Suresh S. Ramalingam, MD

Dr. Ramalingam is Professor of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta.

MUTATIONS IN the epidermal growth factor receptor (EGFR) gene were discovered in 2004. These mutations, localized most commonly to exon 19 or 21, vary in prevalence from 15% to 35% of all cases of lung adenocarcinoma. Similar to the case with various oncogene-addicted cancers, treatment with specific receptor tyrosine kinase inhibitors results in robust therapeutic outcomes for patients with EGFR mutation.

Multiple randomized studies have established the superiority of tyrosine kinase inhibitors against EGFR over standard platinum-based chemotherapy in the front-line therapy setting for patients with advanced-stage disease. These trials demonstrated response rates of 60% to 70% and a median progression-free survival of 9 to 13 months in patients with exon 19 and exon 21 EGFR mutations. Consequently, testing for EGFR mutations and other common driver mutations is considered standard of care for patients with newly diagnosed lung adenocarcinoma.

Although EGFR tyrosine kinase inhibitor therapy is associated with high response rates and robust progression-free survival, acquired resistance invariably develops. The T790M-acquired resistance mutation has emerged as the most common mechanism, seen in approximately 50% of patients. This prompted development of new-generation EGFR inhibitors, such as osimertinib (Tagrisso), which inhibit the common EGFR tyrosine kinase inhibitor–sensitizing mutations and the T790M resistance mutation. Osimertinib was specifically studied in patients with T790M-mediated acquired resistance and has demonstrated superiority over chemotherapy. This resulted in U.S. Food and Drug Administration approval of osimertinib in the acquired-resistance setting.

Effective First-Line Therapy

MORE RECENTLY, osimertinib has been studied as initial therapy for patients with EGFR mutation–positive disease. In a cohort of 60 patients treated with osimertinib, response rates of approximately 75% to 80% and a median progression-free survival of approximately 20 months were noted. These highly promising findings have now been confirmed by the FLAURA clinical trial, reported in The New England Journal of Medicine and reviewed in this issue of The ASCO Post.¹

The FLAURA study established superiority for osimertinib over standard first-generation tyrosine kinase inhibitors (erlotinib [Tarceva] and gefitinib [Iressa]). The response rate was approximately 80%, and the median progression-free survival was 18.9 months for patients treated with osimertinib. Notably, the tolerability profile was more favorable with the newer agent. The duration of response was also twofold higher for patients treated with osimertinib. Although immature, the overall survival results also suggest a favorable trend for patients treated with osimertinib. Based on all of these findings, osimertinib is now an effective first-line therapy option for patients with EGFR mutation and has already been included in the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®).

Next Step: Novel Combinations

MECHANISMS OF resistance to first-line osimertinib therapy are beginning to be understood. It is anticipated that knowledge of the mechanisms of resistance will result in novel combination approaches based on osimertinib as the next step in the management of patients with EGFR mutations.

With the advent of immunotherapy, there is great interest in studying immune checkpoint inhibitors in patients with driver mutations. The results from randomized studies to date suggest that patients with EGFR-activating mutations have relatively low response rates and limited efficacy with immune checkpoint inhibition. For this reason, for patients with an EGFR-activating mutation, it is important to use EGFR tyrosine kinase inhibitors as a standard approach in the front-line setting.

With the results of the FLAURA study, a new standard of care has been introduced for the treatment of EGFR mutation–positive disease. This novel agent provides patients with an effective treatment option that has better central nervous system activity and improved safety over existing agents. ■

DISCLOSURE: Dr. Ramalingam reported no conflicts of interest.

REFERENCE

1. Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med 378:113-125, 2018.