Dacomitinib Delayed Progression for NSCLC, Increased Adverse Events

June 6, 2017

Dacomitinib delayed progression of EGFR-positive non–small-cell lung cancer, but led to more adverse events compared with gefitinib.

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Results of the first phase III head-to-head comparison study of epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) showed that the second-generation TKI dacomitinib had significant and clinically meaningful improvement in efficacy compared with first-generation TKI gefitinib for first-line treatment of patients with EGFR-activating mutation–positive advanced non–small-cell lung cancer (NSCLC).

Results of the study (abstract LBA9007) were presented by Tony Mok, MD, professor and chair of the department of clinical oncology at the Chinese University of Hong Kong, at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6.

“Dacomitinib should be one of the new options to be considered as first-line treatment for patients with EGFR mutations,” Mok said.

According to Mok, dacomitinib is able to more effectively block EGFR compared with first-generation inhibitors like gefitinib. However, this increased suppression leads to more adverse events.

In the study, 452 patients with newly diagnosed stage IIIb/IV or recurrent NSCLC with EGFR mutations were randomly assigned to dacomitinib 45 mg or gefitinib 250 mg. Patients had to be naive of treatment with prior TKIs or immunotherapy. The primary endpoint was progression-free survival by blinded independent review.

Patients assigned to dacomitinib had a 41% decreased risk for cancer progression or death compared with those patients assigned to gefitinib (hazard ratio [HR], 0.59; 95% CI, 0.47–0.74; P = .0001). The median progression-free survival was 14.7 months with dacomitinib compared with 9.2 months with gefitinib. The progression-free survival rate at 2 years was 30.6% for dacomitinib compared with 9.6% with gefitinib.

Mok noted that the response rate was similar for the two drugs-at about 75% for dacomitinib and 72% for gefitinib-but that the depth of response was higher with dacomitinib, which implies that “it is a more potent inhibitor of EGFR.” The median duration of response was 14.8 months for dacomitinib compared with 8.3 months for gefitinib (P < .0001). Overall survival data are not yet mature.

The most common severe (grade 3) side effects of dacomitinib were acne (14%) and diarrhea (8%). Liver enzyme abnormalities were the most common severe (grade 3) side effect of gefitinib (8%).

Mok noted that 66.1% of patients assigned dacomitinib required a dose reduction compared with only 8.0% of patients assigned gefitinib. The first dose reduction of dacomitinib was to 30 mg per day and the second dose reduction was to 15 mg per day. The median time to dose reduction for dacomitinib was 2.8 months compared with 3.3 months for gefitinib, but the median duration of dose reduction was 11.3 months for dacomitinib compared with 5.2 months for gefitinib.

Commenting on the study, ASCO Expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center, said that from the perspective of doctors who treat lung cancer, the results of this trial are a substantial advance.

“More than 5 months’ increase in progression-free survival…this would clearly put [dacomitinib] at the front of the pack in terms of efficacy,” Heymach said. “This does come with the cost of toxicity and 68% of patients had a dose reduction, but I would emphasize that these are not life-threatening toxicities.”

Heymach said that if the drug is approved in the United States, patients and physicians must discuss the balance of toxicities and efficacy when deciding on the use of this drug.