Early Results Promising for LDK378 in ALK-positive NSCLC

The experimental second-generation ALK inhibitor LDK378 (Novartis) showed an overall response rate of 60% in a multicenter phase I trial involving 130 patients with ALK-positive non–small cell lung cancer (NSCLC). Patients with responses to the new drug included those who had never taken a targeted therapy as well as those who had become resistant to crizotinib (Xalkori; Pfizer), another ALK inhibitor that was recently approved for use in advanced NSCLC.

“It's quite remarkable to be able to reinduce a response in a patient who has become resistant,” says Alice Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital in Boston and lead investigator of the study.

“Because we had the target ALK-positive population, we were able to see very early on that there were signs of antitumor activity,” adds Shaw, who presented the results on June 3 at the American Society of Clinical Oncology 2013 Annual Meeting in Chicago, IL.

Studies of crizotinib have shown response rates of about 60%, similar to those of LDK378, and progression-free survival (PFS) times of 8 to 10 months. However, “most patients, after a year or so, begin to develop resistance,” says Shaw. “These crizotinib-resistant patients have limited treatment options, so these results are very promising.”

Patients who responded to LDK378 had a median PFS time of 8.6 months. Given the evidence so far, says Shaw, “we're seeing similar durations of treatment with crizotinib and with LDK378 given post-crizotinib.”

Crizotinib was developed to inhibit c-MET; it also inhibits ROS1 and several other kinases, says Shaw. In contrast, according to Novartis, LDK378 is a highly selective ALK inhibitor that does not inhibit c-MET.

Patients experienced side effects including nausea, diarrhea, vomiting, and fatigue. Shaw says they did not experience visual disturbances or edema, side effects sometimes seen with crizotinib.

About 3% to 5% of all NSCLC tumors have ALK mutations. In the United States, about 8,000 new cases of ALK-positive NSCLC occur each year.

Based on early phase I study data, in March 2013 the U.S. Food and Drug Administration (FDA) granted a request from Novartis to designate LDK378 as a Breakthrough Therapy for patients with ALK-positive metastatic NSCLC whose disease progressed during treatment with crizotinib or who could not tolerate crizotinib. (This designation helps to expedite the development and review of drugs.) Phase II trials have begun: one to test LDK378 in patients with advanced cancer resistant to chemotherapy and crizotinib, and another to study LDK378 in patients who have not taken crizotinib.