MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAF^wt metastatic colorectal cancer

Background: MODUL is an adaptable, signal-seeking trial designed to test novel agents in predefined patient subgroups in first-line metastatic colorectal cancer (mCRC). Patients and methods: Patients with measurable, unresectable, previously untreated mCRC received induction with ≤8 cycles of FOLFOX + bevacizumab followed by randomization to maintenance treatment comprising control [fluoropyrimidine (FP)/bevacizumab: 5-fluorouracil 1600-2400 mg/m² 46-h intravenous (i.v.) infusion day 1 q2 weeks plus leucovorin 400 mg/m² 2-h infusion i.v. day 1 q2 weeks or capecitabine 1000 mg/m² b.i.d. orally days 1-14 every 21 days; bevacizumab 5 mg/kg 15-30-min i.v. infusion q2 weeks] or experimental treatment in one of four biomarker-driven cohorts. In patients with BRAF wild-type (BRAF^wt) tumors (cohort 2), experimental treatment was FP/bevacizumab + atezolizumab (800 mg 60-min i.v. infusion q2 weeks). Primary efficacy endpoint was progression-free survival (PFS; intent-to-treat population). Enrollment is complete; efficacy and safety findings from cohort 2 are presented. Results: Four hundred and forty-five patients with BRAF^wt mCRC were randomized (2 : 1) to maintenance in cohort 2. At a median follow-up of 10.5 months, PFS outcome hypothesis was not met [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.72-1.17; P = 0.48]; overall survival (OS) was immature. At a median follow-up of 20.3 months (2-year survival follow-up), PFS benefit was also not met (HR 0.95; 95% CI 0.77-1.18; P = 0.666); OS HR with nearly two-thirds of patients with events was 0.83 (95% CI 0.65-1.05; P = 0.117). No new safety signals were identified. The most common grade ≥3 treatment-emergent adverse events (TEAEs) for experimental versus control arms were hypertension (6.1% versus 4.2%), diarrhea (3.1% versus 2.1%), and palmar-plantar erythrodysesthesia syndrome (1.0% versus 2.5%). Four patients experienced TEAEs with fatal outcome, two were study treatment-related: hepatic failure (experimental arm) and large intestine perforation (control arm; bevacizumab-related). Conclusions: Adding atezolizumab to FP/bevacizumab as first-line maintenance treatment after FOLFOX + bevacizumab induction for BRAF^wt mCRC did not improve efficacy outcomes.