Dacomitinib Approved, but Might Not Be Used

The FDA approved the EGFR inhibitor dacomitinib (Vizimpro; Pfizer) as a first-line therapy for patients with metastatic, EGFR-mutant non–small cell lung cancer (NSCLC). Clinicians, however, doubt that the drug will be used much in clinical practice, as it joins a crowded field of EGFR inhibitors that includes osimertinib (Tagrisso; AstraZeneca), the current standard of care. Instead, they are focused on the next wave of therapeutic options.

Dacomitinib was approved based on the results of the phase III ARCHER 1050 trial, in which patients treated with the drug had a median progression-free survival (PFS) of 14.7 months and a median overall survival of 34.1 months, compared with 9.2 months and 26.8 months, respectively, in patients who received the EGFR inhibitor gefitinib (Iressa; AstraZeneca) (Lancet Oncol 2017;18:1454–66; J Clin Oncol 2018;36: 2244–50). Serious side effects, most commonly diarrhea, rash, and a skin condition called paronychia, affected 27% of patients.

In addition to gefitinib and osimertinib, the EGFR inhibitors erlotinib (Tarceva; Genentech and Astellas) and afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals) are also approved as first-line therapies.

Lecia Sequist, MD, MPH, of Massachusetts General Hospital in Boston, MA, says that comparing dacomitinib to gefitinib made sense when the trial was designed. In the interim, however, osimertinib was approved and quickly became the new standard of care because it extended PFS and caused fewer side effects than gefitinib or erlotinib.

“More knowledge and more options are always important, but I'm not sure there's going to be much uptake of dacomitinib in the front-line setting,” she says.

Benjamin Levy, MD, of Johns Hopkins University in Baltimore, MD, and Washington, DC, agrees, adding that a major benefit of osimertinib over dacomitinib is its toxicity profile: Osimertinib is generally well tolerated, whereas dacomitinib frequently causes diarrhea, acne, and rashes. Moreover, data from the phase III FLAURA trial suggests that osimertinib may be effective at treating brain metastases (J Clin Oncol 2018 Aug 28 [Epub ahead of print]).

“I still think that osimertinib remains the standard for first-line [therapy] based on toxicity, and based on its ability to elicit meaningful responses in patients with brain metastasis,” he says.

Joshua Bauml, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, is interested in new therapeutic strategies to extend survival of patients who receive first-line osimertinib to address tumor heterogeneity and resistance.

“We have all these drugs, they're highly active, but they are not cures. Patients will develop resistance, and they will unfortunately die from that,” he says. “What we need to really do is to delve into the science and see how we can advance the care for these patients.”

Sequist and her colleagues recently established that acquired RET fusions drive resistance in some patients, and these patients may benefit from receiving osimertinib in combination with the RET inhibitor BLU-667 (Blueprint Medicines; Cancer Discov 2018 Sep 26 [Epub ahead of print]). Similarly, MET amplification can cause osimertinib resistance, but some research has shown that that can be countered with osimertinib plus the MET inhibitor savolitinib (AstraZeneca and Chi-Med). In addition, researchers are exploring the use of EGFR inhibitors with chemotherapy. Levy notes that there is also interest in testing combinations of immunotherapies, chemotherapy, and angiogenesis inhibitors.

“If you're going to give osimertinib front line, the question really is, what do you do next and what are the most active therapies?” Levy says.

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