69Testing cabozantinib with or without atezolizumab in patients with advanced papillary kidney cancer (NCT05411081)

Abstract Background The role of combination immune therapy is not fully established in PRCC. The S1500 (PAPMET) clinical trial established single-agent cabozantinib as the standard of care for PRCC [PMID 33592176] with a median progression-free survival (PFS) of 9.0 months compared to 5.6 months with sunitinib. Additionally, trials have shown activity of PD-(L)1 antagonists as monotherapy [PMID 33529058] or in combination with targeted therapy [PMID 34491815]. In a single-arm study of cabozantinib/nivolumab the median PFS was 12.5 months [PMID 35298296]. In contrast, some data from retrospective studies suggest no benefit with combination therapy [PMID 36610815] over sequential single agent studies. Importantly no prior randomized studies of immune therapy in PRCC have compared sequential therapy versus upfront combination therapy. Toxicity is higher with combination therapy suggesting some equipoise and rationale for testing combinations in PRCC. We hypothesize that the combination will have higher clinical activity than single-agent cabozantinib while maintaining a reasonable quality of life. Methods This is a prospective randomized phase II clinical trial conducted through the NCTN and led by SWOG. The primary endpoint is a comparison of PFS between cabozantinib and cabozantinib/atezolizumab. Secondary endpoints include comparison of objective response rate, overall survival and safety. Patients are treated with cabozantinib 60mg/day versus cabozantinib 60mg/day + atezolizumab 1200 mg q3 weeks. Dose reductions of cabozantinib are allowed. Dose delays of either treatment are allowed. The sample size is planned for 200 patients to be enrolled and randomized 1:1 to each treatment arm. Treatment is allowed to continue even with discontinuation of the second agent in the combination arm. Significance & Vision Current clinical practice for patients with PRCC is defined by the approved treatment methods for clear cell RCC. It is unclear if combination strategies are as successful for PRCC as ccRCC. Additionally, the long-term follow up of prior TKI/IO studies in ccRCC do not demonstrate immunologic synergy suggesting that combination approaches might lead to increased toxicity without significant clinical benefit is many patients. Here we aim to establish the true clinical value of combination therapy for this disease. Additionally a rich biobank of liquid samples, soft-tissue tumor samples and stool samples will be collected in order to further basic scientific research with the aim of developing disease specific treatments for patients with PRCC. Trial Schema