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Review
. 2019 Apr 1;25(7):2033-2041.
doi: 10.1158/1078-0432.CCR-18-2275. Epub 2018 Nov 15.

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Funda Meric-Bernstam  1   2   3 , Amber M Johnson  2 , Ecaterina E Ileana Dumbrava  4 , Kanwal Raghav  5 , Kavitha Balaji  4 , Michelle Bhatt  4 , Rashmi K Murthy  6 , Jordi Rodon  4   2 , Sarina A Piha-Paul  4
Affiliations
Review

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Funda Meric-Bernstam et al. Clin Cancer Res. .

Abstract

The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Furthermore, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Furthermore, there is a rapidly growing number of new therapeutics targeting HER2 including small-molecule inhibitors, antibody-drug conjugates, and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2-targeted therapies.

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Conflict of interest statement

Conflict of Interests:

Drs. Balaji, Dumbrava, Johnson, Raghav, and Michelle Bhatt have nothing to disclose.

Dr. Murthy reports research funding from Roche/Genentech, Cascadian Therapeutics, Pfizer/Alliance, Daiichi Sankyo, and EMD-Serono.

Dr. Piha-Paul reports research funding from GlaxoSmithKline, AbbVie, XuanZhu, Incyte, Principia, Pieris, Novartis, FivePrime, Pfizer, Puma, Helix Biopharma, Curis, Newlink Genetics, Medimmune, Medivation, Taiho, and Tesaro.

Dr. Rodon reports research funding from Bayer and Novartis as well as personal fees from Servier, Peptomyc, and Lilly.

Dr. Meric-Bernstam reports funding from Novartis, AstraZeneca, Taiho Pharmaceuticals, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, PUMA Biotechnology, CytomX Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, and AbbVie as well as personal fees from Sumitomo Group, Dialectica, Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals, OrigiMed, Xencor, and Aduro.

Figures

Figure 1.
Figure 1.. HER2 alterations across tumor types
A.Prevalence of HER2 amplifications across diverse cancer types in a cohort of 37,436 sequenced cases extracted from AACR Project GENIE (version 3.0.0, accessed on 16th July 2018) (12).. B. Prevalence of HER2 mutations across diverse cancer types (version 3.0.0, accessed on 16th July 2018).
Figure 2.
Figure 2.. Activating HER2 mutations.
Mutations defined as ‘activating’ based on published data demonstrating that the alteration increases the activity, expression, or stability of the encoded protein. Additionally, alterations shown to enhance downstream signaling or increase tumorigenic properties when expressed are shown (56). Mutation Mapper from cBIO portal was used to visualize mutations (57,58).
Figure 3.
Figure 3.. Approved and emerging HER2 targeted therapies in clinical development.
HER2 targeted therapies approved by the United States Food and Drug Administration (FDA) for HER2-positive cancer or currently in clinical trials (from www.clinicaltrials.gov, last accessed July 11th 2018). “FDA” = the drug is approved by the FDA.
See this image and copyright information in PMC

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