FDA Grants Dacomitinib Priority Review for Frontline EGFR+ NSCLC

Mace Rothenberg, MD

The FDA has granted a priority review designation to dacomitinib for the frontline treatment of patients with EGFR-positive locally advanced or metastatic non—small cell lung cancer (NSCLC), according to Pfizer, the manufacturer of the pan-human EGFR tyrosine kinase inhibitor (TKI).

UPDATE 9/28/2018: FDA Approves Dacomitinib for Frontline EGFR+ NSCLC

The application is based on the phase III ARCHER 1050 trial, in which dacomitinib reduced the risk of disease progression or death by more than 40% and resulted in an average 6.5-month improvement in response duration compared with gefitinib (Iressa) as a first-line treatment for patients with advanced, EGFR-positive NSCLC.

The median progression-free survival (PFS) for patients who received dacomitinib was 14.7 months compared with 9.2 months for participants who received gefitinib (HR, 0.59; 95% CI, 0.47-0.74; P <.0001). The median duration of response (DOR) was 14.8 months with dacomitinib versus 8.3 months with gefitinib (HR, 0.40; 95% CI, 0.31-0.53; P <.0001).

The priority designation will expedite the development and review of dacomitinib in this setting. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision by September 2018. Pfizer also reported that the European Medicines Agency has accepted the Marketing Authorization Application for dacomitinib for the same indication.

“While significant progress has been made in the treatment of patients with non—small cell lung cancers harboring EGFR-activating mutations, it remains a challenging disease and new treatment options are needed,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

“In the pivotal clinical trial that supports these applications, dacomitinib showed clinically meaningful improvement in progression-free survival over gefitinib, one of the first EGFR-targeted therapies to demonstrate activity in this disease. These filing acceptances are an important step toward increasing treatment options for patients with locally advanced or metastatic EGFR-mutated non—small cell lung cancer.”

ARCHER 1050 was designed with a primary endpoint of PFS as assessed by blinded independent review, with DOR, overall response rate (ORR), and safety as secondary endpoints. The trial recruited patients with newly diagnosed stage IIIB/IV, EGFR-positive NSCLC who had not received prior systemic therapy including TKIs and an ECOG performance status of 0 or 1. Patients also could not have any metastases in the central nervous system (CNS).

A total of 452 patients were randomized in a 1:1 ratio to either receive 45 mg daily of dacomitinib (n = 227) or 250 mg daily of gefitinib (n = 225). Baseline patient characteristics were balanced across the 2 arms of the study, including in terms of race and smoking status. In the dacomitinib arm, about 75% of participants were Asian and nearly 65% were never-smokers. In the gefitinib arm, 78% were Asian and 64% were never-smokers. The median age was 61 to 62 years.

Although PFS was similar in both arms at the 6-month mark, the difference in PFS became very apparent by the 24-month mark. At 24 months, 30.6% of patients in the dacomitinib arm were progression free, compared with 9.6% in the gefitinib group. However, there was not a statistically significant difference in ORR, with 74.9% of patients in the dacomitinib achieving a response versus 71.6% of patients in the gefitinib arm (P <.3883). Overall survival data were not yet mature at the time of the analysis.

In terms of adverse events (AEs), there was more toxicity observed in the dacomitinib arm than in the gefitinib arm. Gastrointestinal all-grade AEs were more common in the dacomitinib arm compared with the gefitinib arm, including diarrhea (87.2% vs 55.8%, respectively) and decreased appetite (30.8% vs 24.6%). More patients in the dacomitinib arm compared with the gefitinib arm also experienced paronychia (61.7% vs 20.1%), dermatitis acneiform (48.9% vs 28.6%), and stomatitis (43.6% vs 17.9%). However, increases in ALT levels were observed more in the gefitinib arm (39.3%) compared with the dacomitinib arm (19.4%).

The most frequent grade 3 AEs in the dacomitinib arm were rash (14%) and diarrhea (8%). Two percent of patients receiving dacomitinib had grade 4 AEs. There were two grade 5 AEs, diarrhea and liver disease. Discontinuation due to treatment-related AEs occurred in 10% versus 7% of the dacomitinib versus gefitinib arms, respectively.

Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase 3 trial. J Clin Oncol. 2017;35(suppl; abstr LBA9007).