Evaluation of pharmacodynamic (PD) biomarkers in advanced cancer patients treated with oxidative phosphorylation (OXPHOS) inhibitor, OPC-317 (OPC)
Authors: J.Q. Eu, K. Yadav, Y.-C. Lim, J. Hirpara, L.R. Kong, Z.C. Ng, V.K. Lee, S.C. Lee, D.S. Tan, R.A. Soo, C.E. Chee, W.P. Yong, R. Sundar, J.S. Lim, L. Wang, N. Ohi, T. Tsunoda, S. Pervaiz, B.-C. Goh, A.L. Wong
Journal: Annals of Oncology (2019)

Abstract   Background  We reported that metabolic reprogramming towards OXPHOS-induced drug resistance in oncogene-addicted tumors. OXPHOS is an attractive drug target but clinical PD markers of OXPHOS inhibition are lacking. We present interim PD biomarker data from a dose-finding/phase IIa study of OPC in an advanced cancer population enriched for molecular pathway-driven tumors.    Methods  After the dose-finding phase of OPC monotherapy at 3 levels (600mg, 400mg, 300mg), the study is now enrolling HER2+ breast cancer, EGFR+ NSCLC and c-KIT+ GIST patients to receive OPC 300mg, 3x/week, 21 days, in combination with their respective pathway inhibitors. Baseline (BL) and C1D15 tumor biopsies were analysed for mitochondrial DNA (mtDNA) copy number [qPCR] and immunohistochemistry (IHC) markers of mitochondrial biogenesis/OXPHOS [PGC1α, TFAM, SIRT1] and cancer stem cells [ALDH1A2]. Blood collected on days 1, 4/5 and 11/12 was analysed by flow cytometry of PBMCs for mitochondrial membrane potential (MMP) and serum metabolomics of amino/organic acids by LC-MS/GC-MS.    Results  13 patients (8 with molecular pathway-activated cancers) have been enrolled so far; 5 had evaluable paired biopsies. There were no G3/4 toxicities at the 300mg dose level (n = 8). Tumor mtDNA copy number declined significantly with treatment (-45.0 + 6.0%, C1D15 vs BL, p = 0.006). The expected decrease in IHC expression of ALDH1A2, TFAM, PGC1α (C1D15 vs BL) occurred in 80% (4/5), 60% (3/5) and 40% (2/5), respectively; expected rebound increase in SIRT1 expression was seen in 80% (4/5). Serum metabolomics (C1D4 vs BL) showed significant increase in TCA intermediates, citrate (+18.7 + 14.2%, p = 0.004) and fumarate (+29.7 + 37.1%, p = 0.043), indicative of NADH accumulation following OXPHOS inhibition. There was a non-significant rise in serum lactate (+17.2+ 27.1%, p = 0.094) and reduction in PBMC MMP [0.71 + 0.67 vs 0.29 + 0.23, BL vs C1D11/12, p = 0.068] (n = 11).    Conclusions  We identified novel tumor/blood PD biomarkers with clear evidence of target modulatory effects at clinically tolerable doses of OPC. With validation, they can aid the clinical development of OXPHOS inhibitors as a novel class of cancer therapy.    Clinical trial identification  NCT03158324.    Legal entity responsible for the study  Otsuka Pharmaceutical Co. Ltd.    Funding  Otsuka Pharmaceutical Co. Ltd.    Disclosure  D.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. R. Sundar: Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Lilly; Advisory / Consultancy: Eisai; Research grant / Funding (self): Paxman; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Taiho Pharmaceutical. J.S. Lim: Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Synthon; Travel / Accommodation / Expenses: AstraZeneca. N. Ohi: Full / Part-time employment: Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Shiga, Japan. T. Tsunoda: Full / Part-time employment: Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan. B. Goh: Research grant / Funding (institution): Otsuka Pharmaceutical Co. Ltd. A.L. Wong: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Otsuka Pharmaceutical Co Ltd. All other authors have declared no conflicts of interest.