Abstract PS3-11-10: Neoadjuvant HSP90 inhibition with ganetespib significantly improves distant relapse-free survival in I-SPY2 patients with HER2-negative breast cancer with low expression of immune genes and no DNA repair deficiency

Abstract Introduction: The I-SPY2 neoadjuvant platform trial (NCT01042379) evaluates new therapies in high molecular risk, stage 2-3 breast cancer patients. Between 2010 and 2022, 24 therapies were tested in 2,117 patients. One-third of these patients had HER2-negative tumors with low expression of immune genes and no DNA repair deficiency (DRD) (HER2-/Immune-/DRD- subtype). These patients had very low pathologic complete response (pCR) rates (∼10% on average) across all treatment and control arms. We performed a high-throughput drug screen (n=386 compounds) in triple-negative (TN), immune-low, DRD-low breast cancer patient-derived organoids with confirmed in vitro resistance to platinum chemotherapy to identify effective treatments for this tumor type. HSP90 inhibitors, including ganetespib, were one of the most potent drug classes in the screen. HSP90 is an abundant chaperone protein involved in the folding of oncoproteins under basal conditions and during stress response. Neoadjuvant ganetespib was tested in I-SPY2 in combination with standard chemotherapy in HER2-negative breast cancer but did not meaningfully improve pCR rates (PMID 36456573). Here, we re-evaluate the ganetespib arm by Response Predictive Subtypes with 5-year median follow-up data, focused on patients with breast tumors of the HER2-/Immune-/DRD- subtype. Methods: HER2-/Immune-/DRD- patients (N=221; 79% HR+, 21% TN) and HER2-/Immune+ and/or DRD+ patients (N=219; 32% HR+, 68% TN) were randomized to neoadjuvant ganetespib (150 mg/m2 ganetespib every 3 weeks with paclitaxel, then doxorubicin plus cyclophosphamide (AC)) (n=38 HER2-/Immune-/DRD- and n=55 HER2-/Immune+ and/or DRD+), or standard neoadjuvant chemotherapy control (paclitaxel-AC) (n=183 HER2-/Immune-/DRD- and n=164 HER2-/Immune+ and/or DRD+). The primary endpoint, pCR, was defined as the absence of invasive disease in the breast and regional nodes at surgery. Distant relapse-free survival (DRFS) was assessed using Kaplan-Meier curves, with hazard ratios (HR) estimated by Cox regression. Residual cancer burden (RCB) and serial MRI-based functional tumor volume (FTV) were collected as investigational early measures of treatment efficacy in the neoadjuvant setting. Results: In HER2-/Immune-/DRD- patients, pCR rates were low in the ganetespib and control arms (13% vs. 9%), compared with 38% vs. 31%, respectively, in HER2-/Immune+ and/or DRD+ patients. In both subtypes, patients who achieved a pCR with either treatment had excellent DRFS (100% at 5 years). Interestingly, in HER2-/Immune-/DRD- patients treated with ganetespib with no pCR (n=32), we observed only 1 DRFS event, compared with 35 DRFS events in HER2-/Immune-/DRD- control-treated patients with no pCR (n=166); HR 0.12 (95% CI 0.02-0.90; p-value: 0.039). The respective DRFS at 5 years was 96% with ganetespib vs. 77% with control, showing a significantly improved DRFS with neoadjuvant ganetespib for HER2-/Immune-/DRD- patients, despite their non-pCR. This treatment effect remained significant when adjusted for hormone receptor status. Among non-pCR patients, RCB measure and FTV decrease explained a portion of ganetespib’s significant DRFS benefit. In contrast, ganetespib did not improve DRFS in HER2-/Immune+ and/or DRD+ patients compared with control. Conclusion: Our data suggest a promising role for ganetespib in improving long-term outcomes for patients with HER2-/Immune-/DRD- tumors, which account for 38% of all molecularly high-risk breast cancers, even in the absence of a pathologic complete response. Continuous measures of RCB and FTV may serve as early predictors of ganetespib’s long-term survival benefit in HER2-/Immune/-DRD- patients. Citation Format: T. B. V. Bui, D. M. Wolf, C. Yau, R. W. Sayaman, K. Chow, S. W. Choi, M. C. Bruck, K. Santos-Parker, A. M. Glas, J. E. Lang, A. Forero-Torres, L. Brown-Swigart, G. L. Hirst, E. F. Petricoin, J. Perlmutter, W. F. Symmans, P. R. Pohlmann, D. Yee, L. Pusztai, I-SPY investigators, N. M. Hylton, A. M. DeMichele, J. M. Rosenbluth, L. J. Esserman, L. J. Van 'T Veer. Neoadjuvant HSP90 inhibition with ganetespib significantly improves distant relapse-free survival in I-SPY2 patients with HER2-negative breast cancer with low expression of immune genes and no DNA repair deficiency abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-10.