This phase II trial evaluated the role of single agent ganetespib, an Heat Shock Protein 90 (HSP90) inhibitor, in unselected Metastatic Breast Cancer (MBC). The study did not meet its prespecified criteria for overall response rate (ORR) in this heavily pretreated population. However, clinical activity was noted in HER2-positive and triple-negative breast cancer (TNBC), which warrants further study as part of rational combinations.Background:
Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC.Patients and Methods:
Patients were treated with single agent ganetespib at 200 mg/m2 once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1.Results:
Twenty-two patients were enrolled with a median age of 51(range, 38–70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0–1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7–19), and median overall survival was 46 weeks (95% CI, 27-not applicable).Conclusion:
The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.