Dacomitinib Sets PFS Record in Phase III NSCLC Trial

CHICAGO -- A second-generation targeted therapy showed better efficacy for patients with advanced non-small cell lung cancer (NSCLC) that has a mutation in the epidermal growth factor receptor (EGFR) compared with a current agent, but at a cost of greater toxicity, a researcher said here.

In a phase III clinical trial, the investigational drug, dacomitinib, extended the time to relapse or death by 41% compared with standard gefitinib (Iressa) therapy, according to Tony Mok, MD, of the Chinese University of Hong Kong.

But the increased potency came with more adverse events related to blocking the receptor, he told reporters at the annual meeting of the American Society of Clinical Oncology.

Nonetheless, the so-called ARCHER 1050 study -- the first head-to-head trial of two EGFR tyrosine kinase inhibitors -- offers a new treatment option for patients with NSCLC that is driven by EGFR mutations, Mok concluded.

Currently, U.S. patients with such a tumor have three targeted therapy options -- gefitinib, erlotinib (Tarceva), and afatinib (Gilotrif) -- whose outcomes are roughly similar, commented ASCO expert John Heymach, MD, of the MD Anderson Cancer Center in Houston.

Although the three haven't been compared in a head-to-head fashion, outcomes from separate trials are "typically within one or two months" for all of them, Heymach told reporters.

Dacomitinib treatment extended median progression-free survival by 5.5 months versus gefitinib -- to 14.7 months -- "a really substantial advance ... that would clearly put it at the front of the pack in terms of efficacy," Romero said.

On the other hand, he cautioned that the increased toxicity "clearly requires close monitoring by experienced care providers."

Mok and colleagues randomly assigned 452 patients with stage IIIB or IV NSCLC, with no previous systemic therapy, to 45 mg daily of dacomitinib or 250 mg a day of gefitinib. They excluded patients with brain metastases because of concerns over how well the drugs penetrate the blood-brain barrier.

The primary endpoint of the study was progression-free survival -- defined as progressive disease or death -- as measured by an independent review committee. The researchers also looked at response rates and overall survival, as well as safety.

For this analysis, he said, 136 dacomitinib and 179 gefitinib patients had either progressed or died -- 59.9% and 79.6% respectively -- yielding a median progression-free survival of 14.7 months for the new drug and 9.2 months for gefitinib. The hazard ratio for progression was 0.59 in favor of dacomitinib.

Objective response rates were similar -- 74.9% for dacomitinib and 71.6% for gefitinib -- but the duration of response was significantly longer for dacomitinib: 14.8 months versus 8.3 months.

Mok said the overall survival data remains immature.

But because dacomitinib is more effective at blocking EGFR than gefitinib, it also has more off-target effects, he said. In particular:

• 87.2% of dacomitinib patients reported diarrhea, reaching Grade 3 in 8.4%, while just 55.8% of the gefitinib patients reported the condition and 0.9% reached Grade 3
• 61.7% of patients in the dacomitinib arm had paronychia, including 7.5% at Grade 3, compared with 20.1% and 1.3% among gefitinib patients
• 48.9% in the dacomitinib arm had dermatitis acneiform and 13.7% were Grade 3, versus 28.6% and 0% respectively for gefitinib.
• And 43.6% taking dacomitinib had stomatitis (3.5% at Grade 3) versus 17.9% and 0.4% for gefitinib

On the other hand, gefitinib patients were more likely to have increases in alanine aminotransferase (ALT), at 39.3% versus 19.4% for dacomitinib, Mok reported.

Toxicity with both drugs forced dose reductions from time to time, with the reductions needed both sooner and more frequently in the dacomitinib arm.

With dacomitinib, the first dose reduction came at a mean of 2.8 months versus 3.3 months in the gefitinib arm.

All told, 66.1% of dacomitinib patients had their dose reduced, for a median duration of 11.3 months, compared with 8% of gefitinib patients, who stayed on the lower dose for a median of 5.2 months.

Among gefitinib patients, dose reduction amounted to reducing the frequency of dosing from 250 mg daily to 250 mg every two days. In the dacomitinib arm, the first dose reduction was to 30 mg daily and the second was to 15.

Patients in both groups reported similar improvements in key disease-associated symptoms, such as cough, chest pain, and fatigue, Mok reported.

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