Final results from a phase 1 trial and expansion cohorts of cabozantinib and nivolumab alone or with ipilimumab for advanced/metastatic genitourinary tumors

Abstract Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase 1 study. We now report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase 1 patients and 7 expansion cohorts. CaboNivo cohorts included: 1) mUC, 2) mRCC, 3) adenocarcinoma of the bladder/urachal, and CaboNivoIpi cohorts included: 1) mUC, 2) mRCC, 3) penile cancer, 4) rare GU tumors, and an exploratory biomarker correlation with peripheral blood immune subsets (NCT02496208). Patients (n = 120) received CaboNivo (n = 64) or CaboNivoIpi (n = 56), with median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), 33 of whom had mUC, ORR was 38% (overall study) and 42% in mUC, complete response 11% and 21%, partial response 27% and 21%, duration of response 20 and 28 months, respectively. Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. In response to treatment, immunosuppressive monocytic MDSCs, classical monocytes, and all dendritic cell subsets decreased; Activated proliferative CD4+ T cells and CD8+ T cells and CTLA-4 on CD4+ T cells increased and were associated with improved PFS and OS. Both CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in many metastatic GU histologies, with distinctive patterns of response among innate and adaptive peripheral blood immune subsets and potential differential adaptive resistance in response between CaboNivo and CaboNivoIpi to prolonged effector T-cell activation.