EGFR mutations are one of the most common mutations in lung adenocarcinomas, which have an approximate 70% response rate to targeted therapy with tyrosine kinase inhibitors (TKI).
The tyrosine kinase mutation is located sub-membrane, which explains why treatment response to these tumors could not be predicted with immunohistochemistry markers to EGFR (HER-1).
Most mutations in the EGFR-TK domain are exon 19 deletions, exon 21 (L858R), or exon 18 (G719X). Resistance commonly occurs with a T790M mutation in exon 20 (many EGFR mutation testing assays do not cover exon 20 – which should be evaluated in patients who progress on therapy).
EGFR activating mutations are present in approximately 10% of non-Asian lung adenocarcinomas (up to 50% of Asians by some studies), and characteristically occur in non-smoking women. Tumors tend to be well-differentiated adenocarcinomas (lepidic pattern).
Therapy
There are multiple TKIs available for treatment. Gefitinib, erlotinib, and afatinib are such drugs available.
Gefitinib (IRESSA®)
Gefitinib (sold/marketed by AstraZeneca) was the first EGFR TKI on the market. Unfortunately in the early 2000s, it was found not to be “effective” and was pulled off the market. A small number of patients clearly responded, and further investigation identified the EGFR-TK mutations, which largely correlated to treatment response. Gefitinib was approved for use in Europe in 2009, and again finally in the US in 2015 for first line therapy in advanced disease.
Erlotinib (TARCEVA®)
Erlotinib was approved in 2013 as first-line therapy in advanced diseasewith an activating EGFR-TK mutation (exon 19 deletions or exon 21 L858R). Tarceva® is produced by Astellas Pharma.
Afatinib (GILOTRIF®)
Afatinib was approved in 2013 for first-line therapy in advanced disease with an activating EGFR-TK mutation (exon 19 deletions or exon 21 L858R).
- Testing performed through a companion diagnostic therascreen EGFR RGQ PCR Kit.
Osimertinib (TARGRISSO®)
Osimertinib is a second line TKI sold/marketed by AstraZeneca used in the specific setting of an EGFR T790M mutation (exon 20). Approximately 2/3rds of EGFR mutated tumors that progress on conventional EGFR TKI therapy have acquired a T790M mutation, which results in resistance to first-line therapy.
- It is critical when testing samples suspected of an EGFR T790M mutation, that the assay will detect the mutation. A FDA-approved test is the “cobas® EGFR Mutation Test v2.”
- Testing for the mutation is preferably based on formalin-fixed paraffin embedded tissue (FFPE). If FFPE tissue is not available, then a liquid biopsy (plasma specimen) with circulating tumor cells may be tested.
References
Lynch TJ, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350(21):2129-39 (ISSN: 1533-4406)
Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22. 290(16):2149-58.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014 Jan 7. 110 (1):55-62.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24. 362 (25):2380-8.
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1.