A pilot trial evaluating the rapid sequencing of approved therapies in patients (pts) with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Qin Qian , Zubizarreta Nicole J. , Galsky Matt D. , Liaw Bobby Chi-Hung , Patel Vaibhav G. , Sfakianos John P. , Mehrazin Reza , Palese Michael , Badani Ketan , Waingankar Nikhil , Brody Rachel , Bhardwaj Nina , Doshi Amish , Simpson William L , Yankelevitz David F , Horowitz Amir , Tsao Kai 
Published: March 2023

TPS751 Background: Five doublet combinations incorporating immune checkpoint inhibitor (ICI) with or without tyrosine kinase inhibitor (TKI) are now approved for the first line treatment (tx) of advanced ccRCC. In COSMIC-313, the triplet combination with cabozantinib (CABO)-ipilimumab (IPI)-nivolumab (NIVO) demonstrated promising efficacy compared to IPI-NIVO in pts with intermediate/poor risk disease, but definitive overall survival (OS) benefit has yet to be shown, and is associated with higher incidence of adverse events. Currently, the optimal first /subsequent lines of therapies remain to be defined, and predictive biomarker to guide optimal tx approach is urgently needed. Pre-clinical studies allude to the ability of TKIs, such as CABO, to promote an immune-permissive environment and thus enhance ICI response. This open-label, single-arm, investigator-initiated pilot trial will evaluate the rapid sequencing from CABO to IPI-NIVO with the hypothesis of enhanced efficacy when compared to IPI-NIVO doublet, and potentially lower toxicity when compared to the concurrent triplet combination. Correlative studies, before and after administration of each systemic therapy, will be performed with the goal of identifying potential predictive biomarkers of response and resistance. Methods: Advanced, ccRCC pts will be treated with CABO 60mg PO once daily (QD) for 12 weeks (W) followed by IPI 1mg/kg + NIVO 3mg/kg IV every (Q)3W for 4 cycles. Subsequent therapy is dependent on response, and can be NIVO 480mg IV Q4W (CR/PR/SD), lenvatinib 18mg + everolimus 5mg PO QD (PD on both prior regimens), or re-initiation of CABO 60mg PO QD (CR/PR/SD at CABO but PD on IPI-NIVO). Key inclusion criteria are histologically confirmed, metastatic or unresectable RCC with predominantly clear cell component (sarcomatoid differentiation <50%), tx naïve in the advanced disease setting, and measurable disease per RECIST 1.1 criteria. IMDC or MSKCC favorable, intermediate, and poor risk groups are included. Pts with active CNS disease or contraindications to CABO, IPI, and/or NIVO are excluded. Tumor biopsies and blood/urine samples will be collected for correlative studies. The primary endpoint is efficacy of the sequential approach, based on overall response rate (ORR) as assessed by investigator per RECIST 1.1. The ORR will be estimated by a two-sided 95% confidence interval. The trial plan to enroll 20 pts, which will allow us to estimate a range of plausible ORRs from 0.42 to 0.62 with a precision of ±0.23. Additional efficacy endpoints (ORR per modified RECIST for immune response, duration of response, progression free survival, OS), safety, pt reported outcomes, correlative biomarkers and their association with clinical outcome as determined by tumor immune/genomic profiling will also be evaluated. The trial is currently enrolling pts. Clinical trial information: NCT05188118 .