Shaw, Alice T., Kim, Dong-Wan, Mehra, Ranee, Tan, Daniel S.W., Felip, Enriquetta, Chow, Laura Q.M., Camidge, D. Ross, Vansteenkiste, Johan, Sharma, Sunil, De Pas, Tommaso, Riely, Gregory J., Solomon, Benjamin J., Wolf, Juergen, Thomas, Michael, Schuler, Martin, Liu, Geoffrey, Santoro, Armando, Lau, Yi-Yang Yvonne, Goldwasser, Meredith, Boral, Anthony and Engelman, Jeffrey A. (2014) LDK378 in Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer. New England Journal of Medicine, 370 (13). pp. 1189-1197.

Abstract

Background:
Non–small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement is sensitive to the ALK inhibitor crizotinib, but invariably resistance develops. LDK378 is a novel ALK inhibitor with greater preclinical antitumor potency than crizotinib.

Methods:
In this phase 1 study, patients with advanced malignancies harboring genetic alterations in ALK received oral LDK378 at doses of 50 to 750 mg once daily. Expansion cohorts received the maximum tolerated dose (MTD). Patients were assessed for safety, pharmacokinetics, and antitumor activity. Tumor biopsies were performed pre-LDK378 treatment to identify ALK resistance mutations in a group of patients with NSCLC who had progressed on crizotinib.

Results:
Fifty-nine patients were enrolled in the dose-escalation part. The MTD of LDK378 was 750 mg once daily; dose-limiting toxicities included diarrhea, vomiting, dehydration, transaminase elevation, and hypophosphatemia. Seventy-one additional patients were treated in the expansion part, totaling 130 patients. Among 114 patients with NSCLC who received LDK378 ≥400 mg per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 79 crizotinib-treated patients, the response rate was 57% (95% CI, 45 to 68). Responses were observed in patients with different ALK resistance mutations, and in patients without detectable mutations. Among patients with NSCLC who received LDK378 ≥400 mg per day, median progression-free survival was 8.6 months (95% CI, 5.7 to 9.9).

Conclusions:
LDK378 is highly active in patients with advanced, ALK-rearranged NSCLC, including patients who progressed on crizotinib, with and without ALK resistance mutations. (Funded by Novartis; ClinicalTrials.gov number, NCT01283516)

Item Type:	Article
Keywords:	LDK378; anaplastic lymphoma kinase; ALK; lung cancer; clinical trial; phase 1;
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/11035