Elsevier

Clinical Colorectal Cancer

Volume 13, Issue 4, December 2014, Pages 207-212
Clinical Colorectal Cancer

Original Study
Ganetespib, a Novel Hsp90 Inhibitor in Patients With KRAS Mutated and Wild Type, Refractory Metastatic Colorectal Cancer

https://doi.org/10.1016/j.clcc.2014.09.001Get rights and content

Abstract

Background

Heat shock protein 90 (Hsp90) is a cellular chaperone that is required for the maturation and stability of a variety of proteins that play key roles in colon cancer initiation and progression. The primary objective of the current study was to define the safety and efficacy of ganetespib, a novel, selective small-molecule Hsp90 inhibitor, in patients with refractory metastatic colorectal cancer.

Patients and Methods

The study was a single-arm, Simon 2-stage, phase II trial for patients with chemotherapy-refractory, metastatic colorectal cancer. Patients received ganetespib 200 mg/m2 intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined.

Results

Seventeen patients were treated (median age, 58; range, 44-79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors.

Conclusion

In this first phase II investigation of an Hsp90 inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug's promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned.

Introduction

Heat shock protein (Hsp) 90 belongs to a class of molecular chaperone proteins that help modulate cellular responses to environmental stress by supporting stabilization, folding, and function of many oncogenic proteins, and other proteins responsible for cancer cell growth and survival. Cancer cells upregulate Hsp90 in response to stress,1, 2, 3 allowing critical Hsp90-bound proteins to escape proteolytic degradation, and thereby promote cellular proliferation.4, 5 Additionally, Hsp90 expression has been shown to enable the tumor cells to escape apoptosis.6

A number of treatment regimes are available for patients with metastatic colorectal cancer (CRC) including chemotherapies with 5-fluoracil–based regimens, irinotecan, oxaliplatin, and targeted therapies such as anti-vascular endothelial growth factor (VEGF) treatment with bevacizumab and anti-epidermal growth factor receptor (EGFR) treatment with cetuximab or panitumumab (for patients with V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumors). Unfortunately, eventually metastatic CRC becomes unresponsive to medical therapy. Currently, there is no effective standard treatment for this refractory patient population and no known drug for which the response rate would be expected to be greater than approximately 0% to 1%. Therefore, new approaches are needed.

KRAS Kristen and Neuroblastoma RAS viral oncogene homolog-activating mutations have been shown to result in resistance to anti-EGFR–targeted therapies in CRC, and recent data have also shown similar resistance in tumors with mutated v-Raf murine sarcoma viral oncogene homolog B (BRAF),7 and in patients with mutations in the PI3K/protein kinase B (Akt) pathway.8 The attempt to identify a single driver mutation has been disappointing thus far, as evidenced by the still relatively low response rate of approximately 20% to 25% in RAS wild type tumors to anti-EGFR therapy and the lack of response to the BRAF inhibitor vemurafenib (PLX4032) in BRAF V600E-mutated cells.9 Thus, it is becoming increasingly more evident that the biology of CRC is different from malignancies in which there is a clear-cut driver mutation, such as HER2-mutated breast cancer or EGFR-mutated non–small-cell lung cancer. Hsp90 inhibition enables the simultaneous blockade of multiple oncogenic transduction pathways and tumor–stroma interactions, thereby potentially inhibiting cancer cell growth and survival. Thus, Hsp90 inhibition represents an attractive potential therapeutic target in CRC.

Ganetespib is a novel second small molecule Hsp90 inhibitor. It is a resorcinol-containing triazole compound that binds to the N-terminus of Hsp90 and is structurally unrelated to the geldanamycin class of Hsp90 inhibitors. Preclinical and phase I studies appear to demonstrate less toxicity (including lack of ocular and hepatic toxicity) than the earlier Hsp90 inhibitors and effective downregulation of key oncogenic proteins in CRC cell lines.10, 11 In the phase I study, single-agent ganetespib was well tolerated and a patient with metastatic CRC achieved a partial response.12

Because of this response, favorable toxicity profile, and compelling preclinical data, we hypothesized that ganetespib as a single agent would have clinically meaningful activity in refractory metastatic CRC.

Section snippets

Study Population

Patients were required to have pathologically confirmed CRC with measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) criteria and documentation of previous progression during at least 1 chemotherapeutic regimen. Patients were further required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, age 18 or older, and have an estimated life expectancy of > 3 months. Adequate kidney and bone marrow function were

Patient Characteristics

Seventeen patients were enrolled and treated in this trial between June 2010 and November 2011. The median age was 58 years (range, 44-79 years). Patient characteristics are summarized in Table 1. All patients had received previous chemotherapy as required for study eligibility with most having received 3 or more previous regimens. All patients with KRAS wild type tumors had received previous anti-EGFR therapy. Two patients were removed from the study because of events unrelated to treatment

Discussion

In this phase II study, the single-agent Hsp90 inhibitor ganetespib did not demonstrate meaningful antitumor activity in chemotherapy-refractory metastatic CRC.

The OS and PFS were consistent with refractory metastatic CRC. IHC analysis also did not reveal any significant differences in marker expression between 1 of the 2 patients with stable disease and the remaining 13 who had disease progression. Unfortunately, the patient with stable disease for 23 weeks did not have sufficient tissue for

Conclusion

Ganetespib alone did not demonstrate any meaningful antitumor activity in patients with refractory metastatic CRC. Single-agent ganetespib had a mild toxicity profile and was well tolerated. Preclinical studies suggest that Hsp90 inhibitors are able to enhance the efficacy of anticancer agents, and potentially overcome drug resistance.28, 29, 30 Several studies have been conducted with Hsp90 inhibitors in combination with cytotoxic chemotherapies including the GALAXY-I study of ganetespib with

Disclosure

Dr. Proia is an employee of Synta Pharmaceuticals. All other authors declare no conflicts of interest.

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