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Diagnosis and Treatment of ERBB2-Positive Metastatic Colorectal CancerA Review

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Importance  Amplification of ERBB2 (formerly referred to as HER2) is present in nearly 3% of patients with metastatic colorectal cancer overall and 5% of patients with KRAS and NRAS wild-type tumors. Despite the availability of several ERBB2-targeted therapeutic options for patients with ERBB2-positive breast and gastric/gastroesophageal tumors, to date, there are currently no approved therapies for patients with ERBB2-positive metastatic colorectal cancer, although ERBB2-targeted therapies are recommended in National Comprehensive Cancer Network guidelines. Recent evidence indicates that anti-ERBB2 therapeutic strategies are active in patients with ERBB2-positive metastatic colorectal cancer and could potentially represent a new standard-of-care.

Observations  The protein ERBB2 is a member of a family of epidermal growth factor receptors that also includes epidermal growth factor receptor (ERBB1), ERBB3, and ERBB4. Amplification of ERBB2 leads to overexpression of the ERBB2 tyrosine kinase receptor, resulting in aberrant signaling and cell migration, growth, adhesion, and differentiation. Colorectal tumors that harbor ERBB2 amplification are more likely to originate on the left side of the colon, are associated with primary and acquired resistance to anti–epidermal growth factor receptor therapies, and have increased incidence of central nervous system metastases. Using immunohistochemistry, fluorescence in situ hybridization, next-generation sequencing, and liquid biopsy techniques, several randomized clinical trials have evaluated the efficacy of ERBB2-targeted therapies in patients with ERBB2-positive metastatic colorectal cancer. These therapies include monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors, many of which were associated with favorable efficacy and safety profiles when treating patients with ERBB2-positive metastatic colorectal cancer.

Conclusions and Relevance  The results of this review suggest the ERBB2 receptor is a promising target for patients with metastatic colorectal cancer; however, to date, no therapies are approved for use in this patient population. Therefore, it is imperative to continue to work to address this unmet need so that patients with ERBB2-positive metastatic colorectal cancer have therapeutic options should they become refractory to treatment with standard therapies.

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Article Information

Accepted for Publication: December 14, 2021.

Published Online: March 3, 2022. doi:10.1001/jamaoncol.2021.8196

Corresponding Author: Tanios Bekaii-Saab, MD, Division of Hematology and Oncology, Mayo Clinic, 5701 E Mayo Blvd, Phoenix, AZ 85054 (bekaii-saab.tanios@mayo.edu).

Author Contributions: Drs Strickler and Bekaii-Saab had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Strickler, Yoshino, Siena, Bekaii-Saab.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Strickler, Yoshino, Siena, Bekaii-Saab.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Strickler.

Supervision: Strickler, Siena, Bekaii-Saab.

Conflict of Interest Disclosures: Dr Strickler reported nonfinancial support from Seagen during the conduct of the study as well as personal fees from AbbVie, AstraZeneca, Bayer, GlaxoSmithKline, Natera, Pfizer, Seagen, Viatris, Mereo Biopharma, Silverback Therapeutics, and Inivata and grants from Bayer, Erasca, AStar D3, Silverback Therapeutics, Nektar, Roche/Genentech, Sanofi Genzyme, Gossamer Bio, AbbVie, Amgen, Daiichi-Sankyo, Curegenix, and Seagen outside the submitted work. Dr Yoshino reported grants from Taiho Pharmaceuticals, Sumitomo Dainippon Pharma, Chugai Pharmaceutical, Amgen, Sanofi, Daiichi Sankyo, Merck Sharp and Dohme, Parexel International, and ONO Pharmaceutical outside the submitted work. Dr Graham reported service on the advisory board of Incyte Advisory, personal fees from Mayo Clinic, and grants from Bristol Myers Squibb outside the submitted work. Dr Siena reported being an advisory board member for Seagen, Daiichi Sankyo, Roche-Genentech, Novartis, and Guardant during the conduct of the study. Dr Bekaii-Saab reported research funding from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seagen, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and Bristol Myers Squibb; consulting fees from Ipsen, Arcus, Array Biopharma, Pfizer, Seagen, Bayer, Genentech, Incyte, Merck, Stemline, AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Xilis, AstraZeneca, and Foundation Medicine; service on independent data monitoring and data safety monitoring committees for Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Lilly, PanCan, and 1Globe; scientific advisory board service for Imugene, Immuneering, and Sun Biopharma; and holding patents WO/2018/183488 and WO/2019/055687.

Additional Contributions: Medical writing support was provided by Sarah A. Laredo, PhD and editorial support was provided by Travis Taylor, BA, both of Scion, supported by Seagen Inc. according to Good Publication Practice guidelines (http://annals.org/aim/article/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3).

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Zymeworks Inc. A safety and efficacy study of ZW25 (zanidatamab) plus combination chemotherapy in HER2-expressing gastrointestinal cancers, including gastroesophageal adenocarcinoma, biliary tract cancer, and colorectal cancer. Accessed June 3, 2021. https://clinicaltrials.gov/ct2/show/study/NCT03929666
Lopez  DM , Barve  M , Wang  J ,  et al.  Abstract B005: a phase I study of A166, a novel anti-HER2 antibody-drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors.   Mol Cancer Ther. 2019;18(12 Supplement):B005-B005. doi:10.1158/1535-7163.TARG-19-B005 Google Scholar
Hamblett  K , Barnscher  S , Davies  R ,  et al.  Abstract P6-17-13: ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers.   Cancer Res. 2019;79(suppl 4). doi:10.1158/1538-7445.SABCS18-P6-17-13Google Scholar
Zymeworks Inc. A dose finding study of ZW49 in patients with HER2-positive cancers. Accessed June 3, 2021. https://clinicaltrials.gov/ct2/show/NCT03821233
Klus Pharma Inc. Study of A166 in patients with relapsed/refractory cancers expressing HER2 antigen or having amplified HER2 gene. Accessed June 3, 2021. https://clinicaltrials.gov/ct2/show/NCT03602079?term=A166&cond=colorectal+cancer&draw=2&rank=1
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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