FDA Expands Afatinib's Approval for Lung Cancer

H. Jack West, MD

The FDA has expanded the frontline indication for afatinib (Gilotrif) to include the treatment of patients with metastatic non—small cell lung cancer (NSCLC) whose tumors harbor uncommon EGFR alterations in L861Q, G719X, and/or S768I.

The approval for uncommon, non-resistance EGFR mutations was based on findings from 32 patients in the phase II LUX-Lung 2 trial (LL2) and the randomized phase III trials known as LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6). The confirmed objective response rate (ORR) with afatinib in these patients was 66% (95% CI, 47%-81%). Of those responding, 52% had duration of response lasting ≥12 months and 33% had response duration of ≥18 months.

Afatinib was initially approved by the FDA in 2013 for the treatment of patients with metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions. In 2016, this indication was expanded to include patients with squamous histology following progression on a platinum-based chemotherapy.

"For our patients who have up until now had no proven options, we actually have an evidence-based treatment option in afatinib—in addition to chemotherapy—that I think will be a very valuable addition," H. Jack West, MD, thoracic oncologist, Swedish Cancer Institute of Swedish Medical Center, told OncLive in an interview. "Over the last 2 years we have learned that EGFR mutation isn't just a binary ‘yes or no, you have it.’ It's more nuanced than that, and 88% to 90% of patients have 1 or 2 common EGFR mutations but that leaves 10% to 12% of our mutations in EGFR that are rare mutations."

The overall frequency of patients with uncommon EGFR mutations was 18% in LL2 (n = 23), and 11% in both LL3 (n = 37) and LL6 (n = 40). A posthoc analysis examined 75 patients (13%) across the 3 trials who received afatinib and were positive for uncommon EGFR mutations, which included resistant alterations. The approval was specifically for those with nonresistant EGFR alterations, which were present in 32 patients in the trials.

"Historically, for these rare mutations, we might have been futile in giving one of the first-generation inhibitors, like erlotinib (Tarceva) or gefitinib (Iressa), which has not been particularly successful. But, afatinib has been studied better, and clearly does have some activity for the majority of these," said West. "It does not work well for exon 20 insertions or T790M but for many of the other mutations that we do pick up we do now have an option with the approval of afatinib for these rare mutations."

In the 32 patients, the median age was 60.5 years (range, 32-79), and the majority were Asian (97%). Most patients had an ECOG performance status of 1 (63%), with 38% having a score of 0. Two-thirds of patients were never smokers (66%) and most had stage IV disease (97%), with the remainder having stage IIIb NSCLC. Prior systemic therapy for advanced or metastatic disease had been received by 12% of patients.

Overall, 21 patients had a single alteration, with the remainder having 2. The 1 patient with a single S7681 mutation had a response lasting 37.3 months with afatinib. Six of 8 patients (75%) with G719X alterations (n = 8) responded, with response duration lasting up to 25.2 months. Seven of 12 patients (58%) with L861Q mutations responded, with response duration ranging from 2.8 to 20.6 months.

The most common co-occurring alterations were in S768I and G719X, where 4 of 5 patients responded (80%). One of 2 patients with S768I and L858R alterations responded, with an ongoing response duration of 34.5+ months. Two of 3 patients with G719X and L861Q alterations responded and the 1 patient with L861Q and Del 19 did not respond.

An analysis of safety specific to the uncommon alterations was not conducted. The FDA noted that across studies the most common adverse events (AEs) reported in ≥20% of patients were diarrhea, rash, acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, and pruritus. For the broader indication, serious AEs were reported in 29% of patients treated with afatinib. The most frequent serious AEs were diarrhea (6.6%).vomiting (4.8%), and dyspnea, fatigue, and hypokalemia (1.7% each).

The recommended dose from the FDA was 40 mg once daily, which is the broadly approved dose. For those with renal impairment, the label recommends starting at a dose of 30 mg daily. In pivotal studies for afatinib, 57% of patients required a dose reduction due to AEs and 14% of patients discontinued treatment due to AEs.