Phase I Trial of Atezolizumab plus Trimodal Therapy in Patients with localized Muscle-Invasive Bladder Cancer.

Abstract

PURPOSE\nImmune checkpoint programmed death-ligand 1 (PDL-1) inhibitor therapy has shown response in metastatic muscle invasive bladder cancer (MIBC). We evaluated the safety and tolerability of atezolizumab (anti-PDL-1) in combination with trimodal therapy (TMT) in patients with localized MIBC.\n\n\nMETHODS\nA prospective non-randomized phase I study using a 3+3 design was conducted in patients with localized MIBC (T2-T4a N0M0) treated on a bladder preservation program. Following trans-urethral resection of bladder tumor, patients received concurrent radiotherapy at a fixed dose of 50 Gy/20 fractions, gemcitabine (100 mg/m2, IV once weekly x 4) and atezolizumab (1200 mg IV every 3 weeks x 16 cycles). Primary endpoint was safety/toxicity profile.\n\n\nRESULTS\nBetween May 2018 and March 2019, 8 patients (6 males and 2 females) were enrolled. The first 5 patients received atezolizumab at 1200 mg, three of whom developed grade 3 side effects (2 of them dose limiting toxicity). Atezolizumab dose was reduced to 840 mg for 3 additional patients. The study was terminated due to the presence of three grade 3 adverse events (2 of them dose limiting toxicity) despite the reduced atezolizumab dose. Gastro-intestinal (GI) events were the main toxicity. No grade 4-5 adverse effects were observed.\n\n\nCONCLUSION\nConcurrent administration of atezolizumab with concomitant hypofractionated radiotherapy and gemcitabine appears to be associated with unacceptable GI toxicity. While numbers studied are small, our results suggest considerable caution with its concurrent use with trimodal therapy for MIBC.