440O - Results of a First-In-Human Phase I Study of the Alk Inhibitor LDK378 in Advanced Solid Tumors

Abstract

ABSTRACT Background Translocations of the anaplastic lymphoma kinase (ALK) gene occur in 3–8% of NSCLC. LDK378 is a novel, potent small molecule ALK inhibitor that produces tumor regressions in ALK-driven (ALK+) NSCLC xenografts. A Phase 1 study is being conducted with the primary objective of determining the MTD and safety profile in patients (pts) with ALK+ cancers. Other objectives are to assess safety, PK, and antitumor activity in pts with ALK+ NSCLC, either previously untreated with ALK inhibitors, or relapsed following ALK inhibitor treatment, and other ALK+ cancers. Methods LDK378 was administered orally once-daily on a continuous 21-day schedule, in adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy. Dose escalation was guided by a Bayesian logistic regression model to determine the MTD, and started at 50 mg/day. Results As of 25 April2012, 56 pts (primary site: lung 50 pts [37 with prior crizotinib]; breast 4 pts; other 2 pts; median age 53 (22–76) years; 88% ECOG PS 0/1) had received LDK378 at doses of 50–750 mg/day. Of 47 pts evaluable for response (per investigator), there were 24 (51%) responses. All responses were in ALK+ NSCLC (FISH positive in ≥15% of tumor cells). In 26 pts with NSCLC who had progressed following crizotinib and were treated at ≥400 mg/day there were 21 (81%) responses. Dose limiting toxicities (DLTs) have occurred in 2/14 pts at 400 mg/day, 2/9 pts at 600 mg/day, and 1/9 pts at 750 mg/day. DLTs included diarrhea, vomiting, nausea, dehydration, and ALT elevation. The MTD was 750 mg/day. At the cutoff date, 36 (64%) pts remain on treatment. Discontinuations were due to adverse events (AEs) in 1 (2%), and disease progression in 19 (34%) pts. The most frequent AEs (all grades) were nausea 33 (59%), vomiting 30 (54%), and diarrhea 27 (48%) pts. The most frequent Grade 3/4 AE was diarrhea (5 [9%] pts). Oral absorption of LDK378 was rapid with a Tmax of 5–6 hours, and half-life was about 36 hours. Conclusions Daily oral LDK378 is well tolerated and the MTD was 750 mg/day. Striking activity was seen in ALK+ NSCLC pts treated at doses ≥400mg, who had previously progressed following crizotinib. Disclosure A.T. Shaw: I have a consultant/advisory role for Pfizer, Novartis, Chugar, Ariad, and Daiichi. D.R. Camidge: I have a compensated consultant/advisory role with Novartis Pharmacuticals Inc. S. Sharma: I have a compensated consultant/advisory role for Novartis (LEAD Summit). I have received honoraria for Novartis LEAD Summit. I have received research funding from Novartis (Phase Ib clinical trial). D.S.W. Tan: I have received research funding from Novartis. M. Goldwasser: Employment or leadership position to disclose: Associate Director Biostatistics: Novartis Pharmaceuticals. D. Dai: Employment or leadership position to disclose. Clinical Pharmacology Expert: Novartis Pharmaceuticals; Stock ownership: Myself; Novartis Pharmaceuticals. A.L. Boral: I am an employee of Novartis Institutes for Biomedical Sciences (Executive Director). I have stock ownership (Novartis). All other authors have declared no conflicts of interest.