Analysis of Phase II Study of Cabozantinib (cabo) with Nivolumab (nivo) and Ipilimumab (ipi) in Advanced Renal Cell Carcinoma with Divergent Histologies (Rccdh).

4539 Background: We previously reported on treatment intensification with the combination of Cabo/Nivo/Ipi in 39 patients (pts) with metastatic RCCdh in a multi-center single arm phase II trial with a starting cabozantinib dose of 40 mg/day (d). Clinical utility was limited with an objective response rate (ORR) of 21% and significant treatment related adverse events (TrAEs) (77% ≥Grade 3 TrAEs). Therefore, we explored the safety and potential efficacy by using a lower starting dose of cabozantinib of 20 mg/d (NCT04413123). Methods: Eligible pts had metastatic RCCdh with ECOG performance status of 0-1 and may have received one line of prior therapy excluding immunotherapy or Cabo. Pts underwent a baseline biopsy and received Nivo 3 mg/kg and Ipi 1 mg/kg intravenously Q3 weeks (W) for 4 cycles followed by Nivo 480 mg IV Q4W. Cabo was given continuously at a dose of 20 mg/d; reductions to 20 mg every other day were allowed; after completion of Ipi, the Cabo dose could be increased to 40 mg/d. The primary endpoint was ORR by RECIST 1.1. Safety was a secondary endpoint. A one-stage design with 20 subjects (for 7 or more responses) would provide 75% power to distinguish an ORR of 40% versus 20% at one-sided alpha of 0.1. Results: 20 pts were enrolled and received at least 1 study drug at 7 sites from Feb. 2023 to Apr. 2024. Following histologic subtypes were included: papillary (n = 11), chromophobe (n = 1), translocation (n = 3), unclassified RCC (n = 2) and other (n = 3). 4 (20%) pts received prior systemic therapy. 10 (50%) pts received all 4 doses of Nivo and Ipi; 13 (65%) pts received maintenance nivolumab. Cabo was increased to 40 mg in 11/13 of these patients. Median follow-up was 9.4 (range 4.6-17.7) months. ORR was 25% (5/20, two-sided 80% CI, 13-41%, Table 1). 6- and 12-month progression free survival rates were 65% and 42% respectively. 11 (55%) pts developed grade 3 or 4 TrAEs (6 were due to elevation in liver function tests) and 1 (5%) had grade 5 TrAE (intraoperative hemorrhage) in setting of disease progression. 5 (25%) required high dose steroids (≥40 mg prednisone or equivalent) of which only 3 (15%) received for hepatitis. All therapy was discontinued due to toxicity in 1 (5%) pt. Conclusions: Although the study did not reach the target of 7 responses to uphold the alternative hypothesis, reduction of the starting dose of Cabo to 20 mg/d in combination with Nivo/Ipi results in numerically lower ≥ grade 3 TrAEs than starting at 40 mg/d (60% vs 77%) and clinical activity in a subset of patients. Clinical trial information: NCT04413123 . Total (N=20) Histology Prior Systemic Therapy N(%) Papillary Chromophobe Translocation Unclassified RCC Other No Yes PR 5 (25) 2 1 0 2 0 4 1 SD 8 (40) 5 0 2 0 1 7 1 PD 7 (35) 4 0 1 0 2 5 2 PR=partial response, SD=stable disease, PD=progressive disease.