Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future

Bray, 2018, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J Clin, 68, 394, 10.3322/caac.21492 Conroy, 2011, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med, 364, 1817, 10.1056/NEJMoa1011923 Von Hoff, 2013, Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N Engl J Med, 369, 1691, 10.1056/NEJMoa1304369 Martinelli, 2017, GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer, Gut, 66, 1665, 10.1136/gutjnl-2015-311256 O'Kane, 2019, Integrative molecular profiling and response to chemotherapy on the COMPASS trial, Proc Am Soc Clin Oncol, 37, 188, 10.1200/JCO.2019.37.4_suppl.188 Reni, 2016, Phase 1B trial of nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma, Br J Cancer, 115, 290, 10.1038/bjc.2016.209 Hamada, 2017, Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data, Br J Cancer, 116, 1544, 10.1038/bjc.2017.128 Weiss, 2018, Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma, Invest New Drugs, 36, 96, 10.1007/s10637-017-0525-1 Hidalgo, 2010, Pancreatic cancer, N Engl J Med, 362, 1605, 10.1056/NEJMra0901557 Sparmann, 2004, Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis, Cancer Cell, 6, 447, 10.1016/j.ccr.2004.09.028 Athuluri-Divakar, 2016, A small molecule ras-mimetic disrupts ras association with effector proteins to block signaling, Cell, 165, 643, 10.1016/j.cell.2016.03.045 O'Neil, 2016, A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer, Ann Oncol, 27, 10.1093/annonc/mdw095 Kessler, 2019, Drugging an undruggable pocket on KRAS, Proc Natl Acad Sci USA, 116, 15823, 10.1073/pnas.1904529116 Martin Tran, 2016, T-cell transfer therapy targeting mutant KRAS in cancer, N Engl J Med, 375, 2255, 10.1056/NEJMoa1609279 Moore, 2007, Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group, J Clin Oncol, 25, 1960, 10.1200/JCO.2006.07.9525 Schultheis, 2017, Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study, Ann Oncol, 28, 2429, 10.1093/annonc/mdx343 Singhi, 2017, Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma, J Natl Compr Canc Netw, 15, 555, 10.6004/jnccn.2017.0058 Pishvaian, 2018, Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions, Proc Am Soc Clin Oncol, 36, 521, 10.1200/JCO.2018.36.4_suppl.521 Jonna, 2019, Detection of NRG1 gene fusions in solid tumors, Clin Cancer Res, 25, 4966, 10.1158/1078-0432.CCR-19-0160 Heining, 2018, NRG1 fusions in KRAS wild-type pancreatic cancer, Cancer Discov, 8, 1087, 10.1158/2159-8290.CD-18-0036 Jones, 2019, NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma, Clin Cancer Res, 25, 4674, 10.1158/1078-0432.CCR-19-0191 Shindo, 2017, Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma, J Clin Oncol, 35, 3382, 10.1200/JCO.2017.72.3502 Golan, 2019, Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N Engl J Med, 381, 317, 10.1056/NEJMoa1903387 O'Reilly, 2018, Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma, Cancer, 124, 1374, 10.1002/cncr.31218 Pihlak, 2018, Advances in molecular profiling and categorisation of pancreatic adenocarcinoma and the implications for therapy, Cancers (Basel), 10, E17, 10.3390/cancers10010017 Ziemke, 2016, Sensitivity of KRAS-mutant colorectal cancers to combination therapy that cotargets MEK and CDK4/6, Clin Cancer Res, 22, 405, 10.1158/1078-0432.CCR-15-0829 DuFort, 2016, Mounting pressure in the microenvironment: fluids, solids, and cells in pancreatic ductal adenocarcinoma, Gastroenterology, 150, 1545, 10.1053/j.gastro.2016.03.040 Blair, 2019, Dissecting the stromal signalling and regulation of myeloid cells and memory effector T cells in pancreatic cancer, Clin Cancer Res, 25, 5351, 10.1158/1078-0432.CCR-18-4192 Hingorani, 2016, Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer, Clin Cancer Res, 22, 2848, 10.1158/1078-0432.CCR-15-2010 Hingorani, 2018, HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma, J Clin Oncol, 36, 359, 10.1200/JCO.2017.74.9564 Ramanathan, 2019, Phase Ib/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus folfirinox alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313, J Clin Oncol, 37, 1062, 10.1200/JCO.18.01295 Katagiri, 2018, HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of sonic hedgehog, Oncotarget, 9, 10525, 10.18632/oncotarget.24156 De Jesus-Acosta, 2014, A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA), Proc Am Soc Clin Oncol, 32, 257, 10.1200/jco.2014.32.3_suppl.257 Tong, 2019, Efficacy and safety of gemcitabine plus anti-angiogenesis therapy for advanced pancreatic cancer: a systematic review and meta-analysis of clinical randomized phase III trials, J Cancer, 10, 968, 10.7150/jca.26672 Candido, 2018, CSF1R+ macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype, Cell Rep, 23, 1448, 10.1016/j.celrep.2018.03.131 Beatty, 2011, CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans, Science, 331, 1612, 10.1126/science.1198443 O'Hara, 2019, A phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients, Cancer Res, 79 Nywening, 2016, Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial, Lancet Oncol, 17, 651, 10.1016/S1470-2045(16)00078-4 Ma, 2019, A CD40 agonist and PD-1 antagonist antibody reprogram the microenvironment of nonimmunogenic tumors to allow T-cell-mediated anticancer activity, Cancer Immunol Res, 7, 428, 10.1158/2326-6066.CIR-18-0061 Stiff, 2016, Myeloid-derived suppressor cells express Bruton's tyrosine kinase and can be depleted in tumor bearing hosts by ibrutinib treatment, Cancer Res, 76, 2125, 10.1158/0008-5472.CAN-15-1490 Feig, 2013, Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer, Proc Natl Acad Sci USA, 110, 20212, 10.1073/pnas.1320318110 Kultti, 2014, Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment, BioMed Res Int, 2014, 10.1155/2014/817613 Seo, 2019, Mobilization of CD8+ T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer, Clin Cancer Res, 25, 3934, 10.1158/1078-0432.CCR-19-0081 Melisi, 2018, Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer, Br J Cancer, 119, 1208, 10.1038/s41416-018-0246-z Strauss, 2018, Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors, Clin Cancer Res, 24, 1287, 10.1158/1078-0432.CCR-17-2653 Yoo, 2019, AB053. P-21. M7824 (MSB0011359C), a bifunctional fusion protein targeting transforming growth factor β (TGF-β) and PD-L1, in Asian patients with pretreated biliary tract cancer (BTC): efficacy by BTC subtype, Hepatobiliary Surg Nutr, 8 Jiang, 2016, Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy, Nat Med, 22, 851, 10.1038/nm.4123 Jiang, 2019, Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion, Gut Murakami, 2019, Role of the tumor microenvironment in pancreatic cancer, Ann Gastroenterol Surg, 3, 130, 10.1002/ags3.12225 Christmas, 2018, Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs, Cancer Immunol Res, 6, 1561, 10.1158/2326-6066.CIR-18-0070 Mazur, 2015, Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma, Nat Med, 21, 1163, 10.1038/nm.3952 Noel, 2019, Phase II trial of SM-88 in patients with metastatic pancreatic cancer: preliminary results of the first stage, Proc Am Soc Clin Oncol, 37, 200, 10.1200/JCO.2019.37.4_suppl.200 Alistar, 2017, Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial, Lancet Oncol, 18, 770, 10.1016/S1470-2045(17)30314-5 Evan, 2017, Re-engineering the pancreas tumor microenvironment: a “regenerative program” hacked, Clin Cancer Res, 23, 1647, 10.1158/1078-0432.CCR-16-3275 Barati Bagherabad, 2019, Targeted therapies in pancreatic cancer: promises and failures, J Cell Biochem, 120, 2726, 10.1002/jcb.26284 Ligorio, 2019, Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer, Cell, 178, 160, 10.1016/j.cell.2019.05.012 Popovic, 2018, Emerging strategies for combination checkpoint modulators in cancer immunotherapy, J Clin Invest, 128, 3209, 10.1172/JCI120775 Jaffee, 2001, Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation, J Clin Oncol, 19, 145, 10.1200/JCO.2001.19.1.145 Le, 2015, Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer, J Clin Oncol, 33, 1325, 10.1200/JCO.2014.57.4244 Le, 2019, Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE Study), Clin Cancer Res, 25, 5493, 10.1158/1078-0432.CCR-18-2992 Morrison, 2018, Immunotherapy and prevention of pancreatic cancer, Trends Cancer, 4, 418, 10.1016/j.trecan.2018.04.001 Shima, 2019, Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma, Cancer Sci, 110, 2378, 10.1111/cas.14106 Zaidi, 2019, Anti-CTLA-4 synergizes with dendritic cell-targeted vaccine to promote IL-3-dependent CD4+ effector T cell infiltration into murine pancreatic tumors, Ann N Y Acad Sci, 1445, 62, 10.1111/nyas.14049 Le, 2017, Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science, 357, 409, 10.1126/science.aan6733 Nichetti, 2018, The role of mesothelin as a diagnostic and therapeutic target in pancreatic ductal adenocarcinoma: a comprehensive review, Target Oncol, 13, 333, 10.1007/s11523-018-0567-0 Hassan, 2014, Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma, Clin Cancer Res, 20, 5927, 10.1158/1078-0432.CCR-14-0804 Mizukami, 2018, The anti-mesothelin monoclonal antibody amatuximab enhances the anti-tumor effect of gemcitabine against mesothelin-high expressing pancreatic cancer cells in a peritoneal metastasis mouse model, Oncotarget, 9, 33844, 10.18632/oncotarget.26117 Thomas, 2004, Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients, J Exp Med, 200, 297, 10.1084/jem.20031435 Man, 2018, The novel oncolytic adenoviral mutant Ad5–3Δ-A20T retargeted to αvβ6 integrins efficiently eliminates pancreatic cancer cells, Mol Cancer Ther, 17, 575, 10.1158/1535-7163.MCT-17-0671 Chesney, 2018, Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma, J Clin Oncol, 36, 1658, 10.1200/JCO.2017.73.7379 Adusumilli, 2014, Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity, Sci Transl Med, 6, 10.1126/scitranslmed.3010162 Maliar, 2012, Redirected T cells that target pancreatic adenocarcinoma antigens eliminate tumors and metastases in mice, Gastroenterology, 143, 1375, 10.1053/j.gastro.2012.07.017 Beatty, 2018, Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial, Gastroenterology, 155, 29, 10.1053/j.gastro.2018.03.029