An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC).

Abstract

7500 Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. Ganetespib has been well tolerated and has shown promising antitumor activity in early trials in multiple cancers. Methods: Patients (pts) with advanced NSCLC who failed prior treatments received 200 mg/m2 ganetespib as a 1-hr infusion once weekly for 3 of a 4-wk cycle in a Simon two-stage study design assessing primary endpoint of PFS rate at 16 wks. Initial cohorts were defined by mutation status: A) EGFR B) KRAS C) EGFR and KRAS wild type (WT). If ≥2/14 pts in A, B or C were progression-free at 16 wks, enrollment increased to 23 pts for that cohort. Tumor response was assessed every 8 wks. Cohort D was added to include 35 additional EGFR and KRAS WT pts with adenocarcinoma histology. Additional mutational analysis of BRAF, PIK3CA, ERBB2 and MET, as well as FISH analysis for ALK translocation, were performed for Cohorts C and D. Results: 73 pts (31 M, 42 F; median age 62 yrs, range 28-82; ECOG 0-1; prior therapies range 1-10) received a median of 2 cycles (range 1-12) of ganetespib in cohorts A (14), B (17), and C+D (42). AEs reported in ≥20% of pts included diarrhea, fatigue, nausea, anorexia, constipation, and dyspnea and were generally grade 1-2. Expansion criteria were achieved for cohort C, including a durable partial response (PR) and seven pts with prolonged stable disease (≥16 wks). Cohort D continues recruitment. Mutational analyses of Cohort C and D samples will be presented. Conclusions: Ganetespib administered as a single-agent is well-tolerated in pts with NSCLC at 200 mg/m2 once weekly without severe liver, ocular, cardiovascular or renal toxicity. Clinical activity has been observed in pts with advanced NSCLC tumors harboring wild-type EGFR and KRAS.