ASCO Update: Investigational ALK Inhibitor LDK378 Highly Act

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Investigational ALK Inhibitor LDK378 Highly Active in Crizotinib-Refractory ALK-Positive NSCLC

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The investigational anaplastic lymphoma kinase (ALK) inhibitor LDK378 showed substantial clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), with an overall response rate of 81% in patients previously treated with the U.S. Food and Drug Administration- approved ALK inhibitor crizotinib.

Results of this dose-escalation phase I study (Abstract 3007) were presented by Ranee Mehra, MD, of Fox Chase Cancer Center, at yesterday’s Oral Abstract Session on Developmental Therapeutics— Experimental Therapeutics.

LDK378 targets ALK, a key gene implicated in the development of some lung cancers, lymphomas, and childhood neuroblastomas. Approximately 6% of all NSCLCs are ALK-positive; these cancers are more likely to affect nonsmokers and younger individuals. LDK378 is a selective ALK inhibitor that has demonstrated enhanced potency over crizotinib and noteworthy antitumor activity in preclinical models, including in crizotinib-resistant tumors.

Dr. Mehra and her colleagues conducted a phase I study to evaluate the safety, tolerability, and early activity of the drug in patients with cancers carrying ALK genetic alterations. A total of 56 patients enrolled in the study; the median age was 53 (range: 22 to 78) and 66% of patients were female. Patients primarily had NSCLC (89%), but some had breast cancer (7%) and other cancer types (4%). The majority of patents (66%) had been treated previously with crizotinib.

In the dose-escalation phase of the study, patients received between 50 mg and 750 mg of LDK378 per day. Most patients (83%) received at least 400 mg, the dose thought to be required for clinical activity. The maximum tolerated dose was 750 mg per day, although dose-limiting toxicities were observed in patients receiving 400 mg per day and higher. Common adverse events included nausea (59%), vomiting (54%), diarrhea (48%), fatigue (21%), and dyspnea (16%). Serious adverse events included one case each of transaminase elevation, vomiting, dehydration, and interstitial lung disease. These were all reversible after stopping treatment.

LDK378 showed substantial activity in patients with ALK-positive NSCLC. The overall response rate was 81% among the 26 patients previously treated with crizotinib who then received LDK378 at doses of 400 mg per day or greater. The objective response rate among all 33 patients with NSCLC receiving at least 400 mg per day was 67%. Antitumor activity was also observed in brain metastases at the maximum tolerated dose of 750 mg. No responses were observed in other tumor types, including in ALK-amplified breast cancer.

The treatment duration ranged from 1 to 53 weeks, and 64% of patients are continuing to receive therapy.

In her discussion of the results, Eunice L. Kwak, MD, PhD, of Massachusetts General Hospital Cancer Center, called this “an amazing trial” in its ability to rapidly enroll eligible patients, identify the maximum tolerated dose, and move forward with the expansion phase of the study.

Dr. Kwak noted that these findings raise an array of new questions regarding the use of ALK inhibitors. Important topics for additional research include the identifi cation of resistance mutations or mechanisms in which LDK378 is effective, the optimal sequencing of ALK-targeted therapies, mechanisms of primary resistance, activity in brain metastases, and the role of combination therapy with multiple targeted agents. Accrual to the dose-expansion cohorts of the phase I study is ongoing and should provide additional insight into this promising drug.