A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and Pembrolizumab Combination Therapy in Patients with Advanced Renal Cell Carcinoma

This open-label, two-part, multicenter study involving 42 treatment-naive patients with advanced renal cell carcinoma assessed the possibility of an immune checkpoint blockade in combination with antiangiogenic treatment. The overall clinical benefit rate of 60% showed encouraging efficacy across cohorts; however, significant safety issues associated with this treatment indicated that this combination is unsafe. Background: This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and Methods: This was an open-label, t wo-par t, multicenter study involving treatment-naive patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results: Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions: Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.