Pancreatic cancer is the third leading cause of cancer death. Its prognosis is grim, with a 5-year survival rate of 7.2 percent. Over 50 percent of pancreatic cancer patients present with metastatic disease, when treatment is considered to be only palliative. It is anticipated that pancreatic cancer will become the second-leading cancer-related cause of death in the U.S. in the next decade. Only a subset of patients is eligible for surgery. The recurrence rate post-surgery warrants adjuvant treatment for most of the patients with resected disease. Pancreatic cancer is considered to be a systemic disease early on.
The most efficacious front-line treatments are FOLFIRINOX (a four-drug combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel, which provide a median overall survival (OS) of 11.1 months and 8.5 months, respectively (N Engl J Med 2011;364(19):1817-1825, N Engl J Med 2013;369(18):1691-1703). However, these treatments have moderate toxicity and are usually restricted to patients with good performance status.
Pancreatic cancer remains a challenging disease to decode despite tremendous research efforts.
Pancreatic ductal adenocarcinoma (PDA) is defined by a number of intrinsic hallmarks (high rate of KRAS-activating and TP53-inactivating mutations) and extrinsic hallmarks (such as microenvironment—desmoplasia, hypoxia, immune suppression, propensity for local and distant invasion, reprograming of cellular metabolism, and tumor immune invasion (Clin Cancer Res 2012;18(16):4266-4276, Cancer Lett 2016;380(1):272-280, Gut 2011;60(6):861-868, J Huazhong Univ Sci Technolog Med Sci 2015;35(6):874-879, Eur Rev Med Pharmacol Sci 2013;17(4):436-446). We now have evidence that intrinsic and extrinsic factors regulate metabolic reprograming in pancreatic cancer by regulating metabolic plasticity (Biochim Biophys Acta 2016;1866(2):177-188).
Metabolic reprograming is an emerging hallmark of PDA. This includes aerobic glycolysis, oxidative phosphorylation (OXPHOS), glutaminolysis, lipogenesis and lipolysis, the autophagic status, and antioxidative stress. However, accumulating evidence has revealed that plasticity is another feature of PDA metabolism, in which each cancer cell could remodel the biochemical pathways of energy transduction and associated anabolism in response to various stresses (Int J Biochem Cell Biol 2015;59:167-181). The intrinsic factors for metabolic plasticity induce abnormal mitochondrial metabolism and enhance glycolysis, with alterations in glutamine and lipid metabolism. The extrinsic factors induce cancer cells to reprogram their metabolic pathway and hijack stromal cells (mainly cancer-associated fibroblasts and immunocytes) to communicate, thereby adapting to metabolic stress. This provides a strong rationale for novel therapies that target the mitochondrial metabolism (Biochim Biophys Acta 2016;1866(2):177-188).
CPI-613 is a novel anti-cancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumor cells, causing changes in mitochondrial enzyme activities and redox status, which lead to apoptosis, necrosis, and autophagy of tumor cells (J Mol Med 2011;89:1137-1148). These activities of CPI-613 involve the catalytic and regulatory functions of the pyruvate dehydrogenase complex, its regulatory kinases, and the α-ketoglutarate dehydrogenase complex (J Mol Med 2011;89:1137-1148, Cancer Metab 2014;2(1):4). The anti-tumor activity of CPI-613 in cell culture of multiple cancer cell lines, animal tumor models, and clinical trials against diverse cancers have been documented, with more mature data in pancreatic cancer and leukemia (Cancer Metab 2014;2(1):4, J Clin Oncol 2011;29:suppl;abstr 6590, J Clin Oncol 2012;20 suppl, Case Study and Case Report 2011;1(3):137-145, Case Study and Case Report 2012;2(3):95-101, Case Study and Case Report 2012;2(2):38-45).
In vitro data using two different pancreatic cell lines (PANC-1 and BxPC-3) shows CPI-613 enhances FOLFIRINOX cytotoxicity in both PANC-1 and BxPC-3 cell lines (unpublished data). Due to the safety profile and anti-cancer activities, as well as the preclinical data described above, it was hypothesized that CPI-613, when used in combination with FOLFIRINOX, would enhance therapeutic efficacy with little to no additional toxicity by targeting metabolic reprograming.
A phase I, open-label, dose-escalation clinical trial was conducted to determine the maximum tolerated dose (MTD) of CPI-613 when used in combination with modified FOLFIRINOX, as well as the safety and efficacy of this regimen for the treatment of metastatic pancreatic cancer (Lancet Oncol 2017;18(6):770-778). The MTD of CPI-613 was 500 mg/m2 and 18 patients were treated at the MTD. For the 18 patients treated at MTD, hematologic toxicity was comparable with historical data, while anemia (22%) and thrombocytopenia (16%) were higher. Likely due to pegfilgrastim support, neutropenia occurred in 27.7 percent of patients compared with 45.7 percent in the PRODIGE study where pegfilgrastim was used as secondary prophylaxis. Sensorial neuropathy (16%) was managed with dose de-escalation or discontinuation per standard of care. None of the patients experienced grade 4 neuropathy. The median number of treatment cycles administered at the MTD dose was 11 (range, 4-32).
The study concluded that the treatment was well-tolerated and feasible, and all endpoints were met. The partial + complete response rate was 61 percent (11/18), and the median progression-free survival (PFS) was 11.5 months. These results signal a higher activity of the combination compared with the historical study of FOLFIRINOX in patients with stage IV pancreatic cancer (response rate of 31.6% and median PFS of 6.4 months). The median OS was not estimable since half (n=9) of the patients were still alive at the time of the analysis, January 2017. Additional updates are highly-anticipated and will be submitted to the GI ASCO symposium as currently the survival data has matured and is highly informative of the activity of the treatment combination.
The impressive activity of the combination led to the design of an international, multi-site randomized study of FOLFIRINOX versus mFOLFIRINOX, to start accrual in 2018, co-led by Philip Philip, MD, PhD, FRCP, at the Karmanos Cancer Institute, Detroit, and Angela Tatiana Alistar, MD, at Morristown Hospital, Atlantic Health System, N.J.
ANGELA TATIANA ALISTAR, MD, is Medical Director, Atlantic Medical Group, Carol G. Simon Cancer Center, Department of Medicine, Division of Hematology Oncology, Morristown, N.J.