A phase 1 study of crizotinib and ganetespib (STA-9090) in ALK positive lung cancers.

Abstract

8064 Background: Patients with ALK + non-small cell lung cancer (NSCLC) initially respond to crizotinib, but eventually develop resistance. Treatment of patients with ALK positive lung cancer with HSP90 inhibitors leads to clinical and radiographic response. We hypothesized that treatment of patients with ALK rearranged NSCLC with crizotinib and ganetespib, an HSP90 inhibitor, would be safe. Methods: All patients had ALK rearranged metastatic non-small cell lung cancer not previously treated with crizotinib. Prior chemotherapy was allowed. Patients were treated with crizotinib 250 mg bid continuously; ganetespib was administered intravenously on days 1 and 8 of a 21-day cycle. In a standard 3+ 3 design, ganetespib was explored at 3 different dose levels. The primary objective was to determine the maximum tolerated dose of the combination of crizotinib and ganetespib. Secondary objectives included establishing the safety profile (CTCAE v4) of the combination in patients with ALK+ lung cancer, exploring the efficacy (RR by RECIST 1.1, PFS, and OS). Results: 12 patients were treated with combined crizotinib and ganetespib: 100 mg/m2(n=3), 150 mg/m2(n=3), and 200 mg/m2 (n=6). Women: 8/12, Median Age: 56 (range 41-70), Prior therapy: none (7 pts), 1 line (4 pts), or 2 lines (1 pt). Median duration of treatment: 100 mg/m2=30 weeks, 150 mg/m2=54 weeks, and 200 mg/m2= 6 weeks. There were no first-cycle DLTs. The maximum tolerated dose was crizotinib 250 mg bid/ganetespib 200 mg/m2. The most common toxicities were fatigue, diarrhea, nausea, vomiting, and dizziness. Grade 4 elevation in ALT (n=1) and Grade 3 elevations in lipase (n=2), AST (n=1), and amylase (n=1) were observed. 5 patients stopped therapy due to toxicity. 4 discontinued due to progressive disease. 3 patients continue on treatment. PR = 67% (8/12), SD= 16% (2/12), PD =8% (1/12), Not Evaluable =8% (1/12). Median OS has not been reached (median f/u = 15 months, with 10 patients still alive). Conclusions: In patients with ALK+ lung cancers, crizotinib and ganetespib can be combined, with an MTD of crizotinib 250 mg bid continuously and ganetespib 200 mg/m2 on days 1 and 8 of a 21 day cycle. Further evaluation of this combination in patients not previously treated with crizotinib is warranted. Clinical trial information: (NCT01579994).