A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with Genotypically Defined Advanced Non-Small Cell Lung Cancer

• Type of Material: Article
• Authors: Mark A. Socinski, University of Pittsburgh; Jonathan Goldman, Premiere Oncology; Iman El-Hariry, Synta Pharmaceuticals Corp.; Marianna Koczywas, City of Hope National Medical Center; Vojo Vukovic, Synta Pharmaceuticals Corp.; Leora Horn, Vanderbilt Ingram Cancer Center; Eugene Paschold, Piedmont Hematology Oncology Associates; Ravi Salgia, University of Chicago; Howard West, Swedish Cancer Institute; Lecia V. Sequist, Massachusetts General Hospital; Philip Bonomi, Rush University; Julie Brahmer, Sidney Kimmel Comprehensive Cancer Center; Lin-Chi Chen, Nevada Cancer Institute; Alan Sandler, Knight Cancer Institute; Chandra P. Belani, Penn State Hershey Cancer Institute; Timothy Webb, Genesis Cancer Center; Harry Harper, Hackensack University Medical Center; Mark Huberman, Beth Israel Deaconess Medical Center; Suresh Ramalingam, Emory University; Kwok-Kin Wong, Dana Farber Cancer Institute; Florentina Teofilovici, Synta Pharmaceuticals Corp.; Wei Guo, Synta Pharmaceuticals Corp.; Geoffrey I. Shapiro, Dana Farber Cancer Institute
• Language: English
• Date: 2013-06-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2013 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-12-3381
• Title of Journal or Parent Work: Clinical Cancer Research
• ISSN: 1078-0432
• Volume: 19
• Issue: 11
• Start Page: 3068
• End Page: 3077
• Grant/Funding Information: This study was supported by Synta Pharmaceuticals.; K.-K. Wong and G.I. Shapiro were also supported by the Dana-Farber/Harvard Cancer Center Specialized Program for Research Excellence (SPORE) in Lung Cancer NIH grant (P50 CA90578).
• Keywords: KINASE; POTENT ANTITUMOR-ACTIVITY; Oncology; CHAPERONE; ANAPLASTIC LYMPHOMA; RECEPTOR; B-RAF; RESISTANCE; ALK; CRIZOTINIB; Science & Technology; Life Sciences & Biomedicine; HSP90 INHIBITOR
• Research Categories: Health Sciences, Oncology

Abstract

Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC). Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.