440O - Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors

Date 29 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Drug Development
Presenter Alice Shaw
Authors A. Shaw1, R. Camidge2, E. Felip3, S. Sharma4, D.S.W. Tan5, D.W. Kim6, T. De Pas7, J.F. Vansteenkiste8, A. Santoro9, G. Liu10, M. Goldwasser11, D. Dai12, A.L. Boral13, R. Mehra14
  • 1Medicine, Harvard Medical School, Boston/US
  • 2University of Colorado, Denver/US
  • 3Oncologia Médica, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 4Center For Investigational Therapeutics, Huntsman Cancer Institute, US-84112 - Salt Lake City/US
  • 5Department Of Medical Oncology, National Cancer Center, Singapore/SG
  • 6Department Of Internal Medicine, Seoul National University Hospital, Seoul/KR
  • 7Istituto Europeo di Oncologia, IT-20141 - Milano/IT
  • 8Respiratory Oncology Unit (pulmonology), University Hospital Gasthuisberg, BE-3000 - Leuven/BE
  • 9Istituto Clinico Humanitas, IT-20089 - Rozzano/IT
  • 10Ontario Cancer Institute, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 11Novartis Institutes For Biomedical Research, Novartis Pharmaceuticals, Cambridge/US
  • 12Oncology Clinical Pharmacology, Novartis Pharmaceuticals, East Hanover/US
  • 13Clinical Research, Novartis Institutes for Biomedical Research, Inc, Cambridge/US
  • 14Department Of Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia/US



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.


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.


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.


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.


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.