FDA Grants Priority Review to Afatinib for NSCLC With Rare EGFR Mutations

Martina Flammer, MD

The FDA has granted a priority review to a supplemental new drug application (sNDA) for afatinib (Gilotrif) for the frontline treatment of patients with metastatic non—small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 21 (L861Q), G719X, or S768I substitution mutations.

UPDATE 1/14/2018: FDA Expands Afatinib's Approval for Lung Cancer

Uncommon mutations such as these represent less than 10% of the EGFR mutations found in NSCLC patients, but are associated with poor prognosis and survival, Boehringer Ingelheim, the manufacturer of afatinib, noted in a press release.

The FDA grants priority review designation to drugs that have the potential to provide significant improvements in the safety or effectiveness in the treatment, diagnosis, or prevention of serious conditions compared to available therapies. Under priority review, the FDA typically takes action within 6 months of receiving a supplemental application rather than the standard 10 months.

“The acceptance of the sNDA filing with priority review recognizes our company's ongoing commitment to further study Gilotrif in areas of high unmet medical need for patients with few treatment options," Martina Flammer, MD, vice president, Clinical Development & Medical Affairs Specialty Care, Boehringer Ingelheim Pharmaceuticals, said in a statement. “If approved for this additional indication, Gilotrif would offer the broadest first-line treatment option for patients with EGFR mutation—positive NSCLC.”

Boehringer Ingelheim submitted data from the LUX-Lung 2, 3, and 6 trials to support the sNDA. Overall, tyrosine kinase inhibitor (TKI)—naïve patients with EGFR mutation-positive stage IIIb-IV lung adenocarcinomas (N = 600) were assigned to afatinib in a single group phase II trial (LUX-Lung 2 [LL2]) and randomized phase III trials (LUX-Lung 3 [LL3]and LUX-Lung 6 [LL6]).

The overall frequency of patients with uncommon EGFR mutations was 18% (n = 23) in LL2, and 11% in both LL3 (n = 37) and LL6 (n = 40). Across the 3 trials, 129 patients in LL2, 229 in LL3, and 242 in LL6 received afatinib. A post-hoc analysis examined 75 (13%) patients across the 3 trials who received afatinib and were positive for uncommon EGFR mutations

Investigators stratified patients with point mutations or duplications in exons 18-21 into group 1 (n = 38), patients with de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations into group 2 (n = 14), and those with exon 20 insertions as group 3 (n = 23).

Seventeen percent of patients in LL2, 96% of patients in LL3, and 100% of patients in LL6 started at 40 mg afatinib. One patient in LL3 started at 50 mg because of a protocol deviation. There were no significant demographic differences in patients with uncommon mutations compared with patients with del19 and Leu858Arg mutations.

In group 1, 27 patients (71.1%; 95% CI, 54.1-84.6) in group 1 had objective responses compared with 2 patients each in group 2 (14.3%; 95% CI, 1.8-42.8), and group 3 (8.7%; 95% CI, 1.1-28.0).

Median progression-free survival (PFS) was 10.7 months (95% CI, 5.6-14.7) in group 1, 2.9 months (95% CI, 1.2-8.3) in group 2, and 2.7 months (95% CI, 1.8-4.2) in group 3. Median overall survival (OS) was 19.4 months (95% CI, 16.4-26.9) in group 1 compared with 14.9 months (95% CI, 8.1-24.9) in group 2, and 9.2 months (95% CI, 4.1-14.2) in group 3.

Fourteen patients (77.8%; 95% CI, 52.4-93.6) with Gly719Xaa had an objective response, as did 9 (56.3; 95% CI, 29.9-80.2) with Leu861Gln, and 8 (100%; 95% CI, 63.1-100.0) with Ser768Ile.

“Afatinib showed activity in patients with non—small cell lung cancer tumors that contained the more frequently reported types of uncommon EGFR mutations,” the investigators wrote. “Although these data should be interpreted with caution because of the small number of patients assessed in this study, these data might inform therapeutic options for patients with non—small cell lung cancer with uncommon EGFR mutations.”

At the time of the analysis, 71 patients (95%) of patients assigned to afatinib had discontinued treatment, 48 of whom had initiated other systemic anticancer treatments. Across all subsequent lines of treatment, 59% patients received chemotherapy and 20% received an EGFR TKI. Of the 17 patients who received subsequent treatments in the chemotherapy group, 48% were given an EGFR TKI and 32% were given additional chemotherapy.

Yang JC-H, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harboring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi.org/10.1016/ S1470-2045(15)00026-1.