Afatinib: First Global Approval

Abstract

Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif™) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-positive NSCLC. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif®) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naïve. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.

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

“…17,18 The FDA has approved afatinib for first-line treatment of patients with metastatic nonsquamous NSCLC who have sensitizing EGFR mutations. 19,20 These sensitizing EGFR mutations are found in approximately 10% of Caucasian patients with NSCLC and up to 50% of Asian patients. 21 Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).…”

“…20 The FDA approved afatinib for the first-line treatment of patients with metastatic NSCLC who have sensitizing EGFR mutations. 19,157 Based on this phase III randomized trial and the FDA approval, the NCCN panel recommends afatinib for first-line therapy (category 1) in patients with metastatic nonsquamous NSCLC who have sensitizing EGFR mutations (see NSCL-18, page 507). 17,20,112 Afatinib may also be continued in patients whose disease has progressed if they do not have multiple systemic symptomatic lesions (see "Continuation of Erlotinib, Gefitinib, or Afatinib After Progression," page 525).…”

Real-World Outcomes in Patients with Alk-Positive Non-Small Cell Lung Cancer Treated with Crizotinib

“…Several epidermal growth factor receptor (egfr) and anaplastic lymphoma kinase (alk) inhibitors are now approved that have shown substantial response rates in patients with nsclc who have certain egfr mutations and alk rearrangements [7][8][9][10] . Crizotinib, for example, has been shown in clinical studies to be associated with tumour reduction or stabilization in 90% of alk+ patients, with response duration of up to 15 months 11 and superior efficacy versus standard chemotherapy 12,13 .…”

Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases

“…Crizotinib and ceritinib are approved for use in ALK rearranged tumors, [15][16][17] while erlotinib, gefitinib, and afatinib are approved for tumors with EGFR mutations. [18][19][20][21] In the US population, these therapies are applicable to a minority of patients with lung carcinoma, as ALK rearrangement is present in o 5% of lung adenocarcinomas and EGFR mutations are present in 15-25% of lung adenocarcinomas. KRAS mutations are present in a substantial number of lung adenocarcinomas in the US population (roughly 25-30%), but there are currently no approved targeted therapies for these mutations.…”