Novel Therapy for Resistant EGFR-Mutated Lung Cancer

Patients with EGFR-positive, non-small cell lung cancer (NSCLC) typically respond well to EGFR-targeted therapy, but eventually these tumors become resistant, leaving patients few options other than palliative care.

Patients with EGFR-positive, non-small cell lung cancer (NSCLC) typically respond well to EGFR-targeted therapy, but eventually these tumors become resistant, leaving patients few options other than palliative care.

One of the dominant resistant mutations identified is a T790M mutation within the EGFR gene. In a phase I clinical trial that enrolled 127 patients with this mutation, the response rate was 61%. Among the 61 patients without a detectable EGFRT790M mutation, the response rate was 21%. The overall objective tumor response rate was 51%. The results were published April 30, 2015 in The New England Journal of Medicine.1

The median progression free survival (PFS) was 9.6 months in the EGFR T790M-positive patients compared to 2.8 months in EGFR T790M-negative patients. Eighty-eight percent of the patients responded to the drug for 6 months or longer.

In the patients that did not have a detectable T790M mutation, the mechanism of resistance to anti-EGFR targeted therapies was not clear.

The disease control rate-including partial and complete responses plus stable disease was 95 percent in patients whose tumors harbored the T790M mutation.

A total of 253 patients enrolled on the trial received at least one dose of AZD9291 as part of the dose escalation and trial expansion phases. The median patient age was 60 and about 37% of the patients on trial were male.

The clinical trial, led by Pasi Jänne, MD, PhD, the director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, enrolled NSCLC patients previously treated with at least one therapy including gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif), who have experienced tumor regrowth. This was the first-in-human trial with this agent, AZD9291 (AstraZeneca). The drug has received a fast track designation for approval by the US Food and Drug Administration (FDA).

As many as 74% of patients with EGFR-mutated lung cancer respond to initial targeted therapy, but the vast majority experience disease progression within 1 or 2 years of starting therapy due to acquired resistance. The EGFRT790M mutation is responsible for an estimated 60% of these cases of resistance, preventing EGFR-targeting agents such as gefitinib or erlotinib from binding to the tyrosine kinase domain of the EGFR protein.

AZD9291 is a novel oral, irreversible EGFR tyrosine kinase inhibitor selective for EGFR T790M resistance and tyrosine kinase inhibitor–sensitizing mutations that shows less activity against the wild-type version of the protein compared to other EGFR inhibitors.

The most common adverse events were diarrhea, rash, nausea, and decreased appetite. The rate of serious side effects was low. A total of 22% of patients experienced a serious adverse event and 6% of these events were deemed drug-related. Six percent of patients had to discontinue the drug or have their doses lowered. Six patients had cases of potential pneumonitis-like events. These patients discontinued the drug and the events were resolved. Seven fatal adverse events occurred, including one potentially drug-related pneumonia.

According to the study authors, the most effective strategy for treating resistant EGFR-mutated lung cancer is the combination of afatinib and cetuximab which has shown a response rate of about 29%, but is linked to considerably high skin and gastrointestinal toxicities. “In contrast, we found that AZD9291 as monotherapy was associated with a response rate of 61%, with limited skin and gastrointestinal adverse effects, among patients with EGFR T790M,” stated the authors in their discussion

The study authors note that AZD9291 was “highly active” in those patients with the EGFRT790M mutation who had disease progression following first-line EGFR tyrosine kinase inhibitor therapy.

“Previously, if a patient became resistant to kinase inhibitors like Tarceva, they were treated with chemotherapy,” said Jänne in a statement. “Now there is this option, and the beautiful part is they don’t have the side effects of Tarceva – this drug is better tolerated.”

AstraZeneca plans to file this data with the FDA in the second half of 2015.