Data from Exposure–Response Analysis to Support Nivolumab Once Every 4 Weeks Dosing in Combination with Cabozantinib in Renal Cell Carcinoma

Abstract

<div>AbstractPurpose:<p>A benefit:risk assessment for a less-frequent nivolumab 480 mg every 4 weeks + cabozantinib 40 mg every day dosing regimen was predicted using modeling and simulation of clinical trial data from nivolumab monotherapy studies and from the nivolumab 240 mg every 2 weeks + cabozantinib 40 mg every day dosing regimen, which demonstrated clinical benefit versus sunitinib in previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 9ER trial (NCT03141177).</p>Patients and Methods:<p>Multivariable Cox proportional hazards analyses were conducted using nivolumab monotherapy data in previously treated aRCC and data from CheckMate 9ER to evaluate progression-free survival (PFS), overall survival (OS), and grade ≥2 immune-mediated adverse events (IMAE).</p>Results:<p>Nivolumab 240 mg every 2 weeks + cabozantinib versus nivolumab monotherapy showed improvement in PFS (HR, 0.38; 95% CI, 0.31–0.47), OS (HR, 0.63; 95% CI, 0.46–0.85), and increased risk of grade ≥2 IMAEs (HR, 2.19; 95% CI, 1.79–2.67). Nivolumab exposure was not a predictor of PFS/OS or grade ≥2 IMAEs. Lower nivolumab clearance, male sex, higher baseline bodyweight, and Karnofsky performance (100) were each associated with PFS/OS improvements. Region and International Metastatic Renal Cell Carcinoma Database Consortium poor score were negative OS predictors. Age, baseline albumin, and programmed death ligand 1 status were not significant PFS/OS predictors. Cabozantinib was a significant grade ≥2 IMAE predictor, driven by diarrhea and hepatic events. Model-predicted PFS/OS and grade ≥2 IMAE rates were similar (<2.5% difference) for nivolumab 240 mg every 2 weeks + cabozantinib and 480 mg every 4 weeks + cabozantinib.</p>Conclusions:<p>Comparable benefit:risk was predicted for nivolumab 480 mg every 4 weeks + cabozantinib and nivolumab 240 mg every 2 weeks + cabozantinib.</p></div>