Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer

Abstract

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m² ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379.

Fig. 1. CONSORT diagram.

Details of the screening, randomization, and treatment for patients assigned to ganetespib or standard of care are provided.

Fig. 2. Estimated rate pf pCR with ganetespib versus the concurrent HER2-negative control.

Final pCR probability distributions in ganetespib (red) and control (blue) arms, for A All HER2-negative participants, B HR-negative/HER2-negative participants, and C HR-positive/HER2-negative participants.

Fig. 3. Event-free survival.

Kaplan–Meier plots of event-free survival comparing ganetespib and control arms in A all HER2-negative participants, B triple negative participants, and C HR-positive/HER2-negative participants. Median follow-up in the overall (HER2-negative) population was 3.6 years.

Fig. 4. Analysis of pre-specified mechanism-of-action gene expression biomarkers for ganetespib response.

Association dot-plot showing the level and direction of association between each gene (row) and pCR in the population/model as labeled (columns from right to left): G arm, control arm, interaction with treatment, interaction with treatment in a model adjusting for HR status; and analysis limited to the TN and HR+HER2- subsets. Key = red/blue dot indicates higher/lower levels ~ pCR; size of dot ~ strength of association (1/p likelihood ratio test), with dark outline/white background indicating p < 0.05 (likelihood ratio test) and gray background indicating p > 0.05 (likelihood ratio test). All biomarkers were assessed at the pre-treatment time point.