Treating Patients With Advanced Pancreatic Cancer: Incorporating the Latest Data on Systemic Therapy Into Clinical Practice This program is supported by educational grants from Celgene Corporation and Incyte.

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Faculty Tanios S. Bekaii-Saab, MD Michael J. Pishvaian, MD, PhD Section Chief Professor of Medicine and Pharmacology Department of Gastrointestinal Medical Oncology The Ohio State University Columbus, Ohio John L. Marshall, MD Chief, Division of Hematology/Oncology Department of Medicine Georgetown University Hospital Washington, DC Michael J. Pishvaian, MD, PhD Assistant Professor, Medical Oncology Department of Medicine Georgetown University Hospital Washington, DC

Faculty Disclosures Tanios S. Bekaii-Saab, MD, has no real or apparent conflicts of interest to report. John L. Marshall, MD, has disclosed that he has received consulting fees, fees for non-CME/CE services, and contracted research from Amgen, Bayer, Celgene, and Genentech. Michael J Pishvaian, MD, PhD, has disclosed that he has received a salary from Perthera, consulting fees and fees for non-CME/CE services from Celgene and Sirtex, and contracted research from Celgene, Gilead, Fibrogen, and Halozyme. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Pancreatic Cancer: Incidence = Mortality Recent Developments and Future Directions in the Treatment of Pancreatic Cancer Pancreatic Cancer: Incidence = Mortality Epidemiology 4th most common cause of cancer death In 2015, 48,960 new cases are expected in the US, with 40,560 deaths Incidence much higher after 45 yrs of age Siegel R, et al. CA Cancer J Clin. 2015;65:5-29.

Pancreatic Cancer: Risk Factors Environmental Smoking Chronic pancreatitis Alcohol abuse Obesity Diabetes Genetic (< 20% of cases) Up to 10% have first- degree relative with disease BRCA1/2 positive Peutz-Jeghers syndrome (risk > 26%) Ataxia-telangiectasia FAP and Lynch Syndrome II FAP, familiar adenomatous polyposis. Edderkaoui M, et al. Front Physiol. 2014;5;490. Korsse SE, et al. J Med Genet. 2013;50:59-64. Hezel AF, et al. Genes & Dev. 2006;20:1218-1249.

Pathology of Pancreatic Cancer 3 epithelial cell types Exocrine acinar cells Ductal cells Endocrine cells Ductal carcinoma: ~ 90% of all cases Acinar cell carcinoma 1% to 2% of all exocrine pancreatic neoplasms Most cases in elderly Large, metastatic at diagnosis Winter JM, et al. HPB. 2006;8:324-336. WHO Classification of Tumors.

Pancreatic Cancer by Stage (SEER Database) Recent Developments and Future Directions in the Treatment of Pancreatic Cancer Pancreatic Cancer by Stage (SEER Database) Stage Classification % at Diagnosis 5-Yr Survival, % Localized 9 26 Locally advanced/ unresectable 28 10 Metastatic 53 2 SEER, Surveillance Epidemiology and End Results. Siegel R, et al. CA Cancer J Clin. 2015;65:5-29. 8 8

Criteria for Resectability Resectable No evidence of SMV or PV distortion, abutment, or tumor thrombosis Clear fat planes around celiac axis, hepatic artery, SMA Borderline resectable Venous involvement of SMV/PV with tumor abutment which may distort lumen Encasement of SMV/PV but not nearby arteries, or short segment venous occlusion from either tumor thrombus or encasement but with suitable vessel proximal and distal to allow safe resection and replacement Gastroduodenal artery encasement up to hepatic artery with either short segment encasement or direct abutment of hepatic artery without extension to celiac axis Tumor abutment of SMA ≤ 180˚ of vessel wall circumference PV, portal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein. Adapted from Callery MP, et al. Ann Surg Oncol. 2009;16:1727-1733, and the NCCN guidelines v.2.2015.

Criteria for Resectability Locally advanced/unresectable > 180˚ encasement of SMA, celiac axis, or hepatic artery Aortic invasion or encasement Venous thrombosis of portal vein or SMV for several centimeters, making it unreconstructable No distant metastases or lymph nodes beyond field of resection SMA, superior mesenteric artery; SMV, superior mesenteric vein. Adapted from Callery MP, et al. Ann Surg Oncol. 2009;16:1727-1733, and the NCCN guidelines v.2.2015.

Neoadjuvant mFOLFIRINOX in Borderline/Unresectable Meta-analysis: modified FOLFIRINOX in advanced nonmetastatic pancreatic cancer (N = 43) with goal of downstaging for resection PFS 1.00 Median PFS Resected: 18 mos No resection: 8 mos P < .001 Conclusion: coupling mFOLFIRINOX with surgery allows high resection rates and PFS benefit 0.75 Resection Proportion of Pts Alive Without Progression 0.50 FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, oxaliplatin. 0.25 No resection 10 20 30 40 50 60 70 80 90 100 110 120 Wks Post Treatment Blazer M, et al. Ann Surg Oncol. 2015;22:1153-1159.

LAP-07: Chemo ± RT in LAPC After 4 mos Chemo alone (n = 136) Induction chemotherapy (gemcitabine ± erlotinib) (N = 442) 269 randomized ChemoRT (n = 133) 173 dropped out (mainly due to PD) Secondary analysis: addition of erlotinib to gemcitabine conferred NO benefit Chemoradiation associated with lower rates of locoregional progression compared with continued chemotherapy Regimen, Mos Median OS Median PFS Chemo alone 16.5 8.4 ChemoRT 15.2 9.9 LAPC, locally advanced pancreatic cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RT, radiotherapy. Hammel P, et al. ASCO 2013. Abstract LBA4003. Huguet F, et al. ASCO 2014. Abstract 4001.

Metastatic Pancreatic Cancer: Gem as the Mainstay of Treatment Recent Developments and Future Directions in the Treatment of Pancreatic Cancer Metastatic Pancreatic Cancer: Gem as the Mainstay of Treatment Pivotal study: first-line gemcitabine vs 5-FU in advanced pancreatic cancer Median OS: 5.65 vs 4.41 mos (P = .0025) 1-yr OS: 18% vs 2% Clinical benefit (pain + Karnofsky PS + weight): 23.8% vs 4.8% (P = .0022) Response rate: 5.4% vs 0% (P = NS) 100 Gemcitabine 80 5-FU 60 Pts Surviving (%) 40 20 5-FU, 5-fluorouracil; Gem, gemcitabine; NS, not significant; OS, overall survival; PS, performance status. 2 4 6 8 10 12 14 16 18 20 Mos Burris HA, et al. J Clin Oncol. 1997;15:2403-2413.

Phase III: Gemcitabine vs FOLFIRINOX in Met PanC Stratified by ECOG PS (0 vs 1), center, tumor location (head vs other) FOLFIRINOX Oxaliplatin 85 mg/m2 + LV 400 mg/m2 + Irinotecan 180 mg/m2 + 5-FU bolus 400 mg/m2, then 2400 mg/m2 infusional over 46 hrs (n = 171) Metastatic PDAC 5-FU, 5-fluorouracil; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; LV, leucovorin; Met PanC, metastatic pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma. Gemcitabine 1000 mg/m2 weekly x 7 of 8, then weekly x 3 of 4 (n = 171) Conroy T, et al. N Engl J Med. 2011;364:1817-1825. 14

Gem vs FOLFIRINOX: Baseline Characteristics (ITT) Recent Developments and Future Directions in the Treatment of Pancreatic Cancer Gem vs FOLFIRINOX: 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 (%) 64 (37.4) 66 (38.6) 1 106 (61.9) Pancreatic tumor location, n (%) Head 67 (39.2) 63 (36.8) Body 53 (31.0) 58 (33.9) Tail 45 (26.3) Biliary stent, n (%) No 144 (84.2) 149 (87.1) ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; Gem, gemcitabine; ITT, intent-to-treat. Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

FOLFIRINOX vs Gemcitabine: Efficacy Outcome FOLFIRINOX (n = 171) Gemcitabine (n = 171) ORR, % 31.6 9.4 Median PFS, mos 6.4 3.3 Median survival,* mos 11.1 6.8 1-yr survival, % 48.4 20.6 *HR: 0.57; P < .001 FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival. Conroy T, et al. N Engl J Med. 2011;364:1817-1825. 16

FOLFIRINOX vs Gemcitabine: OS and PFS 100 100 75 75 FOLFIRINOX FOLFIRINOX Pts Alive (%) 50 Gemcitabine Pts Without Progression (%) 50 Gemcitabine 25 25 FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; OS, overall survival; PFS, progression-free survival. 3 6 9 12 15 18 21 24 27 30 33 36 39 42 3 6 9 12 15 18 21 24 27 30 33 36 Mos Mos HR: 0.57 (95% CI: 0.45-0.73; P < .001) HR: 0.47 (95% CI: 0.37-0.59; P < .001) Conroy T, et al. N Engl J Med. 2011;364:1817-1825. 17

FOLFIRINOX vs Gemcitabine: Safety and Tolerability Recent Developments and Future Directions in the Treatment of Pancreatic Cancer FOLFIRINOX vs Gemcitabine: Safety and Tolerability Grade 3/4 AE, n/N (%) FOLFIRINOX (n = 171) Gemcitabine (n = 171) P Value Hematologic Neutropenia 75/164 (45.7) 35/167 (21.0) < .001 Febrile neutropenia 9/166 (5.4) 2/169 (1.2) .03 Thrombocytopenia 15/165 (9.1) 6/168 (3.6) .04 Nonhematologic Fatigue 39/165 (23.6) 30/169 (17.8) NS Vomiting 24/166 (14.5) 14/169 (8.3) Diarrhea 21/165 (12.7) 3/169 (1.8) Sensory neuropathy 15/166 (9.0) 0/169 Elevated ALT 12/165 (7.3) 35/168 (20.8) AE, adverse event; ALT, alanine aminotransferase; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; NS, not significant. Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

mFOLFIRINOX in Metastatic Pancreatic Cancer FOLFIRINOX improves OS, PFS, ORR vs gemcitabine in metastatic pancreatic cancer Modified FOLFIRINOX[1-3] Bolus 5-FU omitted and used growth factor support Attenuated doses Retrospective studies of mFOLFIRINOX[1-3] Improved safety profile with maintained efficacy in metastatic pancreatic cancer 70% suggested as minimal relative dose intensity 5-FU, 5-fluorouracil; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. 1. Mahaseth H, et al. Pancreas. 2013;42:1311-1315. 2. Gunturu KS, et al. Med Oncol. 2013;30:361. 3. Lee JC, et al. ESMO 2014. Abstract 715P.

Phase III Studies: Gem/Plat Doublets in Adv Panc Cancer Study Treatment Median PFS, Mos Median OS, Mos Gruppo Oncologia dell‘Italia Meridionale Study (N = 107) Gemcitabine 2.0 5.0 Gem/cisplatin 5.0 (P = .048) 7.5 (P = .48) German Multicentre Study (N = 190) 3.1 6.0 5.3 (P = .053) 7.5 (P = .15) GERCOR/GISCAD Study (N = 313) 3.7 7.1 Gem/oxaliplatin 5.8 (P = .04) 9.0 (P =.13) ECOG 6201 (N = 833) *Third arm = FDR gem N/A 4.9 5.9 Viret, et al (N = 83) 2.5 6.7 2.2 (P = NS) 8.0 (P =.73) ECOG, Eastern Cooperative Oncology Group; FDR, fixed-dose rate; gem, gemcitabine; GERCOR/GISCAD, French Multidisciplinary Clinical Research Group in Oncology/Italian Group for the Study of Gastrointestinal Tract Cancer; NS, not significant; OS, overall survival; PFS, progression-free survival; Plat, platinum. Combined analysis: gemcitabine/platinum results in significant improvement in OS (HR: 0.85; P = .01) Heinemann V, et al. BMC Cancer. 2008;8:82. 20

PS is Critical in Selecting Treatment for Advanced Pancreatic Cancer Recent Developments and Future Directions in the Treatment of Pancreatic Cancer PS is Critical in Selecting Treatment for Advanced Pancreatic Cancer Meta-analysis of randomized trials confirms that performance status is the critical factor in determining who is more likely to benefit from combination chemotherapy Performance Status Benefit From Combination Therapy? ECOG PS 0-1/Karnofsky PS 90% to 100% Yes (HR: 0.76; P < .0001) ECOG PS 2/Karnofsky PS 60% to 80% No (HR: 1.08; P = .40) ECOG PS, Eastern Cooperative Oncology Group performance status. Heinemann V, et al. BMC Cancer. 2008;8:82. 21

Phase III MPACT: Gem ± 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) nab-Paclitaxel 125 mg/m2 IV q3w + Gemcitabine 1000 mg/m2 on Days 1, 8, 15 q4w (n = 431) Treat until PD Gemcitabine 1000 mg/m2/wk for 7 wks, and then on Days 1, 8, 15 q4w (n = 430) Gem, gemcitabine; KPS, Karnofsky performance score; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; q3w, every 3 weeks; q4w, every 4 weeks; ULN, upper limit of normal. Primary objective: OS Secondary endpoints: PFS, ORR, safety Goldstein D, et al. J Natl Cancer Inst. 2015;[Epub ahead of print].

Gem ± nab-Paclitaxel in Met Panc Cancer (MPACT): OS 1.0 OS, Mos Events, n/N Median 75th Percentile 380/431 8.7 14.8 394/430 6.6 11.1 0.9 nab-P + gem 0.8 Gem 0.7 0.6 Proportion of Surviving Pts 0.5 0.4 HR: 0.72 P < .001 0.3 Gem, gemcitabine; Met Panc, metastatic pancreatic; nab-P, nab-paclitaxel; OS, overall survival. 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Mos Goldstein D, et al. J Natl Cancer Inst. 2015;[Epub ahead of print].

Gem ± nab-Paclitaxel in Met Panc Cancer (MPACT): PFS 1.0 PFS, Mos Events, n/N (%) Median (95% CI) 75th Percentile 277/431 (64) 5.5 9.2 265/430 (62) 3.7 5.9 0.9 0.8 0.7 0.6 Proportion of Pts Without Progression 0.5 0.4 nab-P + gem HR: 0.69 P = .000024 0.3 Gem CI, confidence interval; Gem, gemcitabine; HR, hazard ratio; Met Panc, metastatic pancreatic; nab-P, nab-paclitaxel; PFS, progression-free survival. 0.2 0.1 3 6 9 12 15 18 21 24 Mos Von Hoff DD, et al. ASCO GI 2013. Abstract LBA148. Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

Gem ± nab-Pac in Panc Cancer (MPACT): Response by PET Metabolic Response by PET (Independent Review)[1] Outcome nab-P + Gem (n = 130) Gem (n = 127) HR P Value Metabolic response by PET, % 63 38 -- .000051 ORR by CT, % 31 11 .0001 Median OS in PET cohort, mos 10.5 8.3 0.71 .0096 CT, computed tomography; Gem, gemcitabine; nab-P, nab-paclitaxel; ORR, overall response rate; OS, overall survival; Panc, pancreatic; PET, positron-emission tomography; PFS, progression-free survival; SPARC, secreted protein acidic and rich in cysteine. SPARC analysis: SPARC level was neither prognostic for OS nor predictive of response to treatment[2] 1. Von Hoff DD, et al. ASCO 2013. Abstract 4005. 2. Hidalgo M, et al. ESMO 2014. Abstract O-0004.

Gem ± nab-Paclitaxel in Panc Cancer (MPACT): OS by CA19-9 1.0 nab-P + gem, CA19-9 < median nab-P + gem, CA19-9 > median Gem, CA19-9 < median Gem, CA19-9 ≥ median 0.9 0.8 0.7 0.6 Proportion of Surviving Pts 0.5 0.4 0.3 0.2 0.1 Gem, gemcitabine; nab-P, nab-paclitaxel; OS, overall survival; Panc, pancreatic. 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Mos Results suggest nab-paclitaxel can overcome effect of baseline CA19-9 level as prognostic factor, whereas gemcitabine alone cannot Goldstein D, et al. J Natl Cancer Inst. 2015;[Epub ahead of print].

Gem ± nab-Paclitaxel in Panc Cancer (MPACT): AEs nab-P + Gem (n = 421) Gem (n = 402) ≥ 1 grade 3 Tx-related AE 77 51 Grade ≥ 3 hematologic AE Neutropenia 37 26 Leukopenia 32 16 Thrombocytopenia 13 9 Anemia 14 Receipt of growth factors 15 Febrile neutropenia 3 1 Grade ≥ 3 nonhematologic AE in > 5% pts Fatigue 17 7 Peripheral neuropathy < 1 Diarrhea 6 AE, adverse event; Gem, gemcitabine; nab-P, nab-paclitaxel; Panc, pancreatic; Tx, treatment. Goldstein D, et al. J Natl Cancer Inst. 2015;[Epub ahead of print].

Modified Gem/nab-Paclitaxel: Single Institution Experience N = 47 pts with metastatic, locally advanced, or borderline resectable pancreatic cancer Chemotherapy Dose Administration Frequency Gemcitabine 1000 mg/m2 IVPB over 30 min Once every 2 wks Nab-paclitaxel 125 mg/m2 Supportive Care Dexamethasone 12 mg Orally or IV 30 min prior to chemotherapy Gem, gemcitabine; IVPB, intravenous piggyback; NR, not reached; OS, overall survival; PFS, progression-free survival. Survival Median, Mos 95% CI PFS 4.8 (2.6-7.4) OS 11.1 (5.3-NR) Krishna K, et al. ASCO GI Symposium 2015. Abstract 366.

Modified Gem/nab-Paclitaxel: AEs, Dose Delays, Use of GF Toxicity, n (%) All Grades Grade 3/4 Neutropenia 12 (25) 5 (10) Febrile neutropenia 1 (2.1) -- Anemia 45 (73) 7 (11) Thrombocytopenia 9 (15) 3 (2) Neuropathy 13 (27) 1 (2) Fatigue 3 (6) Diarrhea 14 (23) Variable, n (%) Yes No Dose delay 28 (45) 34 (55) Dose reduction of gemcitabine 12 (19) 50 (81) Dose reduction of nab-paclitaxel 13 (21) 49 (79) Growth factor use 5 (8) AE, adverse event; Gem, gemcitabine; GF, growth factors. Krishna K, et al. ASCO GI Symposium 2015. Abstract 366.

Metastatic Pancreatic Cancer: Cost of First-line Chemo Cost estimation: (direct costs in 2014 US$) Drug costs: Centers for Medicare and Medicaid services average sales price Administration costs: Medicare physician fee schedule Costs for grade 3/4 adverse events: 5-day hospitalization for FN Outpatient costs for nausea, vomiting, diarrhea Costs for growth factor support Costs for blood product transfusion 14,000 Monthly cost of toxicities Monthly cost of administration Monthly cost of drugs 12,000 10,000 8000 Cost (US$) 6000 4000 FN, febrile neutropenia; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin. 2000 Dose-Modified Gemcitabine/ nab-Paclitaxel Gemcitabine/ nab-Paclitaxel Carboplatin/ Paclitaxel FOLFIRINOX Gemcitabine Krishna K, et al. ASCO GI Symposium 2015. Abstract 368.

Phase III Experience: 2nd-line Chemo With Oxaliplatin CONKO-003 study[1] N = 160 with PD on gem Median OS (HR: 0.66) 5-FU/LV: 3.3 mos OFF: 5.9 mos Median TTP (HR: 0.68) 5-FU/LV: 2.0 mos OFF: 2.9 mos AEs: ↑ gr 1/2 neurotoxicity with oxaliplatin PANCREOX study[2] N = 108 with previous gem Median OS (HR: 1.78) 5-FU/LV: 9.9 mos mFOLFOX6: 6.1 mos Median PFS (HR: 1.00) 5-FU/LV: 2.9 mos mFOLFOX6: 3.1 mos AEs: ↑ gr 3/4 neutropenia, fatigue with oxaliplatin 5-FU, 5-fluorouracil; AE, adverse event; FOLFOX, 5-fluorouracil; oxaliplatin, leucovorin; LV, leucovorin; oxali, oxaliplatin; OS, overall survival; PD, progressive disease. 1. Oettle H, et al. J Clin Oncol. 2014;32:2423-2429. 2. Gill S, et al. ASCO 2014. Abstract 4022.

Phase III NAPOLI-1: 2nd-line 5-FU/LV vs MM-398 vs Both MM-398 80 mg/m2 q2w + 5-FU/LV 2400/400 mg/m2 q2w (n = 117) Pts with metastatic pancreatic cancer and previous gemcitabine (N = 417) 5-FU/LV 2000/200 mg/m2 q6w (n = 149) MM-398 120 mg/m2 q3w (n = 151) 5-FU/LV, 5-fluorouracil / leucovorin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q2w, every 2 weeks, q6w, every 6 weeks. Primary endpoint: OS Secondary endpoints: PFS, ORR, CA19-9, safety Cheng LT, et al. ASCO GI 2015. Abstract 234.

2nd-line 5-FU/LV vs MM-398 vs Both (NAPOLI-1): Outcomes OS[1] PFS[2] 1.0 1.0 MM-398+5-FU/LV 5-FU/LV 6.1 (4.8-8.9) 4.2 (3.3-5.3) PFS, Mos Median (95% CI) 0.9 0.9 0.8 0.8 MM-398+5-FU/LV 5-FU/LV 3.1 (2.7-4.2) 1.5 (1.4-1.8) 0.7 Stratified HR: 0.57 (0.41-0.80; P = .0009) 0.7 0.6 0.6 Proportion Alive 0.5 Proportion w/o Progression 0.5 HR: 0.56 (0.41-0.75; P = .0001) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 3 6 9 12 15 18 3 6 9 12 15 18 Mos 5-FU/LV, 5-fluorouracil / leucovorin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Mos Outcome, % 5-FU/LV MM-398 MM-398 + 5-FU/LV ORR 1 6 16 CA19-9 decline > 50% 12 31 36 1. Cheng L-T, et al. ASCO GI 2015. Abstract 234. 2. Von Hoff D, et al. ESMO 2014. Abstract O-0003.

Phase II RECAP: 2nd-line Cape ± Ruxolitinib Ruxolitinib 15 mg BID Days 1-21 + Capecitabine 1000 mg/m2 BID Days 1-14 (n = 64) Pts with metastatic pancreatic cancer, Karnofsky PS ≥ 60, failed gemcitabine (N = 127) Placebo BID Days 1-21 + Capecitabine 1000 mg/m2 BID Days 1-14 (n = 63) BID, twice daily; Cape, capecitabine; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; QoL, quality of life. Primary endpoint: OS Secondary endpoints: clinical benefit response, ORR, confirmed response (4 wks) PFS, QoL, safety Hurwitz H, et al. ASCO 2014. Abstract 4000.

2nd-line Cape ± Ruxolitinib (RECAP): OS (ITT) Ruxolitinib + Cape (n = 64) Placebo + Cape (n = 63) Median OS, days 136.5 129.5 Survival rate, % 3 mos 64 58 6 mos 42 35 12 mos 22 11 1.00 0.75 Proportion Alive 0.50 HR: 0.79 (95% CI: 0.53-1.18; 2-sided P = .25) Cape, capecitabine; ITT, intent to treat; OS, overall survival. 0.25 Ruxolitinib Placebo 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Mos Hurwitz H, et al. ASCO 2014. Abstract 4000.

2nd-line Cape ± Ruxolitinib: OS With CRP > 13 mg/L 1.00 Ruxolitinib + Cape (n = 31) Placebo + Cape (n = 29) Median OS, days 83 55 Survival rate, % 3 mos 48 29 6 mos 42 11 12 mos 0.75 Proportion Alive 0.50 HR: 0.47 (95% CI: 0.26-0.85) 2-sided P = .01 Cape, capecitabine; CRP, C-reactive protein; OS, overall survival. 0.25 Ruxolitinib Placebo 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Mos Hurwitz H, et al. ASCO 2014. Abstract 4000.

2nd-line Cape ± Ruxolitinib (RECAP): Toxicities Grade 3/4 Adverse Event, n (%) Ruxolitinib + Cape (n = 59) Placebo + Cape (n = 60) Hematologic Anemia 9 (15.3) 1 (1.7) Thrombocytopenia 2 (3.3) Neutropenia Nonhematologic Pulmonary embolism 7 (11.9) 3 (5.0) Fatigue 6 (10.2) 7 (11.7) Abdominal pain 8 (13.3) Pneumonia 5 (8.5) 6 (10.0) Stomatitis 4 (6.8) Cape, capecitabine. Hurwitz H, et al. ASCO 2014. Abstract 4000.

Phase III JANUS-1 and -2 Studies: Cape ± Ruxolitinib Pts with metastatic pancreatic cancer who failed or were intolerant of 1st-line chemo (JANUS-1: planned N = 310) (JANUS-2: planned N = 270) Ruxolitinib 5 mg BID + Capecitabine 500 mg/m2 BID Placebo BID + Capecitabine 500 mg/m2 BID Primary endpoint: OS Secondary endpoints: PFS, ORR, DoR, safety/ tolerability BID, twice daily, Cape, capecitabine; DoR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. ClinicalTrials.gov. NCT02117479. ClinicalTrials.gov. NCT02119663.

New Directions in the Treatment of Pancreatic Cancer New targeted agents PARP inhibition for patients with BRCA1/2 mutations Immunotherapy Algenpantucel-L GVAX + CRS-207

Randomized Phase II of GVAX/Cy ± CRS-207 GVAX: irradiated, GM-CSF–secreting allogeneic pancreatic cell lines elicit antigenic response CRS-207: attenuated Listeria engineered to express human mesothelin 90 pts with previously treated metastatic PanC adenocarcinoma 51% ≥ 2 previous regimens Median OS: 6.1 mos for the combination vs 3.9 mos for GVAX/Cy alone Cy, cytarabine; GM-CSF, granulocyte macrophage colony-stimulating factor; OS, overall survival; PanC, pancreatic cancer. Le DT, et al. J Clin Oncol. 2015;33:1325-1333.

PARP Inhibition in BRCA1/2-Associated Cancers: Olaparib Multicenter phase II study of olaparib monotherapy in 298 pts with recurrent, BRCA1/2-mutated cancers Tumor responses seen across spectrum of malignancies Most pts with pancreatic cancer received olaparib as 3rd-line Tx Response, % Ovarian (n = 193) Breast (n = 62) Pancreas (n = 23) Prostate (n = 8) Tumor response 31 13 22 50 SD ≥ 8 wks 40 47 35 25 PD 21 37 39 PD, progressive disease; SD, stable disease; Tx, treatment. Kaufman B, et al. J Clin Oncol. 2015;33:244-250.

Palliative Care Biliary obstruction Pain Fatigue Depression Intestinal obstruction Brescia FJ. Cancer Control. 2004;11:39-45.

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