Future Perspectives in mpca. Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France

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1 Future Perspectives in mpca Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France

2 Number of Novel Therapies and Targets in Pancreatic Cancer Are Expanding Garrido-Laguna I, et al. Nat Rev Clin Oncol. 2015;12(6):

3 Role of Stroma in the Development of Cancer Kota J, et al. Cancer Lett. 2017;391:38-49.

4 Targeting Hyaluronan (HA): A Promising Strategy Pegylated recombinant human hyaluronidase (PEGPH20) Depletes HA in stroma Improves drug delivery HA, a new biomarker (overexpressed in 35%-40% of patients) Whatcott CJ, et al. Cancer Discov. 2011;1(4):

5 Randomized Phase II HALO Trial Gemcitabine +nab-paclitaxel ± PEGPH20 PFS in HA-High Patients Study 202 (Stage 1 and Stage 2) Reduction of thrombembolic events after adding low molecular weight heparin prophylaxis Enoxaparin prophylaxis PAG, % AG, % None mg/day mg/kg/day 10 6 Stage 1 Phase III randomized HALO-301 trial of nab-paclitaxel/gem ± PEGPH20 in metastatic PDA with high HA ongoing; primary endpoint PFS and OS Phase Ib/II FOLFIRINOX ± PEGPH20 Countouriotis A. Study 202 Overall Results and Stage 2 Results [webcast]. Available at: /files/doc_presentations/2017/JP-Morgan-Halozyme-FINAL.pdf. Accessed February 24, 2017.

6 Targeting on Tumor Microenvironment: CD40 Agonist Trials CD40: Member of the tumor necrosis factor superfamily Expressed on the cell surface of immune cells B cells Dendititc cells Macrophages Monocytes Binding of CD154 (primary ligand) CD40 activates T cells by direct interaction Indirect activation by cytokine release Byrne KT, et al. Cell Rep. 2016;15(12):

7 Testing CD40 Antibodies for Pancreatic Cancer In the Laboratory Phase II: 22 patients Combination with gemcitabine Chemonaïve patients Beatty GL, et al. Clin Cancer Res. 2013;19(22):

8 Beatty GL, et al. Clin Cancer Res. 2013;19(22): Clinical Results

9 Immunogenicity of Pancreatic Cancer Limited infiltrating effector T cells seen in tumor specimens Modest mutational burden Minimal clinical activity observed in unselected pancreatic cancer patients with anti CTLA-4 and anti PD-1 monoclonal antibodies von Bernstorff W, et al. Clin Cancer Res. 2001;7(3 Suppl):925s-932s.Clark CE, et al. Cancer Lett. 2009;279(1):1-7. Royal RE, et al. J Immunother. 2010;33(8): Topalian SL, et al. N Engl J Med. 2012;366(26): Alexandrov LB, et al. Nature. 2013;500(7463):

10 Immunotherapy in Pancreatic Cancer Pancreatic cancer is not immunogenic like, eg, melanoma or NSCLC The surrounding tumor stroma restrains the immune system in pancreatic cancer - Single-agent immunotherapy such as checkpoint inhibitors or vaccines showed only modest activity The opportunity is in combinations that may convert a nonimmunogenic pancreatic cancer into immunogenic cancer Several trials are exploring different immunotherapies and immunotherapy combinations including vaccines, anti-ctla-4 antibodies, anti-pd-1/pd-l1 antibodies, anti-cd40 agonists, CAR-T cells, and IDO inhibitors Ma Y, et al. Cancer Res Front. 2016;2(2):

11 Targeting RAS Pathway KRAS mutations are found in over 90% of pancreatic cancer Different approches for targeting RAS pathways were promising preclinically, but none has been sucessful in the clinic so far (major problem seems to be quick development of resistance; thus combination therapies may be a valid new strategy) Dual Blockade of MEK and PI3K/AKT Pathways Downstream of RAS Zeitouni D, et al. Cancers (Basel). 2016;8(4):45. Chung V, et al. JAMA Oncol. 2017;3(4):

12 Exploiting DNA Repair Defects Germline and somatic mutations were identified in eight genes in DNA-damage repair (DDR) pathways Genomic instability cosegregated with inactivation of DNA maintenance genes (BRCA1, BRCA2, or PALB2) and a mutational signature of DNA damage repair deficiency Tumors with genomic signatures of DDR deficits responded to platinum therapy PARP inhibitors are investigated in clinical trials Wadell N, et al. Nature. 2015;518(7540):

13 BRCA Mutations May Predict Benefit of Platinum Therapy and PARP Inhibitors Olaparib Therapy Golan T, et al. Br J Cancer. 2014;111(6): Kaufman B, et al. J Clin Oncol. 2015;33(3):

14 Selected Ongoing Studies of PARP Inhibitors in Advanced BRCA-mutated Pancreatic Cancers Regimens Setting Phase N ClinicalTrials.gov Identifier GemCis +/- veliparib, vs veliparib First line and subsequent II 107 NCT FOLFOX + veliparib Olaparib vs placebo (POLO) First line and subsequent Maintenance after first-line platinumbased chemotherapy I/II 79 NCT III 145 NCT FOLFIRI +/- veliparib Second line II 143 NCT National Institutes of Health. Available at:

15 Multiple factors should be considered when selecting systemic therapy for mpca, including performance status (PS), comorbidity, age, efficacy and toxicity of treatment regimens, and patient preference FOLFIRINOX and gemcitabine/nab-paclitaxel are standard-of-care front-line therapies for patients with good PS Nal-IRI + 5FU/LV is preferred second-line therapy for gemcitabine-refractory metastatic pancreatic cancer (level 1 evidence), and nab-paclitaxel/gemcitabine is an option after progression on FOLFIRINOX Recognition and early management of adverse events is important, patient education is key Because of high prevalence of malnutrition and rapid development of the anorexia-cachexiasyndrome, early nutritional intervention is crucial Stroma in pancreatic cancer may promote cancer progression, limits drug delivery, and is immunosuppressive Biomarker-driven trials are now in progress (eg, PEGPH20 in HA-high pancreatic cancer, PARP inhibitors) Combinations of different treatment approaches, including targeted agents, stromal-depleting agents, and immunotherapy, are under investigation

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