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.

Autor:	Jhaveri KL; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Dos Anjos CH; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Taldone T; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Wang R; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Comen E; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Fornier M; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Bromberg JF; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Ma W; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Patil S; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Rodina A; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Pillarsetty N; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY., Duggan S; Samus Therapeutics, Topsfield, MA., Khoshi S; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Kadija N; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Chiosis G; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.; Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY., Dunphy MP; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY., Modi S; Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2020 Nov 17; Vol. 4. Date of Electronic Publication: 2020 Nov 17 (Print Publication: 2020).
DOI:	10.1200/PO.20.00273
Abstrakt:	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 nab-paclitaxel. 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/m 2 plus nab-paclitaxel 260 mg/m 2 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. Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Komal L. JhaveriConsulting or Advisory Role: Novartis, Pfizer, Spectrum Pharmaceuticals, AstraZeneca, Taiho Pharmaceutical, Jounce Therapeutics, ADC Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genentech, AbbVie, Eli Lilly Research Funding: Novartis (Inst), Genentech (Inst), Debio Pharmaceuticals (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Eli Lilly (Inst), Zymeworks (Inst), Immunomedics (Inst), Puma Biotechnology (Inst) Travel, Accommodations, Expenses: Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca, IntellisphereCarlos H. dos AnjosConsulting or Advisory Role: MSD OncologyTony TaldoneConsulting or Advisory Role: Samus Therapeutics Patents, Royalties, Other Intellectual Property: I am an inventor on patents covering associated composition of matter.Elizabeth ComenEmployment: Survivornet Stock and Other Ownership Interests: Survivornet.com Honoraria: Navigant Consulting, Kantar Health, Grey Global Group, ClearView Healthcare Partners, Decision Resources, Gerson Lehrman Group, Pfizer Consulting or Advisory Role: Bristol Myers Squibb, Pfizer, Genentech, HERON, Novartis Research Funding: Roche Travel, Accommodations, Expenses: Pfizer, NovartisMonica FornierHonoraria: Eisai, Roche/Genentech Consulting or Advisory Role: Eisai Research Funding: Roche/GenentechNagavarakishore PillarsettyStock and Other Ownership Interests: Amedisys, Madrigal Pharmaceuticals, Teva, Verastem, Ampio Pharmaceuticals, Merrimack, Celldex, ZIOPHARM Oncology, Immunogen, Bayer, OncoMed, Lexicon, ION Pharma, Viking Therapeutics Patents, Royalties, Other Intellectual Property: N. Pillarsetty is coinventor on intellectual property on Hsp90/epichaperome targeting agents that were developed at MSKCC and is currently licensed to Samus Therapeutics. N. Pillarsetty has received financial royalties for his IP contributions that are licensed to Samus Therapeutics.Sue DugganEmployment: Samus TherapeuticsGabriela ChiosisStock and Other Ownership Interests: Samus Therapeutics Patents, Royalties, Other Intellectual Property: Samus Therapeutics; hold patents, have patents pending, receive royaltiesMark P. DunphyPatents, Royalties, Other Intellectual Property: Memorial Sloan Kettering Cancer Center holds the intellectual rights to PU-H71 and [124I]-PU-H71 (PCT/US06/03676, PCT/US2012/045861), which have been licensed to Samus Therapeutics. Dr. Dunphy has contributed to the patents and has received financial royalties for his IP contributions.Shanu ModiHonoraria: Novartis Consulting or Advisory Role: Daiichi Sankyo, Macrogenics, AstraZeneca Speakers' Bureau: Genentech, Daiichi Sankyo, AstraZeneca, Seattle Genetics Research Funding: Roche/Genentech, Novartis, Seattle Genetics, Synta, Daiichi Sankyo Travel, Accommodations, Expenses: Genentech, Daiichi Sankyo No other potential conflicts of interest were reported. (© 2020 by American Society of Clinical Oncology.)
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