Patients with lung cancer driven by a mutation in the EGFR gene frequently respond well to inhibitors that block the mutation’s activity. But eventually, those cancers become resistant to the inhibitor drugs – often because of a different EGFR mutation that the tumor cells develop.
According to clinical trial results reported in the April 30, 2015 edition of The New England Journal of Medicine, soon patients in this predicament may have a new treatment option.
A study led by Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, found that an experimental drug targeted to the resistance mutation is highly active in patients with EGFR-positive non-small cell lung cancer (NSCLC) when the disease progressed during treatment with front-line inhibitor drugs. Those drugs include gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif).
Results of the phase 1 study showed that the drug, AZD9291, caused tumor shrinkage in 61 percent of the 127 patients whose cancer contained the mutation EGFR T790-M – the genetic change that enables the lung cancers to evade the EGFR kinase inhibitors. AZD9291 is being developed by AstraZeneca.
Overall, the drug achieved a 95 percent “disease control rate” – partial responses plus complete responses plus “stable disease” (their cancer did not grow) in patients carrying the resistance mutation. The median length of time before the disease progressed was 9.6 months, with 85 percent of patients marking six months or more before progression occurred.
“We anticipate the drug will be approved this year,” said Jänne, noting that AZD9291 has been fast-tracked for approval by the Food and Drug Administration. In 2009, Jänne and colleagues first published on a preclinical compound that was effective in experimental systems harboring EGFR T790-M. Patients received AZD9291 for the first time in 2013.
“Previously, if a patient became resistant to kinase inhibitors like Tarceva, they were treated with chemotherapy,” said Jänne. “Now there is this option, and the beautiful part is they don’t have the side effects of Tarceva – this drug is better tolerated.”
The study found a relatively low rate of serious adverse effects with AZD9291 and only 6 percent of patients had to discontinue the drug or have their doses lowered.
The researchers noted that previous strategies to overcome drug resistance in patients with T790-M mutations involved combinations of drugs that were much less effective than the AZD9291 compound, and had significant toxicities affecting the skin and gastrointestinal tract.
The trial, which included 253 patients, revealed that the drug was less effective in patients whose resistant cancers lacked the T790-M mutation that made them vulnerable to the experimental drug. In those patients, the cause of the resistance was unclear, and only 21 percent saw their tumors shrink when treated with AZD9291, and their median progression-free survival was 2.8 months.
The EGFR mutation that can be targeted by drugs like Tarceva is found in a minority of patients with non-small cell lung cancer – 30 to 40 percent of Asian patients and about 10 to 15 percent of Caucasian patients. These cancers develop resistance to the inhibitors within one or two years. In about 60 percent of these patients, the EGFR T790-M mutation is to blame, while the causes of resistance in the remaining 40 percent are undetermined.
The senior author of the report on the multi-center clinical trial is Malcolm Ranson, MB, ChB, PhD, of the University of Manchester in the United Kingdom.
AstraZeneca funded the research.