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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/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.

Research to Practice, consulted for or served on advisory boards for AstraZeneca (uncompensated), Change Healthcare, Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), and Pfizer (uncompensated).has received research funding from AbbVie (institution), AstraZeneca (institution), Invitae (institution), MerckResearch.

The histological subtype of BC with the strongest signal of efficacy has been triple-negative breast cancer (TNBC). Early trials of single-agent checkpoint inhibitors did not demonstrate a uniformly positive signal. Clinical studies suggest response rates between 5 and 10% in pretreated patients and roughly 20-25% for untreated advanced TNBC. However, in the small subset of patients who do respond, the response is often durable. More encouraging results have been reported with their use in combination with chemotherapy in the neoadjuvant setting. Larger phase III studies are underway to confirm these earlier findings. An immune-directed therapeutic approach for the management of BC is underway, and it is likely that combination therapy will be required to achieve a level of efficacy worthy of use in the BC treatment paradigm. These agents are not without both economic and clinical toxicity; therefore, it is imperative that we identify patients most likely to benefit from these therapies through well-designed biologically plausible clinical studies and by evaluating novel combinatorial approaches with informative biomarker driven correlative studies.

Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with high risk of early relapse, particularly for patients who do not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC), with an event free survival of < 60% at 3 years. Physical disruption of tumors with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. In pre-clinical studies, the combination of cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented cancer recurrence. In clinical studies, the combination of pre-operative ipilimumab (ipi)- +/- nivolumab (nivo)-mediated checkpoint blockade with cryo was safely administered in women with operable, early stage breast cancer and generated intra-tumoral and systemic immune responses (NCT01502592, NCT02833233). In this multi-center, randomized study, we evaluate the disease specific impact of peri-operative ipi, nivo and cryo versus standard care in women with residual TNBC after neoadjuvant taxane-based chemotherapy (NCT03546686). Methods:Eligible pts are aged ≥18 years, with ER, PR and HER2 negative operable tumors ≥ 1.0 cm after neoadjuvant taxane-based chemotherapy. Approximately 160 patients will be randomized to one of two arms: standard-of-care breast surgery (control arm) or ipi/nivo/cryo followed by standard-of-care breast surgery (intervention arm). Subjects randomized to the intervention arm will undergo percutaneous, ultrasound- (or MRI-) guided cryoablation with concurrent research core biopsy 7-10 days prior to surgery, and will receive a pre-operative infusion with ipilimumab at the dose of 1mg/kg IV, and nivolumab 240mg flat dose IV (1 to 5 days prior to cryoablation). After surgery, patients will receive three additional doses of nivolumab 240mg flat dose IV Q2 weeks. Adjuvant capecitabine is recommended for all participants and will be administered per standard-of-care at the treating physician's discretion. Patients will be stratified by prior platinum administration, prior anthracycline administration, and clinical nodal status (positive versus negative) at enrollment. The primary endpoint is 3-year Event Free Survival (EFS). Secondary end points include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Citation Format: McArthur HL, Comen EA, Solomon S, Rodine M, DiLauro Abaya C, Leal JHS, Patil S, Norton L. A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy [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 OT2-06-05.