FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation–Positive Non–Small Cell Lung Cancer

Abstract

On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca UK Limited) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrently, a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen) as a companion diagnostic test was approved. The approval was based on the results of a multicenter, single-arm, open-label clinical study of 106 treatment-na€ ve patients with metastatic EGFR mutation-positive NSCLC who received gefitinib, 250 mg daily, until disease progression or intolerable toxicity. The major efficacy outcome was RECIST v1.1 objective response rate (ORR). The blinded independent central review (BICR) ORR was 50% [95% confidence interval (CI), 41-59] with a median duration of response (DoR) of 6.0 months. Efficacy results were supported by a retrospective exploratory analysis of a subset of a randomized, multicenter, open-label trial on 1,217 patients with metastatic NSCLC. Of the patients randomized, 186 (15%) were retrospectively determined to be EGFR positive and evaluable for a BICR assessment. The HR for progression-free survival (PFS) was 0.54 (95% CI, 0.38-0.79), favoring gefitinib over platinum-doublet chemotherapy. The most common (20%) adverse reactions were skin reactions, increased aspartate and alanine aminotransferase, proteinuria, and diarrhea. Approximately 5% of patients discontinued treatment due to an adverse reaction. Given the safety profile and clinically meaningful ORR, DoR, and PFS, the benefit-risk analysis was deemed favorable for FDA approval.

Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…However, gefitinib was reapproved by the FDA based on a phase IV study and is now available in the United States. 16,147 Erlotinib and gefitinib are orally active TKIs that are very well tolerated by most patients. 148,149 An analysis of 5 clinical trials in patients, mainly from the Western hemisphere (n=223), with advanced NSCLC (stage IIIB or IV) found that those with sensitizing EGFR mutations who received TKIs had a 67% response rate and an OS of approximately 24 months.…”

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

“…One of such EGFR TKIs is gefitinib (commercial name Iressa; AstraZeneca UK limited) which has been recently approved by FDA as a first-line treatment for metastatic EGFR mutation-positive NSCLC patients (Kazandjian et al , 2016), though recent studies revealed that some NSCLC patients without EGFR mutation(s) also respond to TKIs including gefitinib (the first generation) and afatinib (the second generation) (Home, 2016; Gridelli et al , 2011; Chao et al , 2015). Although EGFR TKI therapies have significantly improved the survival of NSCLC patients, acquired drug resistance eventually emerges and significantly limits the therapeutic potency of EGFR TKI treatments (Koehler and Schuler, 2013).…”

Three-color crystal digital PCR

“…Cell-free DNA has therefore now been accepted as a viable alternative to biopsy, as shown by the recent recommendation by Health authorities in the USA and Europe to allow circulating DNA to be used to determine the presence of absence of specific cancerous mutations, and therefore assess the therapeutic pertinence of targeted therapies [45], [46].…”