New EGFR Inhibitor AZD9291 Shows Promising Activity in Treatment-Resistant Non–Small Cell Lung Cancer

Key Points

  • Roughly 50% of patients with EGFR-mutant advanced NSCLC whose disease progressed after standard EGFR therapies experienced tumor shrinkage after treatment with AZD9291.
  • Among the 89 patients with a confirmed T790M mutation, 64% responded to AZD9291 vs 23% of T790M-negative patients.
  • Treatment with AZD9291 appeared to cause fewer skin toxicities than approved EGFR tyrosine kinase inhibitors.

Findings from a phase I study of a new mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AZD9291, point to a promising new treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer (NSCLC) that is resistant to standard EGFR inhibitors. Roughly 50% of patients experienced tumor shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60% of patients), which causes the most common form of EGFR therapy resistance. The study was presented at a presscast in advance of the 2014 ASCO Annual Meeting (Abstract 8009^).

“There is currently no standard treatment for patients with lung cancer who experience disease progression after initial therapy with an EGFR kinase inhibitor,” said lead study author Pasi A. Jänne, MD, PhD, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Although it is still a bit early, our study suggests that AZD9291 may offer an effective new therapy option for these patients, without the skin side effects we typically see with existing EGFR inhibitors.”

EGFR mutations are found in 10% to 15% of Caucasian patients and about 40% of Asian patients with NSCLC. Many of these patients initially respond well to approved EGFR inhibitors erlotinib (Tarceva) and afatinib (Gilotrif), but all ultimately become resistant to this therapy, generally within 10 to 14 months. Many patients become resistant to EGFR inhibitors through the development of another mutation, the T790M mutation. The only therapy that is somewhat effective in patients with the T790M mutation is a combination of two EGFR inhibitors (afatinib and cetuximab [Erbitux]), but it is very toxic.

Responses Seen in 50% of Patients

In this study, 199 patients with advanced NSCLC harboring EGFR mutations, whose disease progressed after one or more standard EGFR therapies, received different doses of AZD9291. 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 with a confirmed T790M mutation, 64% responded to AZD9291 vs 23% of T790M-negative patients. The responses were still ongoing in nearly all patients at data cutoff, with the longest response lasting more than 8 months.

Longer follow-up is needed to determine if this therapy prolongs overall survival. Given that these data show that AZD9291 is working more effectively for patients with the T790M mutation, future studies of this drug will be limited to this subgroup of patients, according to the researchers.

Reduced Skin Toxicity

Importantly, AZD9291 selectively targets EGFR in tumors and appears to cause fewer skin toxicities than approved EGFR tyrosine kinase inhibitors. While existing drugs block both the mutant EGFR in the tumor and the normal EGFR in the skin (and other organs), which often leads to debilitating skin rash or acne, AZD9291 acts mostly on the mutant EGFR in a tumor.

“The reduced skin toxicity seen with AZD9291 heralds greater precision in targeting cancer mutations and sparing healthy tissues which retain normal germline EGFR status," said Peter P. Yu, MD, FASCO, ASCO President-Elect.

This research was supported by AstraZeneca. For full disclosures of the study authors, view the article abstract at

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