Protein tyrosine kinases of the human epidermal growth factor receptor family, including EGFR and HER2, have emerged as important therapeutic targets in non-small-cell lung, breast and gastroesophageal cancers, and are of relevance for the treatment of various other malignancies (particularly colorectal cancer). Classic activating EGFR exon 19 deletions and exon 21 mutations, and HER2 amplification and/or overexpression, are predictive of response to matched molecularly targeted therapies, translating into favourable objective response rates and survival outcomes. By comparison, cancers with insertion mutations in exon 20 of either EGFR or HER2 are considerably less sensitive to the currently available tyrosine kinase inhibitors and antibodies targeting these receptors. These exon 20 insertions are structurally distinct from other EGFR and HER2 mutations, providing an explanation for this lack of sensitivity. In this Review, we first discuss the prevalence and pan-cancer distribution of EGFR and HER2 exon 20 insertions, their biology and detection, and associated responses to current molecularly targeted therapies and immunotherapies. We then focus on novel approaches that are being developed to more effectively target tumours driven by these non-classic EGFR and HER2 alterations.
EGFR and HER2 exon 20 insertion mutations occur in approximately 0.35% and 0.34%, respectively, of all cancers in the American Association for Cancer Research Project GENIE database but are considerably more prevalent in urothelial, non-small-cell lung, breast and central nervous system cancers.
Sensitive targeted assays are essential to reliably detect EGFR or HER2 exon 20 insertions.
First-generation to third-generation EGFR tyrosine kinase inhibitors (TKIs) and HER2 TKIs have modest activity against cancers with exon 20 insertions in EGFR and HER2, respectively.
In 2021, both the EGFR–MET-targeted bispecific antibody amivantamab and the novel EGFR TKI mobocertinib received Accelerated Approval from the FDA for the treatment of patients with advanced-stage non-small-cell lung cancer harbouring EGFR exon 20 insertions.
New drugs and combination approaches for patients harbouring EGFR or HER2 exon 20 insertions are under investigation.
Little is known about the clinical implications of co-mutations, such as TP53 or STK11 mutations, in cancers with EGFR or HER2 exon 20 insertions, warranting further studies.
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We thank the patients, their families and the clinical trial teams who help with drug development. Molecular graphics of PDB structures were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from the NIH (grant P41-GM103311). We thank R. Tufano for annotating variants in genomic databases. The work of V.S. is supported by NIH grant R01CA242845 and by his institution via the NIH Cancer Center Support Grant (P30 CA016672). We acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations of the GENIE data are the responsibility of the study authors.
A.F. has received personal fees from Amgen, Astellas, Bayer, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Pfizer and Roche. V.S. has received grants from and holds advisory board and/or consultant positions for Eli Lilly/Loxo Oncology. V.S. has also received research grants from Abbvie, Agensys, Alfasigma, Altum, Amgen, Bayer, Berghealth, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3, Dragonfly Therapeutics, Exelixis, Fujifilm, GlaxoSmithKline, Idera Pharma, Incyte, Inhibrx, MedImmune, Multivir, Nanocarrier, the National Comprehensive Cancer Network, the National Cancer Institute Cancer Therapy Evaluation Program (CTEP), Northwest Biotherapeutics, Novartis, Pharmamar, Pfizer, Roche/Genentech, Takeda, The University of Texas MD Anderson Cancer Center, Turning Point Therapeutics and Vegenics; holds advisory board/consultant positions with Daiichi-Sankyo, Eisai, Helsinn, Incyte, MedImmune, Novartis, QED Pharma, Relay Therapeutics and Signant Health; has received travel funds from ASCO, ESMO, Incyte and Pharmamar; and has received educational seminar support from Medscape. A.R. has received personal fees for attending advisory board meetings from AstraZeneca, MSD and Novartis. G.L.B. has received personal fees from Boehringer Ingelheim, Janssen-Cilag and Roche. U.M. has received personal fees for participation in speakers bureaus and advisory roles from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Merck, MSD, Roche and Thermofisher. C.R. has received funding from the Lung Cancer Research Foundation-Pfizer Grant 2019. C.R. has also received personal fees for attending advisory board meetings from ArcherDx, BMS, Boston Pharmaceuticals, Inivata, MD Serono and Novartis; fees for speakers bureau from AstraZeneca, MSD and Roche; and non-financial support from GuardantHealth through a research collaboration. A.A. has received personal fees for attending advisory board meetings from Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer and Roche; and for speakers bureaus from AstraZeneca, Eli Lilly and MSD.
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Nature Reviews Clinical Oncology thanks K. Park, who co-reviewed with S. Park; F. Cappuzzo; and S. Vyse for their contribution to the peer review of this work.
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PDB 1M14: https://www.rcsb.org/structure/1M14
PDB 1XKK: https://www.rcsb.org/structure/1XKK
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Friedlaender, A., Subbiah, V., Russo, A. et al. EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment. Nat Rev Clin Oncol 19, 51–69 (2022). https://doi.org/10.1038/s41571-021-00558-1
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