.5 – 54.8] in pRCC, 25.7 mo [95% CI: 0.9 – NE] in chRCC, and 11.1 mo [95% CI: 6.5 – NE] in uRCC. Grade 3/4 immune-mediated adverse events (IMAEs) were noted in 17 (30.9%), including colitis (n=6), pneumonitis (n=3), hepatitis (n=3), nephritis (n=2), thyroiditis (n=1), pancreatitis (n=1), and thrombocytopenia (n=1). Targeted DNA sequencing in 26 patients identified the most frequent alterations, TP53 (42%), PTEN (23%) and TERT (23%), and distinct molecular profiles of pRCC and chRCC, with TERT mutations enriched in pRCC and TP53 mutations more common in chRCC. Conclusions: Nivo/ipi produced favorable outcomes in pRCC. Despite ORR of 25% and 27.8%, respectively, patients with chRCC and uRCC had short PFS, with inferior OS in patients with uRCC. IMAEs with nivo/ipi were consistent with published reports. Outcome pRCC(n=25) chRCC(n=12) uRCC(n=18) Total(n=55) Best Overall Response, n (%) CR 1 (4%) 0 (0%) 1 (5.6%) 2 (3.6%) PR 11 (44%) 3 (25%) 4 (22.2%) 18 (32.7%) SD 4 (16%) 3 (25%) 3 (16.7%) 10 (18.2%) PD* 6 (24%) 4 (33.3%) 8 (44.4%) 18 (32.7%) NE 3 (12%) 2 (16.7%) 2 (11.1%) 7 (12.7%) ORR in pts with SF, n (%) 4/6 (66.7%) 3/8 (37.5%) 4/6 (66.7%) 11/20 (55%) Median OS, mo [95% CI] 36.7 [11.5 – 54.8] 25.7 [0.9 – NE] 11.1 [6.5 – NE] 19.4 [11.5 – 36.7] 12-month PFS milestone (%) [95% CI] 31% [11.4 – 54.7] 25% [0.5 – 49.5] 16.7% [0 – 33.9%] 25% [13.1 – 36.9] Median follow-up, mo [95% CI] 35.1 [12.3 – 72.6] 51.4 [21.2 – 58.8] 33.5 [24.4 – 42.9] 35.1 [30.8 – 52.3] Median duration of response, mo [95% CI] 20.1 [8.3 - NE] 8 [8 – NE] 8.5 [2.9 – NE] 8.5 [8 – NE] Median time on treatment, mo [IQR] 2.9 [0.4 – 10.9] 2.6 [0.9 – 10.2] 2.1 [1.2 – 5.4] 2.1 [0.7 – 10.3]