Alliance A021101: Preoperative mFOLFIRINOX + Chemoradiation in Borderline Resectable Pancreatic Cancer CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

Alliance A021101: Background Pts with advanced pancreatic cancer often have limited survival based on incomplete resection due to involvement with mesenteric vasculature[1] In addition, adjuvant chemotherapy delivery may be incomplete[2] Rationale for systemic therapy and radiotherapy exist, but earlier studies in pts with borderline resectable pancreatic cancer are few Systemic therapy: gemcitabine well tolerated, but success rate low (RR of 9%); mFOLFIRINOX with better success, but less well tolerated[3] Radiotherapy: limited data in any other stage of localized disease Current Alliance A021101 pilot study sought to evaluate mFOLFIRINOX and radiotherapy as preoperative regimen for pts with borderline resectable pancreatic cancer[4] mFOLFIRINOX; modified 5-fluorouracil, oxaliplatin, leucovorin, and irinotecan; RR, response rate. 1. Yamada S, et al. Pancreas. 2013;42:1004-1010. 2. Simons JP, et al. Cancer. 2010;116:1684-1690. 3. Conroy T, et al. N Engl J Med. 2011;364:1817-1825. 4. Katz MHG, et al. ASCO 2015. Abstract 4008.

Alliance A021101: Study Design Multicenter pilot study[1] Primary endpoints Accrual Rate of preoperative treatment-related toxicity or delay Rate of completion of all planned preoperative and operative therapy No evidence of disease progression Pts with borderline resectable pancreatic cancer by Intergroup definition (N = 22) mFOLFIRINOX 2 mos 50.4 gy EBRT + Capecitabine Surgery + Gemcitabine 2 mos Criteria for Radiographic Interface Between Tumor and Vessel for Borderline Resectable[2] Portal vein TVI ≥ 180° and/or reconstructable occlusion Superior mesenteric artery TVI < 180° Hepatic artery Reconstructable short-segment TVI of any degree Celiac trunk EBRT, external beam radiation therapy; mFOLFIRINOX; modified 5-fluorouracil, oxaliplatin, leucovorin and irinotecan; TVI, tumor-vein interface. 1. Katz MHG, et al. ASCO 2015. Abstract 4008. 2. Katz MHG, et al. Ann Surg Onc. 2013;20:2197-2203.

Alliance A021101: Baseline Characteristics Accrual accomplished early with 13 of 14 sites enrolling ≥ 1 pt Baseline Characteristic All Pts (N = 22) Median age, yrs (range) 64 (50-76) Male, n (%) 10 (45) ECOG PS 0, n (%) 14 (64) Median tumor diameter, mm (range) 30 (16-49) Radiographic Interface in Enrolled Pts, n (%) Total TVI < 180 TVI ≥ 180 Portal vein 16 (73) 7 (32) 9 (41) Superior mesenteric artery Superior mesenteric vein 13 (59) 10 (46) 6 (27) Hepatic artery 5 (23) 1 (5) Celiac trunk 2 (9) ECOG PS, Eastern Cooperative Oncology Group performance status; TVI, tumor-vein interface. Katz MHG, et al. ASCO 2015. Abstract 4008.

Alliance A021101: mFOLFIRINOX Preoperative AE Grade 3 AE in 50% of pts Grade 4 AE: n = 1 Dose reductions of mFOLFIRINOX: n = 9 (41%) Treatment delays: n = 10 (46%) Median treatment delay: 1 wk (range: 0.57-3.86 wks) Treatment omissions: n = 1 (0.5%) Event, n (%) Grade 3 Grade 4 Dehydration 4 (18) Diarrhea 3 (14) Leukopenia 2 (9) 1 (5) Thromboembolic event Hypokalemia AE, adverse event; mFOLFIRINOX; modified 5-fluorouracil, oxaliplatin, leucovorin and irinotecan. Katz MHG, et al. ASCO 2015. Abstract 4008.

Alliance A021101: Capecitabine-XRT Preoperative AE Capecitabine-XRT: grade 3 AEs in 36% of pts Lymphopenia most common event: n = 3 (14%) Other events experienced by n = 1 pt: increase in alkaline phosphatase, bilirubin, AST, or ALT; glucose intolerance; hyperglycemia; HTN; nausea; vomiting; leukopenia; paralytic ileus; metabolism disorder; nutrition disorder–other Dose reductions: n = 1 (5%) Treatment delay: n = 1 (5%) Delay 1.6 wks Treatment omissions: n = 3 (14%) Radiation interruptions: n = 5 (24%) AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HTN, hypertension; XRT, radiotherapy. Katz MHG, et al. ASCO 2015. Abstract 4008.

Alliance A021101: Surgery, Pathology, and AEs Among 15 pts undergoing surgery 80% (n = 12) with portal vein resection 27% (n = 4) with hepatic artery resection R0 resection in 93% N0 status in 67% of pathologic specimens < 5% residual tumor cells in 47% Complete pathologic response in 13% 1 death occurred within 90 days of surgery Surgery Grade ≥ 3 AEs, % Pts (N = 15) Anemia 38 Infection with unknown ANC 23 Infection with normal or grade 1/2 ANC 15 Surgical or postoperative hemorrhage Anorexia AE, adverse event; ANC, absolute neutrophil count. Katz MHG, et al. ASCO 2015. Abstract 4008.

Alliance A021101: Best Preoperative Response Best Response, n (%) At Any Point After mFOLFIRINOX After Capecitabine/ XRT CR 2 (9) 2 PR 4 (18) 4 SD 14 (64) 16 11 PD 2 (9)* -- 3 Resection 15 CR, complete response; mFOLFIRINOX; modified 5-fluorouracil, oxaliplatin, leucovorin and irinotecan; PD, progressive disease; PR, partial response; SD, stable disease; XRT, radiotherapy. *Local progression but kept on protocol, n = 1; metastases, n = 1. Katz MHG, et al. ASCO 2015. Abstract 4008.

Alliance A021101: Investigator Conclusions Small, pilot establishes feasibility of conducting intergroup study on borderline resectable pancreatic cancer Accrual surpassed goal Preoperative toxicity manageable Majority of pts underwent resection (64%) Survival data maturing Katz MHG, et al. ASCO 2015. Abstract 4008.

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