Abstract 7632: Final survival outcomes and post-hoc tumor gene expression pathway analyses of complete responders from a phase Ib clinical trial of HSP90 inhibitor onalespib and paclitaxel in patients with advanced triple-negative breast cancer
Authors: Quiroga Dionisia Marie , Savardekar Himanshu , Schwarz Emily , Williams Nicole O. , Johnson Courtney , Brufsky Adam , Chambers Mara , Bhattacharya Saveri , Patterson Maria , Sardesai Sagar D. , Stover Daniel , Lustberg Maryam , Noonan Anne , Cherian Mathew , Bystry Darlene M. , Hill Kasey , Chen Min , Phelps Mitch A. , Stephens Julie , Yu Lianbo , Ramaswamy Bhuvaneswari , Wesolowski Robert , Carson William E. 
Published: March 2024

Abstract
Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance, therefore, it was hypothesized that the potent HSP90 inhibitor onalespib could improve paclitaxel efficacy. As TNBCs are a heterogenous population of tumors, it is important to establish biomarkers of response to this treatment combination.
Methods: Patients with TNBC were treated with intravenous (IV) paclitaxel and IV onalespib at doses ranging from 120 mg/m2 to 260 mg/m2 on days 1, 8, and 15 of a 28-day cycle utilizing a standard 3+3 design. The primary objectives were to determine dose-limiting toxicities and maximum tolerated dose. Secondary objectives included determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Retrospectively, archival tumor tissue was obtained from study patients and processed for RNA expression analysis by NanoString nCounter platform with the Breast Cancer 360 panel. Post-hoc gene expression analysis was performed through Qiagen Ingenuity Pathway Analysis (IPA). Linear models were employed to detect differential expression between conditions while considering cartridge effect.
Results: 31 patients were enrolled in this study, of which 90% received prior taxane therapy. The established recommended phase II dose was 260 mg/m2 onalespib when given with 80 mg/m2 paclitaxel. ORR was 20%, median DOR was 5.6 months. Three patients achieved complete responses (CR), all of whom had received prior taxane therapy. Nanostring profiling analysis revealed that patients who had a CR to treatment expressed higher levels of several breast cancer-associated genes also known to be dependent upon HSP90 activity compared to patients with progressive disease (PD) as their best treatment response. These genes include FGFR4, JAK2, PIK3R1, TGFB3, and TGFBR2 (all p&lt;0.05). Tumor genes overexpressed in patients with PD versus CR included IRF6, MMP7, and KRT17 (all p&lt;0.01). Additionally, IPA showed patients with CR to have substantial upregulation of PD-1, PD-L1, CTLA-4, p53, HER2, and cyclin/cell cycle regulatory signaling pathways compared to patients with PD (all p&lt;0.01).
Conclusions: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and showed anti-tumor activity in patients with advanced TNBC. Gene expression analysis of patient tumor samples suggest that TNBCs with greater activation of immune checkpoint pathways and those with proteins dependent on HSP90 activity, including p53 and HER2, may be more susceptible to HSP90 inhibition.
ClinicalTrials.gov study identification: NCT02474173
Citation Format: Dionisia Marie Quiroga, Himanshu Savardekar, Emily Schwarz, Nicole O. Williams, Courtney Johnson, Adam Brufsky, Mara Chambers, Saveri Bhattacharya, Maria Patterson, Sagar D. Sardesai, Daniel Stover, Maryam Lustberg, Anne Noonan, Mathew Cherian, Darlene M. Bystry, Kasey Hill, Min Chen, Mitch A. Phelps, Julie Stephens, Lianbo Yu, Bhuvaneswari Ramaswamy, Robert Wesolowski, William E. Carson. Final survival outcomes and post-hoc tumor gene expression pathway analyses of complete responders from a phase Ib clinical trial of HSP90 inhibitor onalespib and paclitaxel in patients with advanced triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7632.