Background: Immune checkpoint inhibitors, multi-kinase VEGF agents, and mTOR inhibitors are approved for mRCC. Due to the overlapping mechanisms of action of the twelve approved therapies for mRCC, select patients are referred for phase I clinical trials after progression on multiple lines of treatment. We sought to evaluate the efficacy of phase I trials in patients with mRCC. Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center. Baseline clinical characteristics and outcomes data were retrospectively collected. The historical control was a study of 1112 patients with mRCC who received third-line treatment in the IMDC database (PMID: 27318422). Time to event endpoints were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Between 2014 and 2019, there were 106 cases where 82 patients with mRCC were enrolled in a phase I clinical trials (40 unique trials). 30% (32/108) of the cases were in patients with non-clear cell RCC (nccRCC), and the most prevalent nccRCC histologies were papillary (n = 7) and renal medullary carcinoma (n = 7). The median number of prior systemic therapies was 2 (range 0-9). Across the entire cohort, median PFS was 5.9 months (m), median OS was 31.2 m, and the ORR was 23% (Table). In patients who received at least two prior lines of therapy (n = 70), the median PFS was 4.8 m and median OS was 24.9 m. In patients with metastatic nccRCC, median OS, PFS, and ORR were numerically lower, but statistically did not contradict the supposition that these outcomes did not differ from ccRCC (Table). Conclusions: In the largest pooled phase I clinical trial experience for patients with mRCC, phase I trials may have therapeutic value when compared to historical controls, where median PFS was 3.9 m, median OS was 12.4 m, and ORR was 10.5%. Patients with all histologies of mRCC may derive clinical benefit from phase I clinical trials, yet patients with ccRCC had numerically better outcomes. Patients with mRCC should be considered for phase I clinical trials.

Table legend: * = HR is for nccRCC versus ccRCC.