Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): Findings from Cohort 2 of MODUL – a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy

Background: In patients (pts) with mCRC, molecular screening approaches and new biomarkers are required to fully characterize tumours and identify those likely to benefit. The MODUL study (ClinicalTrials.gov: NCT02291289) is highly adaptable, Phase II signal seeking, and evaluates the theory of tumoural heterogeneity under induction chemotherapy via switch maintenance treatment in first-line mCRC. Methods: MODUL follows an umbrella design; pts with measurable, unresectable, previously untreated mCRC receive 16 weeks of induction treatment with FOLFOX + BEV followed by maintenance randomized to either control (FP/BEV) or experimental treatment in one of four cohorts. Here we report results of Cohort 2 (BRAFwt: FP/BEV + atezolizumab). Primary efficacy endpoint: progression-free survival (PFS, per investigator). Secondary endpoints: overall survival (OS); best overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR); duration of response (DoR); ECOG performance status (PS); safety. Results: 824 pts were screened, 696 of whom were enrolled to receive induction treatment. 445 pts with BRAFwt mCRC were randomized to maintenance treatment in Cohort 2 (297 pts FP/BEV + atezolizumab; 148 pts FP/BEV). In the primary analysis of Cohort 2 (median follow-up 10.5 months), PFS was not met (HR = 0.92; 95% CI 0.72–1.17; p = 0.48) and OS was immature. ORR, DCR, TTP and DoR showed small numerical differences in favour of experimental treatment. Subgroup treatment interactions were observed for gender, ECOG PS, response at end of induction and initial diagnosis (synchronous vs metachronous disease). In the updated analysis (median follow-up 18.7 months), PFS outcome was unchanged (HR = 0.96; 95% CI 0.77–1.20; p = 0.727) and OS with 51% of pts with an event was HR = 0.86; 95% CI 0.66–1.13; p = 0.28. The safety profiles observed are consistent with previous findings with no new safety signals identified. Conclusions: Adding atezolizumab to FP/BEV (standard of care) as first-line maintenance treatment for pts with BRAFwt mCRC did not lead to improvement in efficacy outcomes. Clinical trial identification: NCT02291289. Editorial acknowledgement: Editorial assistance was provided by Lee Miller (Miller Medical Communications). Legal entity responsible for the study: F. Hoffmann-La Roche Ltd. Funding: F. Hoffmann-La Roche Ltd. Disclosure: J. Tabernero: Scientific consultancy role: Bayer, Boehringer Ingelheim, Chugai, Genentech, Inc., Ipsen, Lilly, MSD, Merck Serono, Merrimack, Merus, Novartis, Peptomyc, Pfizer, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, Seattle Genetics, Symphogen, Taiho. D. Arnold: Honoraria for lectures and advisory board participation: F. Hoffmann-La Roche Ltd. A. De Gramont: Honoraria: Chugai, Yakult; Consultancy/advisory board fees: PharmaEngine. M.P. Ducreux: Grants/research supports: Roche, Chugai, Pfizer; Honoraria or consultation fees: Roche, Celgene, Merck Serono, Amgen, Novartis, Sanofi, Pfizer, Lilly, Servier, Bayer; Spouse: Head of BU, Sandoz. E. Van Cutsem: Consulting/advisory role: Bayer, BMS, Celgene, Lilly, Merck, Merck KgA, Novartis, Roche, Servier. Research grants: Amgen, Bayer, BMS, Boehringer, Celgene, Ipsen, Lilly, Merck, Merck KgA, Novartis, Roche, Servier. I. Bosanac, S. Srock: Employed by F. Hoffmann-La Roche Ltd.; Owner of Roche stock through personal and stock-option plans. C. Mancao: Employed by F. Hoffmann-La Roche Ltd.; Owner of Roche stock. F. Gilberg: Employed by F. Hoffmann-La Roche Ltd. J. Winter: Employed by F. Hoffmann-La Roche Ltd.; Roche stock ownership options. H-J. Schmoll: Research funding: Roche, Merck. Advisory board (including travel support): Servier, Gilead, Roche. All other authors have declared no conflicts of interest.