Abstract
The irreversible EGFR inhibitor dacomitinib reduced the chance of lung cancer progression compared with an older, first-generation EGFR inhibitor, gefitinib, in a phase III trial. As reported at the 2017 American Society of Clinical Oncology Annual Meeting, the experimental drug also increased toxicity, which could limit its use, especially with a safer, more effective third-generation EGFR inhibitor not far behind in the development pipeline.
In a phase III trial, the experimental EGFR inhibitor dacomitinib (Pfizer), which has a high affinity for its target, kept lung tumors in check longer than an older such drug in patients whose cancer harbored an EGFR-activating mutation. However, the added efficacy came at the cost of increased side effects that frequently required dose reductions.
“This certainly now becomes a front-line option for newly diagnosed EGFR-mutant patients—no question about that,” said Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who has led other trials of dacomitinib. “But the uptake, I suspect, may be tempered by the toxicity.”
Dacomitinib is a second-generation, irreversible EGFR and pan-HER inhibitor that previously failed to show significant improvements in progression-free survival (PFS) when compared with erlotinib (Tarceva; Genentech and Astellas), an older EGFR-targeted agent, in a phase III trial of unselected patients with non–small cell lung cancer (NSCLC)—meaning those with and without EGFR mutations—whose disease advanced despite prior treatment. Yet, a phase II, single-agent trial of dacomitinib led by Jänne and Tony Mok, MD, from the Chinese University of Hong Kong, found signs of efficacy in treatment-naïve patients, especially among those with EGFR-activating mutations in exon 19 or 21.
Mok and a team from Asia and Europe then launched the first phase III head-to-head comparison of a first- and second-generation EGFR inhibitor as first-line therapy in 452 patients newly diagnosed with EGFR+ NSCLC. Patients were randomly assigned to receive either gefitinib (Iressa; AstraZeneca), a reversible EGFR inhibitor similar to erlotinib, or dacomitinib. At the 2017 American Society of Clinical Oncology Annual Meeting in Chicago, IL, Mok reported that about three quarters of the patients in each group responded, but those who received dacomitinib had a 41% lower risk of cancer progression, with a PFS of 14.7 months, compared with 9.2 months for those who received gefitinib.
PFS was similar to that in the subset analysis of patients with EGFR+ disease in earlier trials of dacomitinib versus erlotinib. Yet, in those studies, the extended time to relapse with dacomitinib didn't translate into longer overall survival. As reported last year, median overall survival was around 2 years regardless of which EGFR inhibitor patients received.
That finding could be seen as a caution against using PFS to gauge dacomitinib's potential, but according to Suresh Ramalingam, MD, lead investigator of the subgroup analysis from Emory University's Winship Cancer Institute in Atlanta, GA, overall survival is no longer much of a clinically relevant metric for first-line therapies for NSCLC. “Patients with lung cancer are receiving more and more lines of therapy now,” he said, so considering PFS and toxicity alone “may be reasonable to change practice.”
Yet, given dacomitinib's toxicity profile—which includes frequent diarrhea, acne, and rashes—Ramalingam doubts the experimental agent will ever become the drug of choice for EGFR-mutant advanced NSCLC, especially because a comparable second-generation EGFR inhibitor, afatinib (Gilotrif; Boehringer Ingelheim), is already approved as a first-line therapy. He sees more promise in a third-generation EGFR inhibitor, osimertinib (Tagrisso; AstraZeneca), that can work even in tumors with the T790M mutation, a common cause of resistance to other EGFR-blocking therapies. Osimertinib is already approved as a second-line anti-EGFR therapy for patients harboring the T790M mutation, and Ramalingam reported last year that the drug produced a PFS of nearly 20 months when used as a first-line treatment in phase I expansion studies.
An added bonus: “Osimertinib actually has even better tolerability than gefitinib or erlotinib because it's far more selective for the mutant cancer cells than the normal cells,” Ramalingam said. Results of a phase III trial of first-line osimertinib versus gefitinib or erlotinib are expected before the end of the year. –Elie Dolgin
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