Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer

• Published in: European journal of cancer (1990) Vol. 184; pp. 137 - 150
• Main Authors: Ducreux, Michel, Tabernero, Josep, Grothey, Axel, Arnold, Dirk, O'Dwyer, Peter J., Gilberg, Frank, Abbas, Alexander, Thakur, Meghna Das, Prizant, Hen, Irahara, Natsumi, Tahiri, Anila, Schmoll, Hans-Joachim, Van Cutsem, Eric, de Gramont, Aimery
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2023
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bevacizumab; Biomarkers; BRAF; Cetuximab; Colonic Neoplasms - drug therapy; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Fluorouracil; HER2; Humans; Leucovorin; Maintenance therapy; Proto-Oncogene Proteins B-raf - genetics; Rectal Neoplasms - drug therapy; Vemurafenib; Vemurafenib - therapeutic use; Vemurafenib; Maintenance therapy; Colorectal cancer; Biomarkers; BRAF; Cetuximab; HER2
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2023.01.023

MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut).
Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS).
Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50–1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90–2.29; P = 0.128).
Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy.
ClinicalTrials.gov: NCT02291289.
•Biomarker-driven maintenance therapy after induction treatment in metastatic colorectal cancer (mCRC) is feasible.•Maintenance vemurafenib/cetuximab/5-FU/LV in BRAFmut mCRC merits further study.•Emergent mitogen-activated protein kinase genomic alterations in BRAFmut mCRC may offer actionable targets.•New strategies to increase microsatellite stable mCRC susceptibility to immunotherapy are required.