Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Cabozantinib Plus Nivolumab Phase I Expansion Study in Metastatic Urothelial Carcinoma Patients Refractory to Immune Checkpoint Inhibitor Therapy.

Abstract

PURPOSE: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). EXPERIMENTAL DESIGN: A phase I expansion cohort of mUC patients who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. RESULTS: 29/30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median 7 cycles). ORR was 16.0%, with one complete response and 3 partial responses (PRs). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months (95% CI: 3.7-33.5), median PFS was 3.6 months (95% CI: 2.1-5.5), and median OS was 10.4 months (95% CI: 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as non-classical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs (PMN-MDSC), lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. CONCLUSIONS: CaboNivo was clinically active, well-tolerated, and favorably modulated peripheral blood immune subsets in mUC patients refractory to CPI.