Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy

ABSTRACT

Introduction

The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time.

Areas Covered

This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed.

Expert Opinion

Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.

KEYWORDS:

• Colorectal cancer
• EGFR
• epidermal growth factor
• epidermal growth factor inhibitors
• HER2
• rechallenge

Article highlights

• Translational research has led to targeted therapies for mCRC patients, with specific subsets benefiting from tailored treatments.

• BRAF V600 mutation is associated with poor prognosis and resistance to chemotherapy. Combination therapies with encorafenib plus cetuximab, have shown improved outcomes in refractory BRAF V600E mCRC patients.

• Selective KRAS G12C inhibitors have demonstrated promise outcomes combined with EGFR inhibitors, emphasizing the potential of dual-inhibitor strategies.

• Utilizing ctDNA-guided anti-EGFR rechallenge could be a safe and effective approach for refractory mCRC patients.

• Various HER2-targeted therapies, including monoclonal antibodies and antibody-drug conjugates, show clinical efficacy in HER2-positive mCRC.

• Bispecific antibodies targeting HER2, EGFR and MET show promising results in preclinical and early clinical studies, offering potential new treatment options for mCRC patients.

Declaration of interest

NS González has received accommodation and travel expenses from Amgen and Merck; and personal speaker honoraria from Amgen.

I Baraibar has received accommodation and travel expenses from Amgen, Merck, Sanofi, and Servier; and personal speaker honoraria from Astra Zeneca.

J Ros declares personal speaker honoraria from Sanofi and Amgen, and accommodation expenses from Pierre Fabre, Servier, Amgen, and Merck.

F Salvà declares to have received personal financial interest, honoraria for advisory role, travel grants and research grants from Hoffmann-La Roche Sanofi Aventis, Amgen, Merck Serono, Servier, Bristol Myers Squibb, and Holmium

M Rodríguez declares to have travel expenses from Merck and Amgen.

A Alcaraz declares to have travel expenses from Merck.

A García declares to have travel expenses from Merck.

J Tabernero reports personal financial interest in form of scientific consultancy role for Alentis Therapeutics, AstraZeneca, Aveo Oncology, Boehringer Ingelheim, Cardiff Oncology, CARSgen Therapeutics, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, hC Bioscience, Ikena Oncology, Immodulon Therapeutics, Inspirna Inc, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Takeda Oncology and Tolremo Therapeutics. Stocks: Oniria Therapeutics, Alentis Therapeutics, Pangaea Oncology and 1TRIALSP, and also educational collaboration with Medscape Education, PeerView Institute for Medical Education and Physicians Education Resource (PER).

E Élez declares personal financial interest for consulting/advisory role and/or honoraria, and/or travel grants and research grants from Amgen, Array BioPharma, Bayer, BMS, Boehringer Ingelheim, Bristol-Myers Squibb, Cure Teq AG, Hoffman-La Roche, Janssen, Lilly, Medscape, Merck Serono, MSD, Novartis, Organon, Pfizer, Pierre Fabre, Repare Therapeutics, RIN institute, Roche, Sanofi, Seagen international GmbH, Servier, Takeda. E.E. declares institutional financial interest in from of financial support for clinical trials or contracted research for Abbvie Deutschland GmbH & Co KG, Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bayer, BeiGene, Bioncotech Therapeutics, Biontech RNA Pharmaceuticals GMBH, Biontech Small Molecules GMBH, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Iovance Biotherapeutics, Inc., Janssen-Cilag SA, MedImmune, Menarini, Menarini Ricerche SPA, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Nouscom SRL.,Novartis Farmacéutica SA, Pfizer, Pharma Mar, Pledpharma AB, Redx Pharma PLC, Sanofi Aventis Recherche & Développement, Scandion Oncology, Seattle Genetics Inc, Servier, Sotio A.S, Taiho Pharma U.S.A. Inc. Wntresearch AB.

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 apart from those disclosed.

Reviewer disclosure

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

Acknowledgments

We thank Sarah MacKenzie for editorial assistance.

Additional information

Funding

This paper was not funded.