Encouraging results were seen in a preliminary study of a second-generation ALK inhibitor in advanced ALK-positive non–small cell lung cancer (NSCLC). The drug—dubbed LDK378—achieved tumor shrinkage in almost all patients enrolled in the study, in all mutational subsets, in crizotinib (Xalkori)-naive and crizotinib-resistant patients, and in patients with central nervous system (CNS) metastases.¹

On the basis of these positive results, LDK378 has been awarded a Breakthrough Therapy designation by the U.S. Food and Drug Administration, and Novartis is about to initiate phase III studies of this new compound.

Study Background

“LDK378 is a potent, next-generation ALK inhibitor for patients with advanced ALK-positive NSCLC. It achieved durable responses and a median progression-free survival of 8.6 months,” said lead investigator Alice T. Shaw, MD, PhD, Associate Professor of Medicine at Massachusetts General Hospital in Boston, who presented the study findings at the ASCO Annual Meeting. “The drug was generally well tolerated, as most of the common adverse events were grades 1 and 2.”

The first-generation ALK inhibitor crizotinib achieves overall response rates of about 60% and median progression-free survival of about 8 to 10 months in ALK-positive patients. But a majority of patients develop resistance within 1 to 2 years, and relapses commonly occur in the central nervous system.

LDK378 is active against ALK and many of the known resistant forms of ALK, including the gatekeeper mutant L1196M. The study included patients with locally advanced or metastatic ALK-positive NSCLC. Central nervous system metastases were allowed. Fifty-nine patients were included in the dose-escalation part of the study and 79 in the dose-expansion phase. Median age was 53 years, and 88% had an ECOG performance status of 0 or 1.

Major Findings

In 122 patients evaluable for response, marked activity of LDK378 was observed, with almost all—including both crizotinib-naive and crizotinib-resistant patients—showing some degree of tumor shrinkage.

A total of 114 patients were treated at doses of 400 to 750 mg/d. In these patients, the overall response rate was 58%, with a rate of 57% in crizotinib-resistant patients and 60% in crizotinib-naive patients. Virtually identical response rates were seen among patients treated at the maximal tolerated dose of 750 mg/d, and this is the dose selected for future trials, Dr. Shaw said.

Median duration of response to LDK378 was 8.2 months. The 6-month progression-free survival rate was 60.7%, but these data are not yet mature, she said.

“We saw marked systemic and CNS responses associated with prolonged progression-free survival and duration of response,” she added.

Adverse Events

LDK378 was generally well tolerated, but nausea, diarrhea, vomiting, and fatigue were observed in > 50% of patients. Grade 3 or 4 adverse events occurring in at least 5% of patients included elevated ALT (19%) and elevated AST (10%). Three patients discontinued therapy due to adverse events, and there have been no treatment-related deaths.

Genotypes of 19 patients were examined, and some had resistance mutations while others did not. Responses were seen regardless of mutational subtype. ■

Disclosure: Dr. Shaw has a consultant or advisory role with ARIAD, Chugai Pharma, Novartis, and Pfizer.

Reference

1. Shaw AT, Mehra R, Kim DW, et al: Clinical activity of the ALK inhibitor LDK378 in advanced, ALK positive NSCLC. 2013 ASCO Annual Meeting, Abstract 8010. Presented June 3, 2013.