CHICAGO—Patients with non-small cell lung cancer (NSCLC) who acquire resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) had a higher overall response rate (ORR) to a novel selective EGFR inhibitor if they carried the T790M mutation, phase 1 study results presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting have shown.

Another benefit: the selective third-generation EGFR-TKI, AZD9291, causes fewer adverse events (AEs), including skin rashes, than existing EGFR TKIs.

“Most patients develop acquired resistance to EGFR TKIs and, in 60% of patients, this is associated with a secondary EGFR mutation, T790M,” said Pasi A. Jänne, MD, PhD, a professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, in Boston, MA. However, there are no approved treatments for patients with this mutation.

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The open-label AURA study investigated the clinical activity of AZD9291 in patients with EGFR-mutant NSCLC and acquired resistance to EGFR-TKIs. A total of 232 patients with EGFR mutations, including those with stable brain metastases were enrolled; 31 across five dose levels in the dose escalation phase and 201 in eight dose expansion cohorts. AZD9291 was administered orally at doses of 20 mg to 240 mg once daily.

“Prospective mandatory central T790M testing was required in the expansion cohorts and was optional for dose escalation cohorts,” Dr. Jänne noted, adding that the T790M mutation causes the most common form of EGFR-TKI resistance.

In the expansion cohorts, median age of the patients was 60 years (range, 28-88 years); 62% were female; and 63% were Asian. More than half (61%) had received immediate prior EGFR-TKI treatment, with the median number of prior therapies being 1 (range, 1–5).

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Among the 205 evaluable patients, ORR was 53% (95% CI: 46%-60%), including one complete response, and there was no difference in ORR by race. The overall disease control rate (DCR [complete response + partial response + stable disease]) was 83%, and the longest duration of response was greater than 9 months, which was ongoing at the time of data cut-off.

No appreciable difference in response was observed based on dose, he said; RECIST [Response Evaluation Criteria In Solid Tumors] responses to AZD9291 were observed at all dose levels and in all subgroups of patients, including those with brain metastases.

In patients with centrally confirmed T790M, the ORR in 107 EGFR T790M-positive patients was 64% (95% CI: 55-%-73%), with a DCR of 94%. In the 50 EGFR T790M-negative patients, the ORR was 22% (95% CI: 12%-36%), with a DCR of 56% (95% CI: 41%-70%).