Erban, John K.

TPS1136 Background: Hsp90 is a molecular chaperone protein required for the stabilization and activation of many proteins, referred to as Hsp90 ‘clients’, including those commonly implicated in breast tumorigenesis such as HER2, EGFR, ER, PI3K, AKT, P53 and VEGFR. Ganetespib is a novel triazolone inhibitor of Hsp90 being studied in over 20 clinical trials, with over 700 patients treated to date. Ganetespib is ~50x more potent than 1st-generation Hsp90 inhibitors, and has been well tolerated in clinical trials with a favorable safety profile. Mild to moderate, transient diarrhea is the most common adverse event associated with ganetespib infusion and is manageable with appropriate supportive care. Ganetespib has shown activity in preclinical models of HER2+, ER+/PR+ and triple negative breast cancer (TNBC). In a phase I trial, ganetespib demonstrated single-agent clinical activity in HER2+ disease with an objective response rate (ORR) of 15% and a disease stabilization rate of 46% in heavily pretreated patients. This efficacy-screening study is designed to provide further evidence of ganetespib activity and identify potentially predictive biomarkers in metastatic breast cancer. Methods: The ENCHANT-1 trial is an international, first-line Phase II study in two cohorts of breast cancer patients: Cohort A, HER2 amplified (n=35), and Cohort B, TNBC (n=35). HER2+ patients must have received prior anti-HER2 therapy in the adjuvant setting. Patients are treated with ganetespib at 150 mg/m2 twice weekly on a three out of four-week regimen. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include metabolic effects as assessed by PET/CT at week 3. Tumor genetic signature and proteomic profiling are performed on patient’s tumors in an effort to develop biomarkers of response. At the time of submission 6 patients have been enrolled into this study. Clinical trial information: NCT01677455.

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [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 PD5-02.