Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer

Abstract

Purpose: IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non-small-cell lung cancer (NSCLC).

Patients and methods: Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes.

Results: Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%).

Conclusion: IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.

Fig 1.

Best percent change in size of target lesions on study. Percent change in measurable tumor at best response is displayed by genotype. (A) Epidermal growth factor receptor (EGFR) mutation status, (B) KRAS mutation status, and (C) ALK rearrangement status.

Fig 2.

Patients with ALK rearrangements on study. (A) Example of a positive fluorescent in situ hybridization (FISH) break-apart assay in a patient with ALK rearrangement. White arrows indicate the wild-type allele with close proximity of the red and green probes yielding a yellow signal. Red arrows indicate the ALK rearrangement with separated red and green probes. (B) Change in size of target lesions over time for patients tested for ALK rearrangement. RECIST, Response Evaluation Criteria in Solid Tumors; PR, partial response; SD, stable disease; PD, progressive disease.

Fig 3.

ALK rearranged cancer cell lines are sensitive to heat-shock protein 90 (Hsp90) inhibitors. (A) Cancer cell lines with epidermal growth factor receptor (EGFR) mutations (H1975, L858R/T790M, and HCC827 exon 19 deletion) or ALK gene rearrangement (H3122 and MGH-006) were treated with increasing doses of the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) for 24 hours. Protein lysates were probed with the indicated antibodies. (B) NCI-H1975, HCC827, MGH-006, and NCI-H3122 cells were treated with increasing doses of 17-AAG for 72 hours. Total cell viability was determined by Syto60 assay. Data are presented as the percent of viable cells relative to cells grown in the absence of drug.

Fig A1.

Epidermal growth factor receptor (EGFR), KRAS, and ALK status for all samples. All patient genotyping for EGFR, KRAS, and ALK status including partial responses (PR) as noted. WT, wild-type; MUT, mutation; UNK, unknown.