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

Abstract

PURPOSE:

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).

METHODS:

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).

RESULTS:

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).

CONCLUSIONS:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov: NCT02291289.

• Authors: Michel Ducreux, Josep Tabernero, Axel Grothey, Dirk Arnold, Peter J O'Dwyer, Frank Gilberg, Alexander Abbas, Meghna Das Thakur, Hen Prizant, Natsumi Irahara, Anila Tahiri, Hans-Joachim Schmoll, Eric Van Cutsem, Aimery de Gramont
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 184 Pg. 137-150 (05 2023) ISSN: 1879-0852 [Electronic] England
• PMID: 36921494 (Publication Type: Randomized Controlled Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Bevacizumab
• Cetuximab
• Proto-Oncogene Proteins B-raf
• Vemurafenib
• Fluorouracil
• Biomarkers
• Leucovorin

Topics

• Humans
• Bevacizumab
• Cetuximab
• Proto-Oncogene Proteins B-raf (genetics)
• Vemurafenib (therapeutic use)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Fluorouracil
• Colonic Neoplasms (drug therapy)
• Rectal Neoplasms (drug therapy)
• Biomarkers
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Leucovorin