Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC.

Lung Cancer - Non-Small Cell Metastatic
Session Type and Session Title: 
Clinical Science Symposium, Targeted Therapies in Lung Cancer: What's New and What's Enough?
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 8010)
Alice Tsang Shaw, Ranee Mehra, Dong-Wan Kim, Enriqueta Felip, Laura Quan Man Chow, D. Ross Camidge, Daniel Shao-Weng Tan, Johan F. Vansteenkiste, Sunil Sharma, Tommaso De Pas, Juergen Wolf, Ryohei Katayama, Yi-Yang Yvonne Lau, Meredith Goldwasser, Anthony Boral, Jeffrey A. Engelman; Massachusetts General Hospital Cancer Center, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Thoracic Tumors Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain; University of Washington/Seattle Cancer Care, Seattle, WA; University of Colorado Cancer Center, Aurora, CO; National Cancer Center Singapore, Singapore, Singapore; University Hospital KU Leuven, Leuven, Belgium; Huntsman Cancer Institute, Salt Lake City, UT; European Institute of Oncology, Milano, Italy; Lung Cancer Group Cologne, Center for Integrated Oncology, University Hospital Cologne, Koeln, Germany; Massachusetts General Hospital, Boston, MA; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Institutes for BioMedical Research, Inc., Cambridge, MA

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Abstract Disclosures


Background: Lung cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the tyrosine kinase inhibitor (TKI) crizotinib (CRZ), but invariably develop resistance. LDK378 is a novel, more potent ALK TKI than CRZ, with significant antitumor activity in preclinical models. Methods: In this multicenter phase I study, 131 patients (pts) with advanced malignancies harboring a genetic alteration in ALK, including 123 with ALK-rearranged (ALK+) NSCLC (as determined by FISH), were enrolled. LDK378 was administered orally at doses of 50–750 mg once daily. All pts were assessed for PK, response to therapy, and adverse events (AEs). In >20 pts with CRZ-resistant disease, tumor biopsy was performed before LDK378 treatment to identify CRZ resistance mutations. Results: As of November 8, 2012, 131 pts had been enrolled (38% male, median age 53 years), including 59 pts in the dose escalation phase, during which the MTD of 750 mg once daily was established, and 72 pts in an expanded cohort at the MTD. Among 88 evaluable NSCLC pts who received LDK378 at 400–750 mg daily, the overall response rate (ORR) was 70%, with 40 confirmed and 22 unconfirmed responses. In the subset of 64 CRZ-resistant pts, the ORR was 73%, with 31 confirmed and 16 unconfirmed responses. As of November 8, 2012 50% of pts with unconfirmed responses were ongoing. Responses were observed in pts with different CRZ resistance mutations as well as in pts without detectable mutation. Responses were also seen in pts with untreated CNS metastases. Among NSCLC pts with confirmed response, median duration of response (DOR) was 7.4 months (95% CI, 6.7 – NR), and 78% had a DOR of ≥6 months. In all 123 NSCLC pts, median PFS was 8.6 months (95% CI, 4.3 – 19.3). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3/4 AEs were ALT elevation (12%), diarrhea (7%), and AST elevation (6%). Conclusions: LDK378 induces durable responses in the majority of pts with advanced, ALK+ NSCLC, including CRZ-resistant pts with and without CRZ resistance mutations. These results suggest that more potent ALK inhibition by LDK378 represents a highly efficacious treatment strategy for ALK+ pts, particularly those who relapse on CRZ. Clinical trial information: NCT01283516.