Two Drugs Beat Back Lung Tumors

Two new EGFR-blocking drugs shrink lung tumors that have developed resistance to standard therapy with tyrosine kinase inhibitors (TKI), according to a pair of new studies.

TKIs such as erlotinib (Tarceva; Genentech) are first-line therapies for patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have certain EGFR mutations. However, the tumors usually become resistant to these therapies, often due to the T790M mutation. Erlotinib and related drugs obstruct EGFR's ATP-binding pocket, but the T790M mutation prevents the drugs from interacting with the pocket, allowing cancer cells to continue growing.

At the recent 2014 Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, sponsored by the European Organization for Research and Treatment of Cancer, the NCI, and the American Association for Cancer Research, two research groups presented evidence on the effectiveness of separate investigational drugs that can bind to and inactivate EGFR despite the T790M mutation.

In a phase I/II trial, Jean-Charles Soria, MD, PhD, of the Institut Gustave Roussy in France, and colleagues in Europe, Australia, and the United States tested the EGFR inhibitor rociletinib (CO-1686; Clovis Oncology), which inhibits activated EGFR with or without the T790M resistance mutation. The researchers enrolled 193 patients with NSCLC, who had received three prior therapies on average, in the ongoing trial.

Among the 27 rociletinib-treated patients who received optimal doses of the drug and for whom the team had CT scan results, 18 had a confirmed response to the drug; the median progression-free survival was 10.4 months.

“Sixty-seven percent activity lasting nearly a year is very good,” says Soria, who presented the group's findings. In some patients, the drug triggered high blood glucose levels, which were controlled with the diabetes drug metformin.

Several other studies of rociletinib are under way, including a phase III trial comparing it to chemotherapy.

The second group, led by Haruyasu Murakami, MD, PhD, of the Shizuoka Cancer Center in Japan, reported results from a phase I trial of another drug, ASP8273 (Astellas Pharma), that also inhibits mutant EGFR. So far, 31 patients with NSCLC, all of whom received prior therapy with a TKI, have been enrolled in the trial.

The researchers found that tumors shrank in 7 of the 9 patients who had both the EGFR and T790M mutations. Although the drug spurred gastrointestinal symptoms such as diarrhea and nausea, it didn't lead to high blood sugar.

“Although the number of patients is still small, ASP8273 would be expected to have clinical benefits,” says Murakami, adding that phase II trials of the drug are being planned.

Two other drugs that are effective against EGFR harboring the T790M mutation, AZD9291 (AstraZeneca) and HM61713 (Hanmi Pharmaceutical), have also shown promise in patients with NSCLC in phase I and phase I/II clinical trials.

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