DACOMITINIB, a second-generation epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitor, outperformed gefitinib (Iressa) as first-line treatment for EGFR-positive advanced non–small cell lung cancer (NSCLC) in the phase III ARCHER 1050 study.1 Dacomitinib improved progression-free survival by about 5 months and the duration of response compared with gefitinib. No new safety signals were observed for dacomitinib in this study, and patient-reported outcomes regarding lung cancer–associated symptoms were similar for dacomitinib and gefitinib.
“ARCHER 1050 is the first randomized phase III study to compare a second-generation EGFR tyrosine kinase inhibitor with a standard first-generation EGFR tyrosine kinase inhibitor for first-line treatment of patients with advanced EGFR-mutated NSCLC. The median progression-free survival of 14.7 months [with dacomitinib] is among the highest ever reported in advanced lung cancer. Dacomitinib should be considered a new treatment option for first-line management of patients with advanced EGFR-mutated NSCLC,” stated lead author Tony Mok, MD, Professor and Chair of the Department of Clinical Oncology, Chinese University of Hong Kong, at the 2017 ASCO Annual Meeting.
“Dacomitinib may be an even more effective treatment for these patients, but patients need to be aware of the side effect-profile when making decisions,” he added.
Each year, about 15,000 people in the United States are diagnosed with EGFR-positive NSCLC, and these patients receive EGFR tyrosine kinase inhibitor as first-line treatment, with either gefitinib, erlotinib (Tarceva), or afatinib (Gilotrif).
Dacomitinib is a more potent inhibitor of EGFR than the first-generation inhibitors, which explains its ability to keep tumor growth under control for a longer duration. However, more potent inhibition also suppresses normal EGFR in healthy tissue, leading to more side effects such as skin rash, acne, and diarrhea.
ARCHER 1050 was a phase III open-label, randomized trial that enrolled 452 patients with EGFR-positive NSCLC and no prior treatment for advanced disease. Patients were not allowed to enroll if they had brain metastasis. Patients were randomized 1:1 to receive either dacomitinib at 45 mg/d or gefitinib at 250 mg/d. Both drugs are in oral formulation. The primary endpoint was progression-free survival by blinded independent review; secondary endpoints included investigator-assessed progression-free survival, objective response rate, duration of response, time to treatment failure, overall survival, safety, and patient-reported outcomes.
Both arms were well balanced for baseline demographic characteristics. Median age was about 61.5 years; about 76% were Asian; 64% were never-smokers; 59% had exon 19 deletion, and 41% had L858R mutation in exon 21.
FOR THE PRIMARY endpoint, median progression-free survival was 14.7 months in the dacomitinib arm vs 9.2 months in the gefitinib arm—a 41% reduction in the likelihood of disease progression favoring dacomitinib (P < .0001). At 24 months, 30.6% of the dacomitinib group vs 9.6% of the gefitinib group were free of progressive disease.
The best overall objective response rate was 74.9% for dacomitinib vs 71.6% for gefitinib. The median duration of response was significantly longer with dacomitinib: 14.8 vs 8.3 months (P < .0001).
Overall survival data were not mature, with only 36.9% of expected events at the time of data cutoff. The side-effect profiles of the two drugs differed. The incidence of diarrhea, skin rash, and mucositis was higher with dacomitinib, and the incidence of hepatic toxicity was higher with gefitinib. The incidence of adverse events associated with dacomitinib was similar to that in other dacomitinib studies.
The most common grade 3 side effects of dacomitinib were acne (14% of patients) and diarrhea (8% of patients). Elevated liver enzymes were the most common severe (grade 3) side effect of gefitinib (8%).
Dose modifications were needed more often with dacomitinib. The median time to dose reduction was 2.8 months with dacomitinib, vs 3.3 months with gefitinib; the median duration of dose reduction was 11.3 months and 5.2 months, respectively. In the dacomitinib arm, 150 patients (66.1%) required dose modification compared with 18 patients (8%) in the gefitinib arm. ■
DISCLOSURE: Dr. Mok owns stock in Sanomics Limited; has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche/Genentech; has served as a consultant or advisor to ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cirina, Clovis Oncology, geneDecode, Ignyta, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGeneX, Pfizer, Roche/Genentech, SFJ Pharmaceuticals Group, and Vertex; and has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eisai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals Group, and Taiho Pharmaceutical.
1. Mok T, Cheng Y, Zhou X, et al: Dacomitinib versus gefitinib for the first-line treatment of advanced non-small cell lung cancer (ARCHER 1050): A randomized, open-label, phase III trial. 2017 ASCO Annual Meeting. Abstract LBA9007. Presented June 6, 2017.