On January 12, 2018 the FDA expanded approval to Boehringer Ingelheim Pharmaceutical, Inc. to market Gilotrif® (afatinib) for the frontline treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor a non-resistant epidermal growth factor receptor (EGFR) mutation . Afatinib, an EGFR tyrosine kinase inhibitor (TKI), was originally approved in 2013 to treat patients with NSCLC whose tumors harbored an EGFR exon 19 deletion or an exon 21 (L858R) substitution . Activated EGFR stimulates cellular growth and survival and has been implicated in the progression and maintenance of several malignancies. About 14-38% of NSCLC tumors harbor activating mutations in the EGFR gene with exon 19 deletions and L858R substitutions being the most common alterations detected . Rare, activating EGFR mutations, which make up about 10% of detected EGFR mutations in NSCLC, include other exons 18-21 point mutations or duplications, exon 20 insertions, and de-novo T790M mutations . The latter mutation is a known resistance mechanism to first- and second-generation EGFR TKIs such as afatinib.
The expanded approval was based on a retrospective subset analysis of patients with rare EGFR mutations in three previously conducted trials: LUX-Lung 2, LUX-lung 3, and LUX-lung 6. Patients with other exons 18-21 point mutations or duplications experienced a 71% objective response rate (ORR), while patients with de-novo T790M mutations and exon 20 insertions experienced only a 14.3% and 8.7% ORR, respectively . Median progression free survival and overall survival were also superior in the group of patients with other exons 18-21 point mutations or duplications compared to the other groups . These data suggest that afatinib is clinically active against certain types of rare EGFR mutations and can help guide treatment decisions based on the specific EGFR mutation detected in a NSCLC sample.
- GILOTRIF® (afatinib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products 2018 January 12, 2018 [cited 2018 April 24]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf.
- GILOTRIF™ (afatinib) tablets, for oral use, Initial U.S. Approval: 2013 Drugs@FDA: FDA Approved Drug Products July 12, 2013 [cited 2018 April 24]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf.
- Zhang, Y.L., et al., The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget, 2016. 7(48): p. 78985-78993.
- Yang, J.C., et al., Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol, 2015. 16(7): p. 830-8.