Phase 2 trial for sequential treatment of high dose cabozantinib (CABO) or CABO plus nivolumab (NIVO) on/after progression on CABO monotherapy in advanced renal cell carcinoma (RCC): Seq-Cabo.

TPS4609 Background: Efficacy outcomes for advanced RCC have improved with vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (IO), and CABO has become an established treatment for both front-line and refractory, advanced RCC. However, most patients develop resistance to CABO. With each subsequent line of therapy, efficacy and survival benefits also shorten and treatment options become limited. It is thus important to explore ways to maximize each line of therapy. Methods: Based on previous studies suggesting 1) dose-dependent effect of VEGFR-TKIs with feasibility/efficacy of CABO dose escalation to 80mg and 2) immune-modulatory effects of CABO, we have designed a two-cohort phase 2 trial to salvage CABO response, either by escalating the dose of CABO to 80mg oral (PO) daily (cohort 1) or by combining CABO 40mg PO daily with NIVO 480mg intravenous (IV) every 4 weeks (cohort 2), based on investigator choice. Subjects will be treated until progression or unacceptable toxicity. Main inclusion criteria include progressive advanced RCC after prior CABO monotherapy for at least 6 months, able to tolerate CABO 60mg PO daily (cohort 1) and 40mg PO daily (cohort 2), radiographically measurable disease, ECOG < 2, and adequate end-organ function. Main exclusion criteria include prior treatment with concurrent CABO/NIVO, uncontrolled co-morbidities, uncontrolled HIV, and concurrent malignancy (excepting completely excised skin cancers and organ-confined Gleason 6 prostate cancer). Primary endpoint is progression free survival (PFS) with key secondary endpoints including overall response rate, disease control rate, duration of response, and overall survival. The null hypothesis of median PFS 3 months will be tested against an alternative hypothesis of median PFS 6 months. Assuming a 2-sided significance level of 10% and 80% power, and estimating 10% drop out, 18 patients per cohort (36 patients total) will be enrolled.Pharmacokinetics, circulating biomarkers, and pre-/post-biopsies are planned for tissue-based analyses. The study is open for enrollment (NCT05931393). Clinical trial information: NCT05931393 .