A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer

Komal Jhaveri, Rui Wang, Eleonora Teplinsky, Sarat Chandarlapaty, David Solit, Karen Cadoo, James Speyer, Gabriella D'Andrea, Sylvia Adams, Sujata Patil, Sofia Haque, Tara O'Neill, Kent Friedman, Francisco J Esteva, Clifford Hudis, Shanu Modi, Komal Jhaveri, Rui Wang, Eleonora Teplinsky, Sarat Chandarlapaty, David Solit, Karen Cadoo, James Speyer, Gabriella D'Andrea, Sylvia Adams, Sujata Patil, Sofia Haque, Tara O'Neill, Kent Friedman, Francisco J Esteva, Clifford Hudis, Shanu Modi

Abstract

Background: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer.

Methods: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy.

Results: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2-4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8-55).

Conclusion: The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer.

Trial registration: ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.

Keywords: Ganetespib; HER2; HSP90 inhibitor; Metastatic breast cancer; Paclitaxel; Phase I trial; Trastuzumab.

Conflict of interest statement

Ethics approval and consent to participate

This clinical trial was conducted in accordance with Good Clinical Practice guidelines. Approval for the protocol was obtained from the institutional review board for both Memorial Sloan Kettering Cancer Center and New York University Langone Medical Center. All participants gave informed consent before they entered the study.

Consent for publication

All authors agreed to this publication.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Most common ganetespib-related grade 1/2 AEs in ≥20% of patients. None of the nine patients experienced DLTs. ALT alanine aminotransferase, AST aspartate transaminase
Fig. 2
Fig. 2
Baseline and follow-up CT scans. Baseline (a) and follow-up (b) CT scans of a 43-year-old patient with left chest wall soft tissue metastases
Fig. 3
Fig. 3
Paclitaxel PK. Preliminary paclitaxel PK data for the nine study patients are not appreciably different from those reported in the literature

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