Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Sep 5;6(9):e2333533.
doi: 10.1001/jamanetworkopen.2023.33533.

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial

Valérie Boige  1   2 , Hélène Blons  2   3 , Eric François  4 , Meher Ben Abdelghani  5 , Jean-Marc Phelip  6 , Valerie Le Brun-Ly  7 , Laurent Mineur  8 , Marie Pierre Galais  9 , Anne-Laure Villing  10 , Vincent Hautefeuille  11 , Laurent Miglianico  12 , Christelle De La Fouchardière  13 , Dominique Genet  14 , Nadia Levasseur  15 , Charles-Briac Levaché  16 , Nicolas Penel  17 , Emmanuel Mitry  18 , Stéphane Jacquot  19 , Thomas Aparicio  20 , Emilie Brument  21 , Sophie Gourgou  22 , Florence Castan  22 , Olivier Bouché  23
Affiliations
Clinical Trial

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial

Valérie Boige et al. JAMA Netw Open. .

Abstract

Importance: The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.

Objective: To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.

Design, setting, and participants: The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.

Interventions: After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.

Main outcomes and measures: The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.

Results: Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).

Conclusion and relevance: The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.

Trial registration: ClinicalTrials.gov Identifier: NCT02404935.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Boige reported receiving grants from Merck during the conduct of the study; and personal fees from Bayer, Ipsen, Amgen, BMS, MSD, and Roche, and nonfinancial support from AstraZeneca outside the submitted work. Dr Blons reported receiving personal fees from AstraZeneca, Janssen, Takeda outside the submitted work. Dr François reported receiving personal fees from Pierre Fabre Oncology outside the submitted work. Dr Ben Abdelghani reported receiving personal fees from Viatris, Amgen, Servier, Merck, Incyte, BMS, Deciphera, Mundipharma, and Pierre Fabre outside the submitted work. Dr Phelip reported receiving personal fees from Merck, Amgen, and Roche; grants from Merck and Roche; and nonfinancial support from Merck and Amgen outside the submitted work. Dr Galais reported providing expert activity to Servier and BMS; receiving nonfinancial support from Cancérodigest; and receiving invitations to conferences from AAA, Servier, and Bayer. Dr Hautefeuille reported serving on the Merck Advisory Board during the conduct of the study. Dr De La Fouchardière reported receiving nonfinancial support from Pierre Fabre Oncology; and personal fees from MSD, BMS, Servier, Amgen, Ipsen, Daichi-Sankyo, Roche, and Lilly outside the submitted work. Dr Mitry reported receiving support to attend a medical conference from Merck-Serono outside the submitted work. Dr Aparicio reported a conference for Amgen. Dr Brument reported receiving grants from Merck during the conduct of the study. Dr Bouché reported receiving personal fees from Apmonia Therapeutics, Bayer, Deciphera, Merck Sereno, Servier, Pierre Fabre, and Amgen outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
RAS and BRAF V600 were centrally assessed. FOLFIRI indicates fluorouracil, leucovorin (folinic acid), and irinotecan; ITT, intent-to-treat.
Figure 2.
Figure 2.. Progression-Free and Overall Survival
Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) from randomization by treatment group (intent-to-treat 2 population). Shaded areas indicate 95% CIs.
Figure 3.
Figure 3.. Kaplan-Meier Estimates of Progression-Free Survival From Randomization According to Mitogen-Activated Protein Kinase (MAPK) Pathway Activation (Intent-to-Treat Population)
Shaded areas indicate 95% CIs.
See this image and copyright information in PMC

Comment in

References

    1. Ron DA, Vera R, Labandeira CM, et al. . Maintenance treatment in metastatic colorectal cancer: in search of the best strategy. Clin Transl Oncol. 2020;22(8):1205-1215. doi:10.1007/s12094-019-02267-9 - DOI - PubMed
    1. Sonbol MB, Mountjoy LJ, Firwana B, et al. . The role of maintenance strategies in metastatic colorectal cancer: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncol. 2020;6(3):e194489. doi:10.1001/jamaoncol.2019.4489 - DOI - PMC - PubMed
    1. Cervantes A, Adam R, Roselló S, et al. ; ESMO Guidelines Committee . Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32. doi:10.1016/j.annonc.2022.10.003 - DOI - PubMed
    1. Aparicio T, Ghiringhelli F, Boige V, et al. ; PRODIGE 9 Investigators . Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018;36(7):674-681. doi:10.1200/JCO.2017.75.2931 - DOI - PubMed
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026 - DOI - PubMed

Publication types

Associated data