Dacomitinib Bests Gefitinib in EGFR-Mutant NSCLC

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Dacomitinib, a second-generation EGFR inhibitor, reduced the risk of disease progression 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-mutant non–small cell lung cancer.

Tony Mok, MD

Tony Mok, MD, professor and chair of the Department of Clinical Oncology at the Chinese University of Hong Kong in Hong Kong, China

Tony Mok, MD

Dacomitinib, a second-generation EGFR inhibitor, reduced the risk of disease progression 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-mutant non—small cell lung cancer (NSCLC), according to data from a phase III trial presented at the 2017 ASCO Annual Meeting.1

In the ARCHER 1050 trial, 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 gefinitib (HR, 0.40; 95% CI, 0.31-0.53; P <.0001).

Mok said the PFS that dacomitinib demonstrated in the study was among the highest observed in clinical trials of EGFR tyrosine kinase inhibitors (TKIs) in the malignancy, including gefitinib, erlotinib (Tarceva), and afatinib (Gilotrif), the 3 agents approved for NSCLC in the United States.

“Dacomitinib should be considered as a new treatment option for first-line management of patients with advanced EGFR-mutated NSCLC,” said lead study author Tony Mok, MD, professor and chair of the Department of Clinical Oncology at the Chinese University of Hong Kong in Hong Kong, China, while discussing the results during a June 5 presscast. “I think this is the first randomized phase III study comparing a second-generation with a first-generation TKI where we demonstrated improvement in efficacy.”

Dacomitinib blocks EGFR more effectively than first-generation inhibitors, which gives it the ability to keep tumor growth inhibited for a longer period of time. It is an irreversible EGFR TKI, which is characterized by inhibition of 3 members of the ErbB protein family, including EGFR/HER1, HER2, and HER4.

Mok noted that the dacomitinib’s efficacy was accompanied by an increase in skin and gastrointestinal toxicities. ASCO expert John Heymach, MD, PhD, also commented about the efficacy versus toxicity balance.

“It’s been nearly 15 years since EGFR-targeted therapies were introduced, helping extend survival for thousands of patients in the time since. The second generation of these therapies is more effective, but can also cause greater side effects, so patients and their doctors will need to weigh the risks and benefits,” Heymach said in a statement.

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). “At the time we designed this study, we were not sure of dacomitinib’s efficacy in the brain. For gefitinib, the efficacy is marginal [in terms of the] data, and so for that reason we decided to exclude patients with CNS metastases,” Mok explained.

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, Mok noted. 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). Mok said overall survival data were not yet mature.

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 general heightened toxicity for dacomitinib may be due to the chemical nature of the drug, Mok said, since it’s an irreversible TKI. Dose modifications for the drug were relatively common, with 150 patients in the dacomitinib arm receiving a dose reduction (66.1%), with a median time to dose reduction of 2.8 months, compared with 18 patients (8.0%) and a median time to dose reduction of 3.3 months.

In prior research, dacomitinib has shown encouraging clinical activity as initial systemic treatment in treatment-naïve patients with advanced NSCLC.2 In a single-arm phase II trial, investigators enrolled a total of 89 patients, including 45 (51%) with EGFR-activating mutations in exon 19 (n = 25) or exon 21 (n = 20).2 The objective response rate was 75.6% among EGFR-mutant patients. “Based on these data, we were quite confident in the hypothesis that dacomitinib may be more efficacious than gefitinib, and this laid the background for the phase III study,” Mok said.

References

  1. 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).
  2. Jänne PA, Ou SH, Kim DW, et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2014;15(13):1433-1441. doi: 10.1016/S1470-2045(14)70461-9.

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