Treatment-resistant non-small cell lung cancer (NSCLC) responds to new drug
An oral drug called ASP8273 caused tumor shrinkage in patients in a phase I clinical trial in Japan, according to research presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. This drug is a way of treating non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations.
Mutations of the epidermal growth factor (EGFR) occur in approximately 30% to 35% of Asian patients with NSCLC and in 10% to 15% of Caucasian patients. EGFR inhibitors called tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, can be used to treat EGFR-mutated NSCLC. However, these patients will eventually develop resistance to EGFR TKI therapy, rendering their disease resistant to current treatments. A further mutation, T790M, accounts for 60% of this acquired resistance.
ASP8273 is a new drug that inhibits the EGFR mutation and the T790M resistance mutation. Earlier research in mice had shown that it caused NSCLC to disappear completely, and so a phase I clinical trial was started in January 2014 to assess the drug's safety and efficacy in humans.
Twenty-four Japanese patients have enrolled so far to receive 1 of 6 levels of doses (25, 50, 100, 200, 400, and 600 mg) once a day. A further seven patients have been enrolled into a second group to evaluate doses of 100 mg, 200 mg, and 400 mg a day (a dose escalation study), and the researchers are planning to enroll a total of 124 patients. Cancer had progressed in all the patients after prior treatment with EGFR TKI therapy, and most of them had the T790M mutation.
"Preliminary results from this study show a high overall response rate of 78%, with tumors shrinking in seven out of nine patients who had both the EGFR and T790M mutations. While the number of patients is still small, this response is comparable with two other drugs in development that target EGFR, CO-1689 and AZ-9291, but ASP8273 has fewer safety concerns than these drugs," said Haruyasu Murakami, MD, of the Shizuoka Cancer Center in Japan.
The most common adverse reactions to ASP8273 were mild cases of diarrhea (in half of the patients), nausea, and vomiting (in a third of the patients). There were none of the severe respiratory complications, heart problems and high blood sugar levels that have occurred during the clinical trials of the other two drugs.
One patient receiving 400 mg a day suffered diarrhea that was severe enough for the dose to be reduced. The four patients who received 600 mg a day had dose-limiting toxicities including severe diarrhea, colitis, and cholangitis. All the patients in the trial who had the T790M mutation remain in the trial without further progression of their disease.
"These data indicate that ASP8273 would be expected to have potential clinical benefits with fewer adverse side effects compared to CO-1689 and AZ-9291," said Murakami.
The researchers are continuing to recruit patients to the phase I dose escalation study.