Best Practices and Promising Agents in Pancreatic Cancer. This program is supported by educational grants from Celgene Corporation and Incyte.

Transcription

1 Best Practices and Promising Agents in Pancreatic Cancer This program is supported by educational grants from Celgene Corporation and Incyte.

2 About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options ( Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3 Core Faculty Tanios S. Bekaii-Saab, MD Co-Leader, GI Cancer Program Mayo Clinic Cancer Center Professor of Medicine Division of Hematology and Oncology Mayo Clinic Phoenix, Arizona Andrew H. Ko, MD Professor Division of Hematology/Oncology Department of Medicine University of California, San Francisco San Francisco, California

4 Agenda Diagnosis and Staging Considerations Current Therapeutic Options for Metastatic Pancreatic Cancer Second-line Agents for Pancreatic Cancer Emerging Agents for Pancreatic Cancer Other Signaling Pathway Targets in Pancreatic Cancer

5 Diagnosis and Staging Considerations

6 Pancreatic Cancer: Scope of the Problem Projected 53,070 new cases of pancreatic cancer in US pts with 41,780 deaths in 2016 Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type Within the decade, pancreatic cancer is expected to rise to the second leading cause of cancer-related mortality in the United States (behind lung cancer) The vast majority of pts (80% to 85%) are inoperable at time of diagnosis Siegel RS, et al. Cancer facts & figures 2016.

7 Pancreatic Cancer by Stage (SEER Database) Stage Classification* Localized/ resectable Localized/ unresectable % at Diagnosis 5-Yr Survival, % Metastatic 53 2 *Unknown: 10%; 5-yr survival 4.4% Siegel R, et al. CA Cancer J Clin. 2015;65:5-29.

8 Screening for Pancreatic Cancer: Identifying High-Risk Individuals Demographic Factors Known genetic syndromes Family history Host/environmental factors Advancing Age, Male, Black, Ashkenazi Jewish Ancestry Lynch syndrome (HNPCC) Familial breast cancer (BRCA2) Peutz-Jeghers Ataxia-telangiectasia Familial atypical multiple mole-melanoma Hereditary pancreatitis As number of first-degree relatives increases (1 2 3+), risk increases by fold Diabetes mellitus (T2DM) Meta-analysis: odds ratio = 1.82 Need to distinguish T2DM as early symptom of pancreatic cancer vs an independent risk factor Chronic pancreatitis Tobacco use Obesity American Cancer Society Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Pancreatic Adenocarcinoma. V National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

9 Current Therapeutic Options for Metastatic Pancreatic Cancer

10 Guidelines for Chemotherapy for Pts With Metastatic Pancreatic Adenocarcinoma First-line Treatment Good performance status Poor performance status Category 1 NCCN Regimens FOLFIRINOX (preferred) Gem + nab-paclitaxel (preferred) Gem + erlotinib Gem monotherapy Clinical trial is the recommended first option for all pts. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Pancreatic Adenocarcinoma. V National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Other NCCN Regimens Category 2A Gem + cape Gem + cisplatin Category 2B GTX FP + Ox Category 2B FDR gem Cape or continuous infusion 5-FU

11 Phase III Study: FOLFIRINOX vs Gemcitabine in Met Pancreatic Cancer Stratified by ECOG PS (0 vs 1), center, tumor location (head vs other) Pts with untreated metastatic pancreatic cancer; ECOG PS 0/1; adequate BM, platelet count, liver and renal function (N = 342) FOLFIRINOX Oxaliplatin 85 mg/m 2 + LV 400 mg/m 2 + Irinotecan 180 mg/m FU bolus 400 mg/m 2, then 2400 mg/m 2 IV over 46 hrs (n = 171) Gemcitabine 1000 mg/m 2 weekly x 7 of 8, then weekly x 3 of 4 (n = 171) Conroy T, et al. N Engl J Med. 2011;364:

12 FOLFIRINOX vs Gemcitabine: Baseline Characteristics (ITT) Characteristic FOLFIRINOX (n = 171) Gemcitabine (n = 171) Median age, yrs (range) 61 (25-76) 61 (34-75) Male, n (%) 106 (62.0) 105 (61.4) ECOG PS, n (%) 0 64 (37.4) 66 (38.6) (61.9) 105 (61.4) Pancreatic tumor location, n (%) Head 67 (39.2) 63 (36.8) Body 53 (31.0) 58 (33.9) Tail 45 (26.3) 45 (26.3) Biliary stent, n (%) No 144 (84.2) 149 (87.1) Conroy T, et al. N Engl J Med. 2011;364:

13 FOLFIRINOX vs Gemcitabine: OS and PFS OS (%) OS Mos FOLFIRINOX Gemcitabine PFS (%) PFS Mos FOLFIRINOX Gemcitabine Median OS: 11.1 vs 6.8 mos HR: 0.57 (95% CI: ; P <.001) Median PFS: 6.4 vs 3.3 mos HR: 0.47 (95% CI: ; P <.001) Conroy T, et al. N Engl J Med. 2011;364:

14 FOLFIRINOX vs Gemcitabine: Efficacy Outcome FOLFIRINOX (n = 171) Gemcitabine (n = 171) ORR,* % HR (95% CI) Median PFS, mos ( ) P <.001 Median OS, mos ( ) P < yr survival, % *RR, FOLFIRINOX vs gemcitabine: CR, 0.6% vs 0%, PR, 31.0% vs 9.4%. Conroy T, et al. N Engl J Med. 2011;364:

15 FOLFIRINOX vs Gemcitabine: AEs Grade 3/4 AE, % Hematologic FOLFIRINOX (n = 171) Gemcitabine (n = 171) P Value Neutropenia <.001 Febrile neutropenia Thrombocytopenia Nonhematologic Fatigue NS Vomiting NS Diarrhea <.001 Sensory neuropathy <.001 Elevated ALT <.001 Conroy T, et al. N Engl J Med. 2011;364:

16 Management of AEs: Irinotecan Diarrhea: early diarrhea usually transient, treat with atropine; late diarrhea ( 24 hrs after injection) may be life threatening, treat promptly with loperamide, fluids, and electrolytes Delay chemotherapy until pretreatment bowel 24 hrs without need for antidiarrhea medication; if grades 2-4 late diarrhea occurs, treat and decrease subsequent doses in current cycle Neutropenia: manage complications promptly with antibiotics Omit irinotecan during a cycle if neutropenic fever occurs or if ANC < 1500/mm 3 ; after pt recovers to ANC 1500/mm 3, subsequent doses should be reduced depending on the level of neutropenia observed Growth factor prophylaxis should be used with FOLFIRINOX Irinotecan [package insert]

17 Management of AEs: Oxaliplatin Peripheral neuropathy: reduce dose if persistent grade 2 neurosensory events do not resolve; consider discontinuing oxaliplatin if persistent grade 3 neurosensory events GI AEs: delay treatment and reduce dose after recovery from grade 3/4 GI toxicities Neutropenia: delay until neutrophils /L after grade 4 neutropenia or febrile neutropenia and reduce next dose Growth factor prophylaxis should be used with FOLFIRINOX Thrombocytopenia: delay until platelets /L after grade 3/4 thrombocytopenia and reduce next dose Oxaliplatin [package insert]

18 FOLFIRINOX vs Gemcitabine: Quality of Life Time until definitive deterioration > 20 points, EORTC-C30 global health status/qol questionnaire Prolongation of QoL in pts treated with FOLFIRINOX compared with gemcitabine, despite greater toxicity Deterioration (Probability) Gemcitabine FOLFIRINOX P < Mos Specifically, longer time to deterioration in: Global health status Physical, cognitive, and social functioning Symptoms such as fatigue, N/V, pain, and anorexia Gourgou-Bourgade S, et al. J Clin Oncol. 2013;31:23-29

19 MPACT: Phase III Gemcitabine ± Nab- Paclitaxel in Metastatic Pancreatic Cancer Stratified by KPS, region, liver metastasis Pts with metastatic pancreatic cancer, no previous treatment for metastatic disease, KPS 70, bilirubin ULN (N = 861) Gemcitabine 1000 mg/m 2 /wk IV + Nab-Paclitaxel 125 mg/m 2 /wk IV for 7 wks, and then on Days 1, 8, 15 Q4W (n = 431) Gemcitabine 1000 mg/m 2 /wk IV for 7 wks, and then on Days 1, 8, 15 Q4W (n = 430) Treat until PD Primary endpoint: OS Secondary endpoints: PFS, ORR, safety Von Hoff DD, et al. N Engl J Med. 2013;369:

20 MPACT: Gemcitabine ± Nab-Paclitaxel in Metastatic Pancreatic Cancer OS OS (%) Median OS, mos Gem + Nab-P (n = 431) Gem (n = 430) HR (95% CI) ( ) P <.001 Gemcitabine + nab-paclitaxel Gemcitabine Mos Von Hoff DD, et al. N Engl J Med. 2013;369:

21 MPACT: Gemcitabine ± Nab-Paclitaxel in Metastatic Pancreatic Cancer PFS* PFS (%) Median PFS, Mos Gem + Nab-P (n = 431) Gem (n = 430) HR (95% CI) ( ) P <.001 Gemcitabine + nab-paclitaxel Gemcitabine *Based on independent review. Von Hoff DD, et al. N Engl J Med. 2013;369: Mos

22 MPACT: Gemcitabine ± Nab-Paclitaxel in Metastatic Pancreatic Cancer: Efficacy Outcome Gem + Nab-P (n = 431) Gemcitabine (n = 430) HR (95% CI) ORR, % 23 7 P <.001 Median PFS, mos ( ) P <.001 Median OS, mos ( ) P < yr survival, % Von Hoff DD, et al. N Engl J Med. 2013;369:

23 MPACT: Gemcitabine ± Nab-Paclitaxel in Pancreatic Cancer OS by Subgroup OS HR for Death (95% CI) All pts Age Younger than 65 yrs 65 yrs or older Sex Female Male Karnofsky performance status Primary tumor location Head Other Liver metastases Yes No No. of metastatic sites > 3 Level of CA19-9 Normal < 59 x ULN 59 x ULN 0.72 ( ) 0.65 ( ) 0.81 ( ) 0.72 ( ) 0.72 ( ) 0.61 ( ) 0.75 ( ) 0.59 ( ) 0.80 ( ) 0.69 ( ) 0.86 ( ) 0.41 ( ) 0.75 ( ) 0.79 ( ) 0.50 ( ) 1.07 ( ) 0.83 ( ) 0.61 ( ) Favors Gem + Nab-Pac Favors Gem Monotherapy Von Hoff DD, et al. N Engl J Med. 2013;369:

24 MPACT: Gemcitabine ± Nab-Paclitaxel in Pancreatic Cancer AEs Event, % Gem + Nab-P (n = 421) Gem Only (n = 402) AE leading to death 4 4 Hematolgic AEs grade 3 Neutropenia Leukopenia Thrombocytopenia 13 9 Anemia Receipt of growth factors Febrile neutropenia 3 1 Nonhematologic AEs grade 3* Fatigue 17 7 Peripheral neuropathy 17 1 Diarrhea 6 1 * 5% of pts. Von Hoff DD, et al. N Engl J Med. 2013;369:

25 Frontline Regimens for Pts With Metastatic Pancreatic Cancer FOLFIRINOX vs Gem Nab-Pac + Gem vs Gem (N = 342) [1] (N = 861) [2] Median age, yrs (range) 61 (25-76) 62 (27-86) Male, % Region (NA/WE/EE/A), % 0/100 (France)/0/0 62/9/15/14 ECOG PS/KPS (0/100, 1/80-90, 2/60-70), % 37/62/1 16/76/8 Pan tumor location (H/B/T), % 39/31/26 43/31/25 Median involved metastatic sites, n ORR, % 32 vs 9 23 vs 7 Disease control rate, % 70 vs vs 33 Median PFS, mos 6.4 vs vs 3.7 Median OS, mos 11.1 vs vs Conroy T, et al. N Engl J Med. 2011;364: Von Hoff DD, et al. N Engl J Med. 2013;369:

26 First-line FOLFIRINOX vs Gemcitabine- Based Tx: OS (Retrospective Analysis) OS (%) FOLFIRINOX Gem-based therapy Gem + nab-paclitaxel Mos P <.0001 First-line Treatment N Median OS, Mos FOLFIRINOX Gem only or gem + other chemotherapy* Gem + nab-paclitaxel *Gem only, n = EMR data from US Oncology Network June 2010 to November 2013 Dosing based on standard doses in US Oncology system Cartwright T, et al. ASCO Abstract 4132.

27 Metastatic Pancreatic Cancer: Cost of First-line Chemotherapy Direct costs in 2014 US$ Drug costs: Centers for Medicare and Medicaid services average sales price Administration costs: Medicare physician fee schedule Costs for grade 3/4 AEs: 5-day hospitalization for FN Outpatient for nausea, vomiting, diarrhea Monthly Cost (US$) 14,000 12,000 10, AEs Administration Drugs Growth factor support Blood product transfusion Gem/ Nab-Pac FOLFIRINOX Gem Dose-Modified Gem/ Nab-Pac Carboplatin/ Pac Goldstein D, et al. ASCO GI Symposium Abstract 368.

28 Second-line Agents for Pancreatic Cancer

29 Novel Formulation: Nanoliposomal Irinotecan (MM-398) Nanoliposomal irinotecan Irinotecan: topoisomerase I inhibitor Liposomal formulation associated with preferentially increased tumor exposure to irinotecan Longer half-life, increased AUC, slower clearance, reduced volume of distribution vs free drug FDA approved October 2015 in combination with 5-FU and leucovorin for the treatment of pts with metastatic adenocarcinoma of the pancreas whose disease has progressed following gemcitabine-based therapy Roy AC, et al. Ann Oncol. 2013;24: Drummond DC, et al. Cancer Res. 2006;66:

30 NAPOLI-1: Nanoliposomal Irinotecan ± 5-FU/LV vs 5-FU/LV Phase III trial Pts with metastatic pancreatic cancer who progressed on gemcitabinebased therapy, KPS 70 (N = 417) Nal-IRI 120 mg/m 2 Q3W (n = 151) 5-FU/LV 2000/200 mg/m 2 /wk x 4 Q6W (n = 119) Nal-IRI 80 mg/m FU/LV* 2400/400 mg/m 2 Q2W (n = 117) *Combination arm added after safety data were available. Pts in 5-FU/LV arm used as controls for combination arm. Wang-Gillam A, et al. Lancet. 2016;387:

31 NAPOLI-1: Nanoliposomal Irinotecan ± 5-FU/LV vs 5-FU/LV Results Tumor Response and Control Median PFS, mos (95% CI) ORR, % (95% CI) Nal-IRI + 5-FU/LV (n = 117) 3.1 ( ) 16 ( ) P =.0001 P < FU/LV (n = 119) 1.5 ( ) 1 (0-2.5) CA19-9 reduction, % P =.0009 Wang-Gillam A, et al. Lancet. 2016;387:

32 NAPOLI-1: Nanoliposomal Irinotecan ± 5-FU/LV vs 5-FU/LV OS Nal-IRI + 5-FU/LV Nal-IRI OS (%) Nal-IRI + 5-FU/LV 5-FU/LV Mos From Randomization OS (%) Nal-IRI 5-FU/LV Mos From Randomization Median OS: 6.1 vs 4.2 mos HR: 0.57 (95% CI: ; P =.0009) Median PFS: 4.9 vs 4.2 mos HR: 0.93 (95% CI: ; P =.5545) Wang-Gillam A, et al. Lancet. 2016;387:

33 NAPOLI-1: Nanoliposomal Irinotecan ± 5-FU/LV vs 5-FU/LV in mpc: AEs AEs, % Nal-IRI + 5-FU/LV (n = 117) Safety Population 5-FU/LV Control (n = 134) Any Grade Grade 3/4 Any Grade Grade 3.4 Diarrhea Vomiting Nausea Decreased appetite Fatigue Neutropenia Anemia Hypokalemia Wang-Gillam A, et al. Lancet. 2016;387:

34 Phase III Experience: Second-line Chemotherapy With Oxaliplatin CONKO-003 [1] PANCREOX [2] Pts (N = 268) PD on gem tx (n = 160) Previous gem tx (n = 108) Treatment OFF 5-FU/LV mfolfox6 5-FU/LV (n = 76) (n = 84) (n = 54) (n = 54) OS, median 5.9 mos 3.3 mos 6.1 mos 9.9 mos HR: 0.66 (95% CI: ) P =.01 HR: 1.78 (95% CI: ) P =.02 PFS, median 2.9 mos 2.0 mos 3.1 mos 2.9 mos HR: 0.68 (95% CI: ) P =.02 HR: 1.00 (95% CI: ) P =.99 ORR, median NR 13.2% 8.5% P = Oettle H, et al. J Clin Oncol. 2014;32: Gill S, et al. ASCO Abstract 4022.

35 Current Treatment Sequencing for Metastatic Pancreatic Cancer First Line Gemcitabine based (eg, gem/nab-paclitaxel, gem/erlotinib) (Poor PS) Gemcitabine FOLFIRINOX; fluoropyrimidine-based therapy + oxaliplatin Second Line (PS 0/1): Nanoliposomal irinotecan + 5-FU; fluoropyrimidine-based therapy (PS 2) Fluoropyrimidine alone or BSC (PS 0/1): Gemcitabine-based (eg, gem/nab-paclitaxel, gemcitabine) (PS 2 or less): Gemcitabine monotherapy or BSC Third line (PS 0/1): Platinum-(??) based regimen if no prior exposure or BSC?? NCCN Category 1 recommended therapies in bold. NCCN. Pancreatic adenocarcinoma. v

36 Emerging Agents for Pancreatic Cancer

37 Investigational Agents for Advanced Pancreatic Cancer Class Novel cytotoxics Stromal-depleting agents Signal transduction inhibitors Examples TH-302 (evofosfamide, hypoxia-activated mustard) did not improve OS in pancreatic trial (2015) Negative PEGPH20 (recombinant hyaluronidase) Vitamin D analogues Necuparanib JAK inhibitors (ruxolitinib) Negative MM-141 (bispecific anti-igfr/her3 antibody) BTK inhibitors (ibrutinib) Notch inhibitors (eg, demcizumab, tarextumab) Negative PARP inhibitors (eg, olaparib) ClinicalTrials.gov.

38 Investigational Immunotherapies for Advanced Pancreatic Cancer Category Vaccines Immune checkpoint inhibitors Anti-CD40 MAbs CCR2 inhibitors Agent(s) CRS-207 (mesothelin-expressing Listeria) Negative in ECLIPSE trial combined with GVAX GVAX Algenpantucel-L ( Hyperacute vaccine) Reolysin Negative Anti PD-1 and anti PD-L1 antibodies (eg, PD-1 nivolumab, pembrolizumab; PD-L1, atezolizumab) Anti CTLA-4 antibodies (eg, tremelimumab) IDO inhibitors (eg, indoximod) Multiple agents PF ClinicalTrials.gov.

39 Stromal-Depleting Therapies: Do They Impede Drug Delivery? Courtesy of E. Collisson.

40 Stromal-Targeted Agents Hedgehog inhibitors [1] Recombinant human hyaluronidase: PEGylatedrHuPH20 [2] Anti-CD40 monoclonal antibodies [3] Vitamin D analogues [4] 1. Olive KP, et al. Science. 2009;324: Provenzano PP, et al. Cancer Cell. 2012;21: Beatty GL, et al. Science. 2011;331: Sherman MH, et al. Cell. 2014;159:80-93.

41 Phase II HALO : Addition of PEGPH20 to Gem/Nab-P in Metastatic PC Pts with stage IV pancreatic cancer, no prior tx for metastatic disease, KPS 70% (planned N = 279) Gemcitabine 1000 mg/m 2 + Nab-Paclitaxel 125 mg/m 2 1x/wk for 3/4 wks/cycle PEGPH20 3 µg/kg IV 2x/wk in cycle 1 then weekly + Gemcitabine 1000 mg/m 2 + Nab-Paclitaxel 125 mg/m 2 1x/wk for 3/4 wks/cycle Treat until progression, intolerable toxicity, death, or choice to discontinue Primary endpoint: PFS Secondary endpoints: ORR, OS, safety, PK ClinicalTrials.gov. NCT

42 Phase II HALO : Results Population, % (Responders/Total) Gemcitabine + Nab-Paclitaxel + PEGPH20 Gemcitabine + Nab-Paclitaxel P Value Total 41 (30/74) 34 (21/61).48 HA-high 52 (12/23) 24 (5/21).04 HA-low 37 (14/38) 38 (9/24).96 Higher rate of thromboembolic events on PEGPH20-containing arm during first stage of enrollment (42 vs 25%); mitigated during second stage with addition of prophylactic enoxaparin Hingorani SR, et al. ASCO Abstract 4006.

43 How Immunogenic Is Pancreatic Cancer? Limited infiltrating effector T-cells seen in tumor specimens Modest mutational burden relative to more immunogenic tumors Medulloblastoma ALL Pilocytic astrocytoma Kidney clear cell Kidney papillary Ovary Prostate Myeloma Lymphoma B-cell Gliona low grade Breast Pancreas Glioblastoma Neuroblastoma CLL Thyroid Kidney chromophobe AML Lung small cell Esophagus Colorectum Cervix Head and neck Stomach Uterus Liver Melanoma Lung squamous Lung adenocarcinoma Bladder 1, Somatic Mutation Prevalence (Number Mutations per Megabase) Minimal clinical activity observed in unselected pancreatic cancer pts with anti CTLA-4 and anti PD-1 monoclonal antibodies Can pancreatic cancers be primed to become more immunogenic? von Bernstorff W, et al. Clin Cancer Res. 2001;7(3 suppl):925s-932s.clark CE, et al. Cancer Lett. 2009;279:1-7. Royal RE, et al. J Immunother. 2010;33: Topalian S, et al. N Engl J Med. 2012;366: Alexandrov LB, et al. Nature. 2013;500:

44 Immunotherapy Platforms in Pancreatic Cancer GVAX Pancreas Irradiated, whole-cell tumor vaccine GVAX GM-CSF Dendritic cell CRS-207 Live-attenuated Listeria monocytogenes Potent activation of innate and antigenspecific immune response acta inlb Tumor antigens Tumor cell destruction Antigen uptake and activation Deletion of virulence genes (acta, inlb) T-cell Le DT, et al. J Clin Oncol. 2015;33: Le DT, et al. ASCO GI Abstract 177. Insertion of mesothelin expression cassette validated immune target

45 Phase II Study: GVAX/CRS-207 vs GVAX Alone in Metastatic Pancreatic Cancer CY/GVAX Arm A (n = 60) CRS-207 Pts with metastatic pancreatic cancer; failed or refused chemotherapy R Randomized 2:1 20-wk treatment course*: 6 doses, Q3W Arm B (n = 30) 24 mos of follow-up *Additional courses if clinically stable 24 mos of follow-up Prior phase I trial of CRS-207 showed markedly improved survival (17 months) in 3 pancreatic cancer pts who had previously undergone boost with GVAX vaccine Primary objective: OS Le DT, et al. Clin Cancer Res. 2012;18: Le DT, et al. J Clin Oncol 2015;33:

46 GVAX/CRS-207 vs GVAX Alone in Metastatic Pancreatic Cancer: Results OS (Probability) Cy/GVAX + CRS-207 Cy/GVAX 2 randomized trials are evaluating GVAX/CRS-207 vs SOC chemotherapy ECLIPSE (NCT ) Events, n/n (%) 34/45 (75.6) 17/21 (81.0) Mos Median, Mos (95% CI) 9.7 ( ) 4.6 ( ) P =.017 (1 sided) P =.033 (2 sided) HR: 0.53 STELLAR: second- or third-line treatment ± nivolumab (NCT ) Toxicities related to CRS-207: transient fevers, rigors, lymphopenia Le DT, et al. J Clin Oncol 2015;33:

47 Phase IIb ECLIPSE: GVAX/CRS-207 vs CRS-207 or Chemo Alone in mpc Pts 18 yrs of age or older with previously treated metastatic pancreatic cancer, ECOG PS 0/1 (N = 301) Cyclophosphamide 200 mg/m 2 Day 0 of Wks 1, 4 + GVAX Pancreas Vaccine (5 10e8 cells) Day 1 of Wks 1, 4 + CRS-207 (1 10e9 CFU) Wks 7, 10, 13, 16 CRS-207 Wks 1, 4, 7, 10, 13, 16 Chemotherapy (various) Primary endpoint: OS Secondary endpoints: safety, response ClinicalTrials.gov. NCT

48 Other Signaling Pathway Targets in Pancreatic Cancer

49 Molecular Subtypes of Pancreatic Cancer Genomic analyses of 456 pancreatic ductal adenocarcinomas identified molecular subtypes of pancreatic cancer 32 recurrently mutated genes KRAS, TP53, SMAD4, CDKN2A 10 pathways KRAS, TGF-b, WNT, NOTCH, ROBO/SLIT signaling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing Expression analyses defined subtypes that correlate with histology: Squamous Pancreatic progenitor Immunogenic Aberrantly differentiated endocrine/exocrine (ADEX) Bailey P, et al. Nature. 2016;531:47-52.

50 Core Signaling Pathways Are Altered in Most Pancreatic Cancers Regulatory Pathway or Process Genetic Alteration of 1 Gene, % Apoptosis 100 Hedgehog signaling 100 KRAS signaling 100 Regulation of G1/S phase transition 100 TGF-b 100 Wnt/Notch 100 JNK signaling 96 Regulation of invasion 92 DNA damage control 83 Homophilic cell adhesion 79 Small GTPase-DEP signaling 79 Integrin signaling 67 Jones S, et al. Science. 2008;321:

51 Other Novel Signaling Pathway Inhibitors Under Investigation in Metastatic PDAC Agent* MOA Phase Planned N Ibrutinib [1] (RESOLVE) Necuparanib [2] MM-141 [3] Indoximod [4] Comments BTK inhibitor II/III 326 Stage IV, KPS 70 Heparin sulfate mimetic Bispecific mab: IGF-IR and ERBB3 IDO (indoleamine 2,3- dioxygenase) inhibitor I/II (randomized) 180 Drug engineered to reduce anticoagulant activity II (randomized) 260 Pts selected for high free serum IGF-1 Ib/II (nonrandomized) *All being studied in combination with gemcitabine/nab-paclitaxel. 98 IDO = enzyme that catalyzes degradation of L-tryptophan suppresses T cell function (= immune checkpoint inhibitor) 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

52 Which Subsets of Pts Might Benefit From Specific Therapies? BRCA- or PALB2- mutation carriers Olaparib: 5/23 pts (22%) with objective response, 8/23 (35%) with stable disease > 8 wks [1] Veliparib: 0/16 pts with objective response, 5/16 (31%) with stable disease > 8 wks [2] MSI-high/mismatch repair-deficient (dmmr) 2 of 4 pts with dmmr pancreatic cancers showed objective response by RECIST to pembrolizumab [3] 1. Kaufman, et al. J Clin Oncol. 2015;33: Lowery, et al. ASCO Abstract Le D, et al. ASCO Abstract 195.

53 Conclusion Improving frontline and second-line treatment options 2 frontline regimens, FOLFIRINOX and gemcitabine/nabpaclitaxel, have demonstrated survival benefit (vs gemcitabine alone) in phase III studies Evidence for second-line/salvage treatment in this disease with nanoliposomal irinotecan and 5-FU after gemcitabinebased therapy Fluoropyrimidine-based and gemcitabine-based regimens are additional options for second-line/salvage therapy Novel therapeutics Active area of research Multiple ongoing randomized phase II/III trials Biomarker evaluation underway

54 Go Online for More CCO Coverage of Pancreatic Cancer! Slides of key data from this and other programs on pancreatic cancer CME-certified video module on pancreatic cancer with expert faculty commentary on key studies clinicaloptions.com/oncology