Combined checkpoint immunotherapy and cytotoxic chemotherapy: Further results from a phase Ib/II trial of pembrolizumab and docetaxel or gemcitabine in patients with advanced or metastatic urothelial cancer

Background: We previously reported tolerability of pembrolizumab plus either docetaxel or gemcitabine in platinum-treated metastatic urothelial cancer patients (pts), given the hypothesis that chemotherapy might enhance tumoral neoantigen expression and modulate immunogenicity of tumor cells, potentially enhancing the response to anti-PD-1 therapy. Herein we report further results from an expansion cohort. Methods: Eligible pts had Zubrod PS 0-1, adequate end-organ function, with progression following up to 2 prior lines of chemotherapy (at least one platinum based). Patients were treated with pembrolizumab 200 mg IV on D1 q3weeks plus either docetaxel 75 mg/m2 IV on D1 (Arm A) or gemcitabine 1000 mg/m2 IV on D1 & D8 (Arm B). Primary endpoint was safety; secondary endpoints were overall response rate (RR) and progression free-survival (PFS). Results: A total of 20 pts have enrolled, 9 in Arm A, 11 in Arm B. Mean age was 66 (range 31-84). Most common AEs ≥ Grade 3 were hyponatremia (8/20), anemia (5/20), fatigue (5/20), neutropenia (4/20), leukopenia (4/20) acute kidney injury (3/20), hypophosphatemia (3/20). There were no treatment-related deaths; 13 died from disease progression. In total, 1 pt had complete response (CR), 5 pts had partial responses (PR), 3 pts had minor responses (MR), 4 had stable disease (SD), and 7 progressed; overall RR was 45% and Disease Control Rate (DCR) was 65%. Arm A had overall RR of 44%, DCR 56%. Arm B had overall RR of 45%, DCR 73%. Median PFS (overall, Arm A & Arm B) were 7, 13.3, and 5.9 months. Conclusions: The combination of pembrolizumab with either docetaxel or gemcitabine is tolerated with no unexpected adverse effects, with evidence of efficacy. Expanded cohorts continue to enroll.