Novel Agent Shows Promise in TKI-Resistant Lung Cancer

Ball-and-stick models of EGFR inhibitors gefitinib (top) and erlotinib (bottom).

A novel agent known as AZD9291 showed promising results in a phase I dose escalation trial among non-small-cell lung cancer (NSCLC) patients whose disease progressed after treatment with EGFR-targeting tyrosine kinase inhibitors (TKIs). Specifically, the agent seems well suited to patients who are positive for the T790M mutation, which can confer resistance to TKI therapy.

Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute in Boston, discussed the new study during a press conference in advance of the American Society of Clinical Oncology (ASCO) Annual Meeting, where the results will be presented at the end of the month. He noted that most NSCLC patients develop acquired resistance to TKI therapy, and that this is associated with T790M in 60% of patients. At present, there is no therapy specifically approved to treat patients with that mutation; AZD9291 is a mutant selective inhibitor of EGFR that may fit that niche.

The study included five cohorts with escalating doses of the drug, from 20 mg up to 240 mg, with 31 patients in each cohort and 168 total patients in eight dose expansion cohorts.

Notably, no maximum tolerated dose was defined and no dose-limiting toxicities were seen. The most common adverse events (AEs) included diarrhea (30% of patients) and rash (24%), and grade 3/4 AEs were seen in only 16% of the total evaluable patients. Six patients had dose reductions, and seven discontinued due to AEs.

There was a marked difference in overall response rate based on T790M status. T790M-positive patients had an overall response rate of 64% (57 of 89), compared with only 23% (10 of 43) T790M-negative patients. The disease control rate in T790M-positive patients was 96%; at the time of data cutoff, the longest response was ongoing at more than 8 months. Interestingly, response activity was observed across all dose levels.

Peter Yu, MD, of Palo Alto Medical Foundation and the president-elect of ASCO, said that increasing our understanding of the underlying mechanisms of resistance is leading to better ways of targeting it. “But it’s more than that,” he said. “As the newer treatments fine tune and hone their targets, we’re seeing less toxicity.”

Jänne said that the US Food and Drug Administration has granted breakthrough therapy designation to the drug, which could help accelerate the testing and approval process. The designation is specifically for patients with metastatic, EGFR T790M mutation-positive NSCLC whose disease has progressed after treatment with an approved TKI. “The promising results from this phase I trial warrant further investigation of the activity of AZD9291,” he said. “Additional clinical development is ongoing.”