Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148 Philip Agop Philip, MD, PhD, FRCP Karmanos Cancer Center Wayne State University Detroit, Michigan

Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) Randomized phase III trial of adjuvant chemotherapy with gemcitabine vs. S-1 for resected pancreatic cancer patients (JASPAC 01 study) K. Uesaka, et al. Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) Abstract #145

JASPAC 01 Surgery Randomization GEM 1000 mg/m2 Q 4 weeks X 6 cycles Stratification Center R0/R1 N0/N1 Randomization No radiaiton therapy GEM 1000 mg/m2 Q 4 weeks X 6 cycles S-1 40-60mg, BID, PO 4 wks on/2 wks off X 4 cycles #145 2013 ASCO GI

JASPAC 01 No Radiotherapy! Surgery Randomization S-1 40-60mg, BID, PO Stratification Center R0/R1 N0/N1 Randomization No radiaiton therapy S-1 40-60mg, BID, PO 4 wks on/2 wks off X 4 cycles GEM 1000 mg/m2 X 6 cycles #145 2013 ASCO GI

JASPAC 01 Overall Survival Primary Endpoint 50 100 1 2 3 4 5 years (%) P<0.0001 for non-inferiority P<0.0001 for superiority 70% 53% S-1 GEM

Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01 GEM v Obs GEM v inf-FU + C-RT GEM v b-FU GEM v S-1 mDFS mon GEM 13.4 11.4 14.3 11.2 FP - 10.1 14.1 23.2 mOS mon 22.8 20.5 23.6 25.5 16.9 23 46.3 From the oettle study the improvement in DFS does not translate well to improvement in survival. What is also lacking in the Japanese study is the pattern of therapy post-recurrence Number of questions; site of disease, maturity of data, post-relapse therapy The other thing is that the RTOG study was the only one with radiation included it is noteworthy In a disease with such a short survival it is possible that small changes can be amplified! Superiority of s-1 may not be that surprising given the efficacy data of the drug in advanced disease, however the magnitude of the benefit over gemcitabine in this adjuvant setting is intriguing with worth more depth study at the molecular level. Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;

Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01 GEM v Obs GEM v inf-FU + C-RT GEM v b-FU GEM v S-1 mDFS mon GEM 13.4 11.4 14.3 11.2 FP - 10.1 14.1 23.2 mOS mon 22.8 20.5 23.6 25.5 16.9 23 46.3 Node positive, % 72 67 63 R0, % 81 66 65 87 From the oettle study the improvement in DFS does not translate well to improvement in survival. What is also lacking in the Japanese study is the pattern of therapy post-recurrence Number of questions; site of disease, maturity of data, post-relapse therapy The other thing is that the RTOG study was the only one with radiation included it is noteworthy In a disease with such a short survival it is possible that small changes can be amplified! Superiority of s-1 may not be that surprising given the efficacy data of the drug in advanced disease, however the magnitude of the benefit over gemcitabine in this adjuvant setting is intriguing with worth more depth study at the molecular level.

JASPAC 01 Superiority of adjuvant S-1 over GEM in Japanese patients with resected panc. ca. “Non-Japanese” studies must be considered to define the role of S-1 in early and late stage disease in conjunction with biomarkers studies (e.g., S-1 metabolism) The role of adjuvant radiation therapy in panc. ca will be determined by the ongoing RTOG/SWOG/EORTC study Superiority in the absence of XRT S-1 alone or in combination such as with radiation therapy

Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) Daniel D. Von Hoff, et al. Abstract #148

1000 mg/m2 IV qw for 7 weeks then qw 3/4 weeks Study Design nab-Paclitaxel 125 mg/m2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m2 IV qw 3/4 weeks Planned N = 842 Stage IV No prior treatment for metastatic disease Karnofsky PS ≥70 Measurable disease Total bilirubin ≤ULN Gemcitabine 1000 mg/m2 IV qw for 7 weeks then qw 3/4 weeks Von Hoff

IMPACT: Efficacy Med OS, mos 8.5 6.7 0.72/ 0.000015 Med PFS, mos 5.5 nab-Pacli + GEM GEM Hazard ratio p value Med OS, mos 8.5 6.7 0.72/ 0.000015 Med PFS, mos 5.5 3.7 0.69/ 0.000024 12-mon alive, % 35 22 0.0002 Objective response, % 23 7 1.1x10-10

Major Treatment Options for Metastatic Pancreatic Cancer Gemcitabine +/- erlotinib FOLFIRINOX Nab-paclitaxel plus gemcitabine Others (e.g., GemCape, GTX) Clinical trial

Major Treatment Options for Metastatic Pancreatic Cancer Gemcitabine +/- erlotinib FOLFIRINOX Nab-paclitaxel plus gemcitabine Others (e.g., GemCape, GTX) Clinical trials

Tolerability: Selected Grade 3+ Toxicities, % nab-pacli + GEM FOLFIRINOX Fatigue 17 23.6 Diahhrea 6 12.7 Neuropathy 9 Neutropenia 38 45.7 Neutropenic fever 3 5.4 Thrombocytopenia 13 9.1 Conroy et al, NEJM, 364:1817-1825, 2011

Efficacy nab-pacli + GEM FOLFIRINOX Median OS, mos 8.7 11.1 Median PFS, mos 5.5 6.4 ORR (%) 23.0 31.6 Conroy et al, NEJM, 364:1817-1825, 2011

Study Populations IMPACT PRODIGE/ACCORD Median age median 63 61 Liver, % 84 88 Head of pancreas, % 43 38 Males, % 58 Good PS, % 60 Median sites of mets 3 2 Number of patients 861 342 Treatment centers Multiple countries Comparing full prtocvol doses Conroy et al, NEJM, 364:1817-1825, 2011

IMPACT Is an example of pre-clinical to pilot testing to Phase III drug stepwise developmental program Nab-paclitaxel plus GEM is a new frontline regimen in patients with metastatic panc. ca. and favorable performance status Nab-paclitaxel +/- GEM (or other drugs) must be investigated in earlier stage disease and in combinations with biologicals The molecular basis of nab-paclitaxel’s activity and its association with a biomarker(s) must be determined (going back to the lab!)

the Final Results of the SCALOP Trial Induction GEMCAP Chemotherapy followed by Gemcitabine (Gem) or Capecitabine (Cap)-based Chemoradiation (CRT) for Locally Advanced Pancreatic Cancer (LAPC): the Final Results of the SCALOP Trial S Mukherjee, et al. SCALOP Investigators In an era of limited informaiton on how best to do stduies or trials Abstract LBA146

Gemcitabine 300mg/m2/week SCALOP GEMCAP x 3 cycles Gem 1000mg/m2 D1,8,15 q 4w Cap 830mg/m2 BD D 1-21 q 4w Progressive dx Tumor >6cm diameter PS 2 >10% wt loss Not encompassable in radiation volume RANDOMIZATION GEMCAP x 1 cycle GEMCAP x 1 cycle Gemcitabine 300mg/m2/week + RT 50.4Gy Capecitabine 830mg/m2 bd + RT 50.4Gy

Gemcitabine 300mg/m2/week SCALOP GEMCAP x 3 cycles Gem 1000mg/m2 D1,8,15 q 4w Cap 830mg/m2 BD D 1-21 q 4w Progressive ds Tumor >6cm diameter PS 2 >10% wt loss Not encompassable in radiation volume 35% RANDOMIZATION GEMCAP x 1 cycle GEMCAP x 1 cycle Gemcitabine 300mg/m2/week + RT 50.4Gy Capecitabine 830mg/m2 bd + RT 50.4Gy

Gemcitabine 300mg/m2/week SCALOP GEMCAP x 3 cycles Gem 1000mg/m2 D1,8,15 q 4w Cap 830mg/m2 BD D 1-21 q 4w Progressive ds Tumor >6cm diameter PS 2 >10% wt loss Not encompassable in radiation volume RANDOMIZATION 4 cycles/4 months of systemic therapy GEMCAP x 1 cycle GEMCAP x 1 cycle Gemcitabine 300mg/m2/week + RT 50.4Gy Capecitabine 830mg/m2 bd + RT 50.4Gy

Summary of Efficacy Data CAPE-RT GEM-RT p PFS at 9 mos, % 62.9 51.4 NS Median PFS, mos 12.0 10.4 Med OS, mos 15.2 13.4 0.025 All Randomized Taken off N 114 74 40 Med OS, mos 12.7 14.6 8.1

What do we learn from SCALOP? Cape-RT is the current preferred standard and will continue as such Ongoing research questions The contribution of chemo-RT (GERCOR, Dr P. Hammel; ALLIANCE, Dr A. Ko) Molecular selection for chemo-RT (RTOG, Dr E. Ben Josef) More effective systemic therapies Develop study designs and endpoints that are appropriate to each question We should continue study them separately

A Phase I/II Study of ABT-888, 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer M. J. Pishvaian, et al. Abstract #147

Phase Ib No patient selection Pre-treatment biopsies for BRCA-1, -2, PALB-B3, FANC gene expression, others

PARPi and Pancreatic Cancer A platinum +/- PARPi strategy is worth pursuing in patients with BRCA-2 mutations Explore biologic combinations with PARPi Need to determine relative contributions of platinum vs. PARPi to anti-tumor activity National or “preferably” international collaborative effort is necessary for a timely completion of clinical trials (e.g., ARCAD) Too early! Still need a lot of pre-clinical evaluations

Thank you

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Take Home Messages Adjuvant S-1 is a new standard for resected pancreas ca. with a potential for its development outside of Japan nab-Paclitaxel/GEM is a new treatment standard for patients with metastatic pancreas ca. warranting further development in conjunction with a biomarker discovery strategy The biology of S1 with respect to pancreas cancer will be worth studying Nab-pacli increases treatment options Tissue collection in these studies helpful to understand

Take Home Messages (2) Capecitabine 1.66 grams/m2/day will continue to be our radisoenstizer of choice in pancreas ca. A treatment strategy of a platinum compound +/- PARPi needs pre-clinical/pilot clinical evaluations in BRCA-2 mutated panc. ca. More tissue-based research and stronger collaborative efforts are necessary for successful studies in pancreatic cancer!

Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01 GEM v Obs GEM v inf-FU + C-RT GEM v b-FU GEM v S-1 mDFS mon GEM 13.4 11.4 14.3 12 FP - 10.1 14.1 24 mOS mon 22.8 20.5 23.6 23 16.9 46 Hazard ratio for overall survival 0.80 0.94 0.56 From the oettle study the improvement in DFS does not translate well to improvement in survival. What is also lacking in the Japanese study is the pattern of therapy post-recurrence Number of questions; site of disease, maturity of data, post-relapse therapy The other thing is that the RTOG study was the only one with radiation included it is noteworthy In a disease with such a short survival it is possible that small changes can be amplified! Superiority of s-1 may not be that surprising given the efficacy data of the drug in advanced disease, however the magnitude of the benefit over gemcitabine in this adjuvant setting is intriguing with worth more depth study at the molecular level. Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;