Abstract P6-20-03: Tumor epichaperome expression using 124I PU-H71 PET (PU-PET) as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2 negative (HER2-) metastatic breast cancer (MBC)
Authors: K Jhaveri, M Dunphy, R Wang, E Comen, M Fornier, ME Moynahan, J Bromberg, W Ma, S Patil, T Taldone, A Rodina, V Sterlin, S Khoshi, J Lewis, L Norton, G Chiosis, S Modi
Journal: Cancer Research (2019)

Abstract Background: The epichaperome is a new cancer target required for tumor survival (Joshi et al. Nature Reviews Cancer 2018). PU-H71 is a synthetic, purine scaffold epichaperome inhibitor that binds to the ATP-binding site of HSP90 specifically when HSP90 is integrated into the epichaperome (Rodina et al. Nature 2016). It has demonstrated antitumor activity in multiple xenograft models. Furthermore, sequential administration of nab-paclitaxel and PU-H71 in TNBC xenograft models augmented epichaperome levels, and in turn resulted in super-synergistic drug action with ablation of xenografted tumors and cures in mice. Methods: This is an open label phase1b study of PU-H71 + nab-paclitaxel in pts with HER2- MBC. Pts received nab-paclitaxel at a standard dose of 260mg/m2 IV Q 3weeks. PU-H71 was administered IV 6 hrs (+/-1 hr) post nab-paclitaxel Q3weeks in 2 escalating dose levels (225mg/m2 and 300 mg/m2). All pts underwent FDG PET/CT every 6 weeks. Additionally, patients had the option to enroll on a separate diagnostic PU-PET protocol to measure epichaperome expression prior to initiating treatment on the phase 1b study, wherein they received a single dose of up to 11mci of 124I-PU-H71 IV and underwent imaging at 3-4hrs and 20-24 hrs. Primary objective was to establish the MTD/RP2D of this regimen. Secondary objectives were to assess PK of PU-H71 + nab-paclitaxel and clinical efficacy. Exploratory analysis included correlation of epichaperome expression at baseline using PU-PET with tumor response. Results: 12 patients (5 ER+/HER2- ; 7 TNBC) were enrolled (6 at 225mg/m2 of PU-H71 and 6 at 300mg/m2). Median Age: 54 yrs (range: 37-71). Median ECOG: 0. Median lines of therapy in the metastatic setting: 6 (range 1-11) including prior taxanes in 75% of pts. Most common toxicities included diarrhea G1 58%; G2 7%, G3 7%) that was easily managed with anti-diarrheal agents, G1 fatigue (25%), G1/2 peripheral neuropathy (17%), G1 hyperglycemia (67%), G1 increases in alk phos (58%), AST (50%) and ALT (42%). Hematological toxicities included G3 leukopenia (42%), G3/4 neutropenia (67%), G3 anemia (50%) and G2 thrombocytopenia (17%). There were no DLTs. 33% (4/12) had PR, 58% (7/12) achieved SD with only 1 PD at the time of first scan; 5 pts are currently ongoing including 2 TNBC pts with PR who have been on therapy &amp;gt; 7 months. PK data will be presented. 8/12 patients also underwent PU-PET at baseline. A higher tumor to muscle SUV ratio at 24 hrs on PU-PET predicted response and increased PU-H71 retention on PU-PET at 24 hrs correlated with a longer duration of response. Conclusion: The RP2D of PU-H71 was 300mg/m2 with 260mg/m2 of nab-paclitaxel administered IV every 3 weeks. The regimen is well tolerated with promising clinical activity in this heavily pre-treated cohort. Tumor epichaperome expression at baseline using PU-PET has the potential to serve as a predictive biomarker of response. A Phase 2 trial of this combination along with baseline PU-PET is currently planned. Citation Format: Jhaveri K, Dunphy M, Wang R, Comen E, Fornier M, Moynahan ME, Bromberg J, Ma W, Patil S, Taldone T, Rodina A, Sterlin V, Khoshi S, Lewis J, Norton L, Chiosis G, Modi S. Tumor epichaperome expression using 124I PU-H71 PET (PU-PET) as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-03.