Afatinib Indication Expands to Include Metastatic NSCLC with Rare, Nonresistant EGFR Mutations

TON Web Exclusives - Lung Cancer

Among North American patients with non–small-cell lung cancer (NSCLC), approximately 20% have genetic mutations that can lead to constant activation of the epidermal growth factor receptor (EGFR) protein.1 Currently, 4 orally administered inhibitors of EGFR are available in the United States to treat specific subsets of these patients: afatinib (Gilotrif), erlotinib (Tarceva), gefitinib (Iressa), and osimertinib (Tagrisso).

Approximately 90% of patients with EGFR-mutation–positive NSCLC have 1 of 2 specific nonresistant mutations: exon 19 deletions or exon 21 L858R substitutions. The presence of either of these mutations predicts patient sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The other 10% of patients with EGFR-mutated NSCLC have “rare” nonresistant mutations, such as S768I, L861Q, and G719X. In these patients, response to EGFR TKIs is variable.2

On January 12, 2018, the FDA approved afatinib for a broadened indication in the first-line treatment of patients with metastatic NSCLC whose tumors have rare, nonresistant EGFR mutations as detected by an FDA-approved test (therascreen® EGFR RGQ PCR Kit, QIAGEN).2,3 Of note, the safety and efficacy of afatinib have not been established in patients whose tumors have resistant EGFR mutations.

“Compared with other EGFR mutations, L861Q, G719X, or S768I substitution mutations are associated with a poorer prognosis and limited treatment options,” said Edward Kim, MD, Levine Cancer Institute, Carolinas HealthCare System, in a press release.2 “The approval of Gilotrif as a targeted therapy for these additional non-resistant EGFR mutations significantly alters the treatment strategy for this population.”  

Afatinib was initially approved by the FDA in 2013 for the treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by the QIAGEN test. In 2016, the drug’s indication was expanded to include the treatment of patients with metastatic NSCLC of squamous histology who progressed after platinum-based chemotherapy.

Patients with metastatic NSCLC and rare, nonresistant EGFR mutations were enrolled in 1 of 3 clinical trials of afatinib: LUX-Lung 2, LUX-Lung 3, or LUX-Lung 6. A pooled analysis of data from these studies showed that afatinib is active in rare EGFR mutations based on objective response rate, duration of response, disease control, progression-free survival, and overall survival.2,3

Of the 75 patients in these trials who had uncommon EGFR mutations, 32 had a nonresistant mutation. Among these 32 patients, the median age was 60.5 years (range, 32-79 years), 66% were women, 97% were Asian, 3% were other races, 63% had an Eastern Cooperative Oncology Group performance status 1, 66% were never smokers, 28% were former smokers, and 6% were current smokers. Baseline disease characteristics were 97% stage IV disease, 3% stage IIIb disease, and 88% had received no prior systemic therapy for advanced or metastatic disease.4

Efficacy data for afatinib in these 32 patients with rare nonresistant EGFR mutations are summarized in the Table.4


“This approval is more welcome news for our lung cancer community,” said Laurie Fenton Ambrose, President and CEO of Lung Cancer Alliance, in a press release.2 “These types of advances are helping expand access to treatment options for patients who might benefit from targeted therapies.”

1. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5:2892-2911.
2. FDA approves new indication for Gilotrif® in EGFR mutation-positive NSCLC. January 16, 2018. Accessed January 24, 2018.
3. FDA broadens afatinib indication to previously untreated, metastatic NSCLC with other non-resistant EGFR mutations. January 16, 2018. Accessed January 24, 2018.
4. Gilotrif (afatinib) tablets, for oral use [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; Revised January 2018.


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Last modified: January 29, 2018

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