Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials

ABSTRACT

Introduction: The addition of monoclonal antibody (mAb) epidermal growth factor receptor (EGFR) inhibitors to classic chemotherapy doublet backbones has improved survival of metastatic colorectal cancer (mCRC). However, the role of triple-drug chemotherapy regimens in combination with an anti-EGFR mAb inhibitor is not yet clear.

Areas covered: The activity of triple-drug chemotherapy regimens when combined with an anti-EGFR mAb in mCRC patients is examined. We describe the overall safety and tolerability profiles based on a literature review of all published phase I and II clinical trials in this setting. Drug exposure, tumor mutational status, and metastases resectability are discussed. A review of PubMed and abstracts of major oncology congresses from 2009 to 2018, with MeSH and full-text search terms for clinical trials of anti-EGFR for ‘metastatic’ or ‘advanced’ ‘colorectal cancer/adenocarcinoma’ was implemented. Only English language publications were included.

Expert opinion: Efficacy data from phase II trials are promising, but the safety profiles are not as encouraging; the development of severe diarrhea and acneiform rash limit the drug exposure that is critical for improved outcomes. Phase II studies of these triplet chemotherapy/anti-EGFR mAb combinations have focused on conversion therapy in liver-limited disease or in the first-line setting in advanced disease. The identification of biomarkers of response and toxicity may support the use of personalized medicine and more precise design of phase III trials.

Trial registration: ClinicalTrials.gov identifier: NCT03231722.

Trial registration: ClinicalTrials.gov identifier: NCT02980510.

Trial registration: ClinicalTrials.gov identifier: NCT01442935.

Trial registration: ClinicalTrials.gov identifier: NCT02063529.

Trial registration: ClinicalTrials.gov identifier: NCT01802645.

Trial registration: ClinicalTrials.gov identifier: NCT02515734.

KEYWORDS:

• Metastatic colorectal cancer
• antibody therapies
• triple-drug chemotherapy
• biomarkers
• epidermal grow factor receptor

Article Highlights

• Several phase II clinical trials in mCRC with triple-drug chemotherapy in combination with an anti-EGFR have been recently published or communicated in congress.

• Promising response rates of approximately 60-87% were observed in these clinical trials.

• The safety profiles of these combinations present a problem; incidences of grade 3-4 gastrointestinal toxicities were high [around 17-53%].

• There are unresolved questions with these combinations, for example, doses of irinotecan and fluorouracil, duration of these therapies and maintenance strategies with anti-EGFR ± with fluorouracil.

• New clinical trials comparing standard of care versus triple-drug chemotherapy in combination with an anti-EGFR are necessary to understand the impact of these therapies in the different settings.

This box summarizes key points contained in the article.

Declaration of interest

G Argilés reports personal fees from F. Hoffmann-La Roche, Bristol Myers Squibb, Bayer, Servier, amgen, Merck Serono and Menarini. E Elez reports grants and personal fees from Sanofi Aventis, Hoffman La Roche, Merck Serono, Amgen and personal fees from Servier.

J Tabernero reports personal fees from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has received invitations to medical meetings by Amgen and Merck Serono.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.