Afatinib Application Accepted by FDA for Squamous Cell Lung Cancer

Jason M. Broderick

An application for afatinib (Gilotrif) was recently accepted by the FDA for the treatment of patients with squamous cell non-small cell lung cancer (NSCLC).

Dr Jörg Barth

An application for afatinib (Gilotrif) was recently accepted by the FDA for the treatment of patients with squamous cell non-small cell lung cancer (NSCLC), following progression on chemotherapy, according to the manufacturer of the irreversible EGFR inhibitor, Boehringer Ingelheim.

A separate regulatory filing for afatinib in the same setting was accepted by the European Medicines Agency, Boehringer reported.

Both applications were based on results from the phase III LUX-Lung 8 study, in which the second-line afatinib was compared with erlotinib (Tarceva) in patients who have advanced squamous cell carcinoma of the lung. In the study, afatinib reduced the risk of disease progression, as well as death, by 19%, compared with erlotinib.

“Working with the US and EU regulatory authorities marks the next stage in our journey to hopefully provide patients with a new, oral treatment for squamous cell carcinoma of the lung, a condition with an extremely poor prognosis,” said Dr Jörg Barth, corporate senior vice president, therapy area head oncology, Boehringer Ingelheim. “This is an encouraging prospect for Boehringer Ingelheim, as we remain fully dedicated to improving and extending the lives of patients with different types of lung cancer.”

The open-label LUX-Lung 8 study included 795 patients with stage IIIB or IV squamous cell NSCLC who had progressed following ≥4 cycles of platinum-based-chemotherapy. Participants were randomized in a 1:1 ratio and received afatinib (n = 398) at 40 mg daily or 150 mg of erlotinib per day (n = 397) until progression. The primary outcome measure was progression-free survival (PFS); the primary secondary endpoint being overall survival (OS).

At a median follow-up of 18.4 months, OS was 7.9 months versus 6.8 months with afatinib versus erlotinib, respectively (HR, 0.81; 95% CI, 0.69-0.95;P= .0077). PFS was 2.6 months with afatinib, while erlotinib was 1.9 months (HR, 0.81; 95% CI, 0.69-0.96;P= .0103). The objective response rates were similar between the 2 arms, at 6% and 11%, respectively (P= .0551).

All-grade adverse event rates were comparable between treatment arms. Fifty-seven percent of patients in each cohort experienced grade ≥3 adverse events. Rates of grade 3 stomatitis (4% vs none) and grade 3 diarrhea (10% vs 2%) were higher in patients that received afatinib versus erlotinib. Incidence of grade 3 rash or acne was higher with erlotinib at 10% versus 6% with afatinib.

More patients reported an improvement in overall health-related quality-of-life with afatinib than erlotinib (36% vs 28%).

Afatinib is an irreversible ErbB family blocker that specifically inhibits EGFR (ErbB1), HER2 (ErbB2), and ErbB4. In 2013, the FDA approved afatinib as a frontline treatment for patients with metastatic NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. The FDA concurrently approved the therascreenEGFR RGQ PCR Kit (QIAGEN) for detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

The approval was based on results from the phase III LUX-Lung 3 trial, in which 345 patients with stage IIIB/IV lung adenocarcinoma were randomly assigned to treatment with either afatinib or a combination of cisplatin and pemetrexed. Patients in the afatinib arm experienced a median PFS of 11.1 months, compared with 6.9 months for those in the cisplatin and pemetrexed arm (HR, 0.58; 95% CI, 0.43-0.78;P= .001).

The difference in survival was more pronounced in patients who expressed either an exon 19 deletion or an exon 21 L858R substitution. Patients with those specific mutations who received afatinib experienced a median PFS of 13.6 months compared with 6.9 months in the cisplatin and pemetrexed arm (HR, 0.47; 95% CI, 0.34-0.65;P= .001).

Diarrhea, rash or acne, and stomatitis were the most common treatment-related adverse events experienced by patients in the study who received afatinib.

If approved for advanced squamous carcinoma, afatinib would be competing with the anti—PD-1 agent nivolumab (Opdivo) in this setting. Nivolumab was approved by the FDA in March for the treatment of patients with advanced squamous NSCLC who have progressed on or after platinum-based chemotherapy. The approval was based on data from the phase III CheckMate-017 trial in which nivolumab improved OS by 41% versus docetaxel in patients with advanced squamous cell NSCLC (9.2 vs 6.0 months; HR, 0.59; 95% CI, 0.44-0.79;P= .00025).

Soria J-C, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial.Lancet Oncol. 2015:16(8);897-907.