Findings from a phase I study of a new mutant selective EGFR tyrosine kinase inhibitor (TKI), 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 percent of patients experienced tumour shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60 percent of patients), which causes the most common form of EGFR therapy resistance.

“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, a professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA.

“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 10-15 percent of Caucasian patients and about 40 percent of Asian patients with NSCLC.

Many of these patients initially respond well to approved EGFR inhibitors erlotinib and afatinib, 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), but it is very toxic.

In the study, 199 patients with advanced NSCLC harbouring 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 percent of patients experienced tumour shrinkage.

Among the 89 patients with a confirmed T790M mutation, 64 percent responded to AZD9291, vs. 23 percent of T790M-negative patients.

The responses were still ongoing in nearly all patients at data cut-off, with the longest response lasting more than eight 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.

Importantly, AZD9291 selectively targets EGFR in tumours and appears to cause fewer skin toxicities than approved EGFR TKIs.

While existing drugs block both the mutant EGFR in the tumour 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 tumour.

This research was supported by Astra Zeneca.

ASCO Perspective

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

Source: ASCO