Measuring tumor epichaperome expression using [(124)I] PU-H71 positron emission tomography as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2-negative metastatic breast cancer Journal Article
| Authors: | Jhaveri, K. L.; dos Anjos, C. H.; Taldone, T.; Wang, R.; Comen, E.; Fornier, M.; Bromberg, J. F.; Ma, W.; Patil, S.; Rodina, A.; Pillarsetty, N.; Duggan, S.; Khoshi, S.; Kadija, N.; Chiosis, G.; Dunphy, M. P.; Modi, S. |
| Article Title: | Measuring tumor epichaperome expression using [(124)I] PU-H71 positron emission tomography as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2-negative metastatic breast cancer |
| Abstract: | PURPOSE Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. METHODS We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nabpaclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. RESULTS Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. CONCLUSION The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned. © 2020 by American Society of Clinical Oncology. |
| Journal Title: | JCO Precision Oncology |
| Volume: | 4 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2020-11-17 |
| Start Page: | 1414 |
| End Page: | 1424 |
| Language: | English |
| DOI: | 10.1200/po.20.00273 |
| PROVIDER: | scopus |
| PMCID: | PMC7713524 |
| PUBMED: | 33283132 |
| DOI/URL: | |
| Notes: | MSK author Sareh Khoshi's first name is misspelled on the original publication -- Article -- Export Date: 4 January 2021 -- Source: Scopus |
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