Dacomitinib Represents Potential New Targeted Therapy for EGFR Mutation–Positive Lung Cancer
Chicago, IL—The investigational, second-generation EGFR inhibitor dacomitinib reduced the risk for disease progression compared with gefitinib as first-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) and EGFR mutation. Results from the phase 3 ARCHER 1050 clinical trial demonstrated a >40% reduction in the risk for disease progression and an average 6.5-month improvement in the duration of response with dacomitinib versus gefitinib.
“Dacomitinib should be considered as a new treatment option for first-line management of patients with advanced EGFR-mutated NSCLC,” said lead investigator Tony Mok, MD, FRCPC, FRCP, Chair, Department of Clinical Oncology, Chinese University of Hong Kong, who presented the ARCHER 1050 clinical trial results at the 2017 ASCO annual meeting. “In addition to the 3 existing drugs, we now have a fourth one,” he added.
Dacomitinib is an irreversible EGFR tyrosine kinase inhibitor that inhibits 3 members of the ErbB protein family—EGFR/HER1, HER2, and HER4—implying that dacomitinib induces a more potent inhibition of EGFR.
The ARCHER 1050 clinical trial enrolled 452 patients with advanced NSCLC who harbored EGFR activating mutations. The patients were randomized to receive dacomitinib 45 mg daily or gefitinib 250 mg daily. Previous systemic treatment of advanced NSCLC was not permitted. Approximately 75% of the patients in each treatment arm were Asian.
At 24 months, 30.6% of patients in the dacomitinib arm did not have disease progression compared with 9.6% in the gefitinib arm, said Dr Mok.
With a median duration of follow-up of 22 months, the median progression-free survival (PFS) was 14.7 months in patients who received dacomitinib compared with 9.2 months in patients who received gefitinib, corresponding to a 41% reduction in the risk for disease progression with dacomitinib (hazard ratio [HR], 0.59; P <.0001).
“The median PFS with dacomitinib of 14.7 months is actually among the highest in most of the randomized phase 3 studies in the first-line setting,” he noted.
The median duration of response was 14.8 months with dacomitinib versus 8.3 months with gefitinib (HR, 0.40; P <.0001). The overall survival data were not yet mature at the time of data cutoff (ie, July 29, 2016).
More potent EGFR inhibition was associated with greater toxicity. Gastrointestinal adverse events of any grade were more common in the dacomitinib arm than in the gefitinib arm, including diarrhea (87.2% vs 55.8%, respectively) and decreased appetite (30.8% vs 24.6%). More patients assigned to dacomitinib experienced paronychia (61.7% vs 20.1%), dermatitis acneiform (48.9% vs 28.6%), and stomatitis (43.6% vs 17.9%). In contrast, a higher percentage of gefitinib recipients had increases in ALT (39.3%) compared with patients receiving dacomitinib (19.4%).
Although the rates of serious adverse events were similar between the 2 arms (27.3% with dacomitinib vs 22.3% with gefitinib), the rate of treatment-related serious adverse events was twice as high in the dacomitinib arm (9.3%) than in the gefitinib arm (4.5%), and 9.7% of dacomitinib recipients permanently discontinued the drug because of treatment-related adverse events compared with 6.7% of the gefitinib group. “The good news is that there is minimal drug-related death,” said Dr Mok, noting that only 2 patients in the dacomitinib arm and 1 in the gefitinib arm died related to the treatment.
A total of 150 (66.1%) patients in the dacomitinib arm required dose reduction, with a median time to dose reduction of 2.8 months compared with 18 (8.0%) patients and a median time to dose reduction of 3.3 months in the gefitinib arm.
Both drugs were neutral on global quality-of-life measures, Dr Mok noted.
ASCO expert John V. Heymach, MD, PhD, Chairman, Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, said that the more-than-5-month difference in PFS is a “substantial advance, and I think it really puts dacomitinib at the front of the pack in terms of efficacy. About 10% of [dacomitinib] patients had grade 3 toxicity involving skin and diarrhea, and a substantial number had dose reductions, but I’d like to emphasize that these aren’t life-threatening toxicities.”