Abstract
Poziotinib, an EGFR inhibitor that was previously shelved as ineffective against non–small cell lung cancer, is showing promising activity in a subset of patients with EGFR exon 20 insertions. According to preliminary data from a phase II trial, the drug led to a 73% overall response rate in patients with this disease subtype, which is typically highly resistant to standard therapy.
A drug that was previously shelved as ineffective against non–small cell lung cancer (NSCLC) is showing promising activity in patients harboring a rare type of EGFR mutation, according to preliminary data presented last month during the International Association for the Study of Lung Cancer's 2017 World Conference in Yokohama, Japan. In a phase II trial, the investigational EGFR inhibitor poziotinib (Spectrum) induced significant responses among patients with exon 20 insertions, an atypical alteration that accounts for up to 15% of EGFR-mutant NSCLC cases.
“Poziotinib appears to be dramatically more active than other EGFR inhibitors in patients with exon 20 insertions,” says the trial's lead investigator John Heymach, MD, PhD, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “All patients in the trial had some degree of tumor shrinkage.”
Previous studies had concluded that poziotinib provided only modest benefit to patients whose tumors progressed on standard EGFR inhibitor therapy. However, the drug was primarily tested in patients with T790M point mutations, the most common known mechanism of resistance.
In the current study, 8 of 11 enrolled patients, all with metastatic EGFR exon 20-mutant NSCLC, experienced between 30% and 50% tumor shrinkage, for an overall response rate of 73%, says Heymach. It's an impressive result, he adds, considering this population's historical response rate—between 3% and 8%—to the EGFR inhibitors currently approved for NSCLC: erlotinib (Tarceva; Genentech/Astellas), afatinib (Gilotrif; Boehringer Ingelheim), gefitinib (Iressa; AstraZeneca), and osimertinib (Tagrisso; AstraZeneca).
“While we still need to see more mature data, poziotinib is demonstrating early clinical efficacy that is very compelling,” says Christina Baik, MD, MPH, a lung cancer specialist at Fred Hutchinson Cancer Research Center in Seattle, WA. “It's the first small-molecule inhibitor to show meaningful clinical efficacy in patients with this mutation.”
Poziotinib's candidacy emerged during a screen conducted as part of MD Anderson's Lung Cancer Moon Shot drug repurposing initiative. Researchers tested a variety of EGFR inhibitors against cell lines and patient-derived xenograft models, and found that poziotinib stood out as considerably more effective in targeting exon 20.
Based on molecular modeling, researchers observed that poziotinib's smaller and more flexible structure allows it to fit into the constrained exon 20 drug-binding pocket better than other EGFR inhibitors. While not the focus of this trial, the researchers have also found that poziotinib is active against NSCLC with HER2 exon 20 mutations.
Investigators speculate that the particular amino acid on exon 20 where a change occurs, as well as the size of the insertion, might influence patients’ response to poziotinib. For example, says Heymach, larger insertions would further constrain the binding pocket and potentially interfere with the drug's action.
“We view poziotinib as a first-generation exon 20 inhibitor that will help us gain insight into developing more targeted drugs in the future,” he says. “We expect that the next generation of these drugs will be tailored for specific mutations within exon 20.” –Janet Colwell
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