Findings from a phase I trial of AstraZeneca's EGFR tyrosine kinase inhibitor AZD9291 suggest that it could be a promising treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer that no longer responds to standard EGFR inhibitors.

Findings from a phase I trial of AstraZeneca's EGFR tyrosine kinase inhibitor (TKI) AZD9291 suggest that it could be a promising treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer (NSCLC) that no longer responds to standard EGFR inhibitors.

Although many patients with NSCLC initially respond to EGFR inhibitors, they typically develop resistance to the drugs, usually within a year. About 60% of these patients become resistant to EGFR inhibitors through the development of the T790M mutation.

“There are no approved treatments for patients who develop this form of resistance,” said Pasi A. Jänne, MD, PhD, a professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA. Jänne presented the trial's findings at a press conference highlighting research that will be discussed at the American Society of Clinical Oncology's Annual Meeting, to be held May 30–June 3 in Chicago, IL.

Jänne's team assessed five different doses of AZD9291 in 199 patients with advanced EGFR-mutant NSCLC whose disease progressed after treatment with one or more EGFR inhibitors. Researchers also tested tumors from 132 patients for the T790M mutation. Responses were observed at all dose levels and in all subgroups of patients, including those with brain metastasis.

Overall, 51% of patients experienced tumor shrinkage. Among the 89 patients who were positive for a T790M mutation, 64% responded to AZD9291, compared with 23% of T790M-negative patients. The responses were still ongoing in nearly all patients at the time the data were assessed, with the longest response lasting more than 8 months. Researchers are continuing to follow the patients to determine whether the therapy prolongs overall survival, Jänne said.

Notably, AZD9291 more selectively targets mutated EGFR in tumors and appears to cause fewer skin toxicities than approved EGFR TKIs. Whereas existing drugs block both the mutant EGFR in the tumor and the normal EGFR in the skin, which often leads to debilitating skin rash or acne, AZD9291 acts mostly on the mutant EGFR in a tumor. Even so, Jänne said that 24% of patients reported a rash, although it was generally mild. Other common side effects included diarrhea and nausea.

“Although it is still a bit early, our study suggests that AZD9291 may offer an effective new therapy option for these patients,” Jänne said.

Given that the data show that AZD9291 works more effectively in patients with the T790M mutation, future studies of this drug will be limited to this subgroup of patients, Jänne added. Because the researchers found no dose-limiting toxicities and all doses were well tolerated, he said that patients in future studies will receive the highest dose tested in the trial—240 mg of AZD9291 a day.

Earlier this year, the FDA granted AZD9291 Breakthrough Therapy designation, which will give AstraZeneca additional contact with the agency and help hasten the drug's development.