Pancreatic Cancer: Current Therapies, Clinical Trials & Future Directions

Pancreatic Cancer: Current Therapies, Clinical Trials & Future Directions Eileen M. O Reilly, M.D. Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of Cornell University

Agenda Operable pancreas cancer Staging, surgery and post-operative therapy Advanced pancreas cancer Treatments, clinical trials New targeted agents Locally advanced, stage III pancreas cancer

Localized Pancreas Cancer 3 key groupings Localized, operable (AJCC stage I-IIB) Localized, borderline resectable Newly recognized, multi-disciplinary assessment, no standard approach Locally advanced, unresectable (AJCC stage III)

Potentially Operable 2.3 cm uncinate process mass Bilirubin 7.3 Alk phos 429 ERCP + plastic stent. Washings adenoca

Surgery for Pancreas Adenoca Splenic vein Duodenum Ampulla Pancreatic duct SMV/SMA SMA Jejunum Pancreaticoduodenectomy (Whipple) 80% Distal Pancreatectomy +/- Splenectomy 20%

Adjuvant Therapy Background N= 6-8000 localized pancreas ca per year Intensely controversial Benefit (modest) established Options Systemic therapy alone Chemoradiation + chemotherapy Lim, JE. Ann Surg, 2003. Garcea, G. J Pancreas, 2008

Resected PC Survival (MSKCC) 1983-2001, N= 618 5- year survival 12% (N= 75) 10-year survival 5% (N= 18) Predictors of Survival Negative margins AJCC stage Ferrone, et al. J Gast Surg, 2008

Adjuvant Therapy Gemcitabine or 5-fluorouracil for 6 months standard Data for inclusion of combined chemotherapy and radiation more controversial US often included Europe, Japan typically chemotherapy alone Large study underway to define absolute benefit of chemotherapy + radiation

Why Neoadjuvant (Pre-operative) Therapy? Risk of recurrence Selects out biology, avoidance of surgery Improved treatment delivery: 20-25% don t receive adjuvant therapy, delay, abbreviated Improved margin negative operations, reduced local recurrence rate, downstaging? Standard approach esophageal, rectal ca

CT Pancreas Angiogram Borderline Resectable Hypovascular pancreas head tumor SMV SMA

Adjuvant/ Neoadjuvant Trials Sponsor Trial N Phase III Trials ESPAC-4 CONKO-005 JSPAC RTOG 8048 Gemcitabine +/- Capecitabine Endpoint: Survival Gemcitabine +/- Erlotinib (R0 only) Endpoint: Relapse-Free Survival Gemcitabine vs. S1 Endpoint: Survival Gemcitabine +/- Erlotinib +/- ChemoRT Endpoint: Survival 1,080 436 360 952 Single Arm Phase II Trials ACOSOG Z05041 Gemcitabine/erlotinib neoadjuvant Endpoint: Survival 2 yrs 90 www.clinicaltrials.gov

US Intergroup/RTOG 0848 - EORTC Resected Pancreas Cancer N= 952 R A N D O M I Z E Gemcitabine x 6 cycles Gemcitabine + Erlotinib x 6 2 nd Randomization +/- ChemoRT Stratification R0 vs R1 resection; T stage; Nodes involved or not Primary Endpoint: Overall Survival with erlotinib and with radiation Tissue acquisition/ correlative science

Inoperable Pancreas Cancer

Multidisciplinary Management Pain management Narcotics, nerve block Supportive/ palliative care Jaundice ERCP + stent, operative bypass Gastric outlet obstruction Stent, PEG, rarely surgery Nutrition Enzyme supplementation, appetite enhancement Thromboembolism > 20% Psychosocial care

Overall Survival CALGB 80303 by Performance Status (Pooled Data) Proportion Surviving 0.6 0.8 1.0 0.0 0.2 0.4 P S =0 P S =1 P S =2 PS 0: 8.0 mths PS 1: 4.8 mths PS 2: 2.8 mths p=0.0001 p= 0.0001 0 5 10 15 20 25 M onths from S tudy E ntry Kindler, et al. J Clin Oncol, 2010

Does Treatment Work in PC? Meta-analysis Meta-analysis N 3458 pts 29 randomized trials 9,971 pts 51 randomized trials Outcome 5-FU vs BSC* Median survival 6.4 vs 3.9 mths Chemo vs BSC HR 0.91 *BSC: Best supportive care Fung, et al. ASCO, 2003. Sultana, et al. J Clin Oncol, 2007

FDA Approval Gemcitabine vs 5-FU (until 2010.) Gemcitabine N= 63 5-FU (N= 63) Clinical Benefit Response 24% 5% 1-year Survival 18% 2% Burris, et al. J Clin Oncol, 1997

Next Decade in Research in Two main strategies: Pancreas Ca Gemcitabine + new drug Gemcitabine compared to new drug Gemcitabine + new drug Slight improvement when added to platinum drugs, capecitabine (oral 5-FU) No benefit for adding bevacizumab (avastin), cetuximab (erbitux), marimistat, irinotecan (CPT- 11), exatecan, pemetrexed (alimta), tipifarnib, etc.

Targeted Therapy in Pancreatic Adenocarcinoma: Is There a Role?

Phase III Anti-Vascular Trials in PC Drug N RR Med OS Reference Gemcitabine + Bevacizumab Gemcitabine + Placebo 590 13% 10% 5.8 mths 6.1 mths Gemcitabine + Erlotinib + Bevaciz. 13.5% 7.1 mths Gemcitabine + Erlotinib 607 8.6% 6 mths Gemcitabine + Axitinib NR 8.5 mths 593 Gemcitabine + Placebo NR 8.3 mths Gemcitabine + Aflibercept NR 7.7 mths Gemcitabine + Placebo 594 NR 6.5 mths Kindler CALGB 80303 Van Cutsem AViTA Kindler Rougier Kindler, HJ. J Clin Oncol, 2010. Van Cutsem, E. J Clin Oncol, 2009. Kindler, HJ. Lancet Oncology 2010. Rougier, P. ESMO, GI, 2010

NCI PA.3 Phase III Trial Untreated Advanced Pancreas Ca N= 569 Endpoint: Survival R A N D O M I Z E Gemcitabine + Erlotinib Gemcitabine + Placebo Moore, et al. J Clin Oncol, 2007

PA.3 Overall Survival Survival Distribution Function 1.00 0.75 0.50 0.25 0 G + Erlotinib (N= 261) G + Placebo (N= 260) 1-Year Survival 23% 17% Tumor Control 57% 49% HR= 0.82 (0.69-0.99) p= 0.038 0 6 12 18 24 Months *Adjusted for PS and extent of disease at baseline From Cox regression model From 2-sided log-rank test Moore, et al. J Clin Oncol, 2007

Rash Severity and Survival Outcome No Rash Gd I Rash Gd 2+ Rash (N= 79) (N= 108) (N= 103) 1-Year Survival 16% 11% 43% Med Survival 5.3 mths 5.8 mths 10.5 mths Moore, et al. J Clin Oncol, 2007

Commonly Used Drug Combinations Frequently used (mixed results) Gemcitabine + low-dose cisplatin Gemcitabine + oxaliplatin Gemcitabine + capecitabine Gemcitabine + erlotinib Other multi-drug combinations (less data, less used) G-FLIP (gem, 5-FU, leucovorin, irinotecan, platinum) PEFG (Cisplatin, epirubicin, 5-FU, gem)

Clinical Trials Phase I Dosing, schedule, side effects, hints of efficacy Phase II Typically restricted to a specific disease Estimation of the effectiveness of the therapy Fuller understanding of side effects Phase III Comparison to best standard treatment Gold standard approach for drug approval Phase IV Post-marketing assessment

Clinical Trials II Support for clinical trials Government Pharmaceutical industry Philanthropy, Institutions Regulatory control/ support for clinical trials Institutional Review/ Privacy Board Large trials Data & Safety monitoring committee Principal investigator - responsibility

New Targets, New Drugs Target Class of Drug Example of Drug IGF-1R Antibody to IGF-1R Tyrosine kinase inhibitor AMG 479, MK0646 PQIP RAS Farnesyl transf. inhibitor Oncolytic viral agents Tipifarnib, Salarasib Reovirus mtor mtor inhibitor Everolimus, temsirolimus Hedgehog (HH) Notch Small molecule HH inhibitor Gamma-secretase inhibitor GDC-0449, IPI-926 R04929097 SRC SRC, bcr-abl inhibitor Dasatinib, AZD 0530 TRAIL Antibody to DR4, DR5 Mapatumumab AMG 655 Integrin Antibody to α5β1 integrin Volociximab PARP PARP inhibitor AZD 2281 (Olaparib), ABT 088 (Veliparib), BSI-201

Randomized Phase II IGF-1R, TRAIL Targeting R A N Gemcitabine + AMG 479 12 mg/kg Metastatic D Pancreas Ca Gemcitabine + O N= 120 M IZ AMG 655 10 mg/kg E Gemcitabine + Placebo Primary endpoint: 6-month survival Kindler, HJ. J Clin Oncol, 2010 (abst # 4035) www.clinicaltrials.gov NCT00630552

Results: Phase II Gem+ AMG 479 Grm + AMG 655 Gem + Placebo 6 month Survival 57% 59% 50% Median Survival 8.7 mths 7.5 mths 5.9 mths Grade 3-4 Fatigue 13% 12% 5% Kindler, HJ. J Clin Oncol, 2010 (abst #4035)

J. Natl. Cancer Inst. 91:1310-1316, 1999 BRCA Mutations & Pancreas Cancer BRCA 2 mutations: increased risk pancreatic adenocarcinoma x 3.5 BRCA 1 mutations: increased risk x 2.2 Ashkenazi Jewish descent most common (founder) mutations BRCA 1: 187delAG, 5382insC BRCA 2: 6174delT Background population frequency of 2-3% J Nat Cancer Inst, 1999, 2002

Poly (ADP-Ribose) Polymerase (PARP) DNA damage endogenous, cytotoxics, radiation, etc. If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks

Loss of Functional BRCA-1 or 2 Affects DNA Double-Strand Break Repair Pathway Ashworth, et al. J Clin Oncol, 2008

PARP Inhibitor Trials in PC Phase Drug Mutation Combination N I AZD2281 None Gemcitabine ~13 II BSI-201 BRCA-2* Gemcitabine 1 I ABT-888 BRCA-1,2-1 I-II AZD2281 None ICM**? II ABT-888 None FOLFOX 2 nd line *Being amended to allow BRCA-1 patients **Irinotecan, Cisplatin, Mitomycin

Newer Chemotherapy Combinations for Pancreas Cancer Gemcitabine + docetaxel + capecitabine (GTX) Gemcitabine + nab-paclitaxel (NabP, Abraxane) Higher response in SPARC + patients N RECIST ORR Med TTF or PFS Med OS GTX 41 33% 6.9 m 14.5 m Gem-NabP (all pts) 49 26% 4.8 m 9 m SPARC (+) pts 8 75% 6.2 m NR SPARC (-) pts 19 26% 4.8 m NR Fine RL, et al. J Clin Oncol. 2009;27(15S). Abst #4623 Von Hoff DD, et al. J Clin Oncol. 2009;27(15S). Abst #4525

FOLFIRINOX vs Gemcitabine Prodige 4- ACCORD 11 Untreated Met Panc Adenoca ECOG 0-1 R A N D O M I Z E FOLFIRINOX Gemcitabine Endpoint: Overall Survival Conroy, et al. ASCO, 2010 (Abst #4010)

FOLFIRINOX Oxaliplatin 85 mg/m 2 (2 hr) Leucovorin 400 mg/m 2 (2 hr) Irinotecan 180 mg/m 2 (1.5 hr) Continuous 5-FU 2400 mg/m 2 (48 hr) Bolus 5-FU 400 mg/m 2 Treatment cycled q 2 weeks Total of 6 months

FOLFIRINOX vs Gemcitabine: Overall Survival 1.00 FOLFIRINOX Gemcitabine Probability 0.75 0.50 Median 11.1 mo HR = 0.57 P < 0.0001 0.25 Median 6.8 mo 0.00 Number at risk Gemcitabine FOLFIRINOX 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 171 134 89 48 28 14 7 6 3 3 2 2 2 171 146 116 81 62 34 20 13 9 5 3 2 2 Conroy T, et al. J Clin Oncol. 2010;28(18s). Abst #4010

FOLFIRINOX vs Gemcitabine Secondary Endpoints FOLFIRINOX (n = 167) Gemcitabine (n = 169) P-Value Low white cells + fever 5.4% 0.6% 0.009 Low platelets 9.1% 2.4% 0.008 Nerve effects 9% - 0.001 Vomiting 14.5% 4.7% 0.002 Diarrhea 12.7% 1.2% 0.0001 White cell booster needed 42.5% 5% Tumor Shrinkage 32% 9% 0.0001 Cessation tumor growth 6.4 m 3.3 m 0.0001 Conroy T, et al. J Clin Oncol. 2010;28(18s). Abst #4010

Localized, Non-operable Pancreatic Cancer (Locally Advanced, Stage III)

CT Angiogram Locally Advanced PC

Pancreas Cancer Disease Patterns Rapid autopsy series (N= 76) 30% died of locally advanced PC 70% died of metastatic disease SMAD4/ DPC4 gene expression loss increases with more advanced pancreas ca Stratification for treatment? Iacobuzio-Donahue CA, et al. J Clin Oncol. 2009;27:1806-1813. Blackford, et al. Clin Can Res, 2009

Optimal Therapy for Stage III Panc Ca? Two recent phase III studies opposing conclusions French study Gemcitabine alone ECOG 4201 Supports inclusion of chemoradiation Retrospective and limited prospective data suggest: Chemo chemo + radiation (stable/responsive disease) better outcome Huguet F, et al. J Clin Oncol. 2007;25:326-331; Krishnan S, et al. Cancer. 2007;110:47-55; Ko A, et al. Int J Rad Biol Oncol, Phys. 2007;68:809-816; Mukherjee S, et al. Clin Oncol. 2008;20:535-540.

GERCOR Phase III (ongoing) Localized PC N= 900 R A N D O M I Z E Gemcitabine x 4 cycles Gemcitabine + Erlotinib x 4 2 nd Randomization +/- ChemoRT Primary Endpoints: Survival +/- Erlotinib +/- Radiation P. Hammel (PI)

Front-Line Treatment Summary Important features Locally advanced vs metastatic, performance status Gemcitabine remains a primary agent Studies suggest benefit of adding platinum Addition of erlotinib slightly improves outcome Addition of capecitabine modestly adds FOLFIRINOX improves survival, tumor shrinkage Significant toxicity Challenge will be balancing benefit vs. side effects

Front-Line Phase III Trials NCT Trial Design N Target Sponsor 00789633 Gem +/- Masitinib 320 Ckit, PDGFR, FAK AB Science 00498225 Gem vs S1 vs Gem + S1 750 Cytotoxic Taiho 00486460 Gem +/- Curcumin, Celecoxib NFKβ, COX-2 Tel Aviv Royal Liverpool 00425360 Gem/Capecit. +/- GV1001 1,110 Telomerase University Hospital (Telovac) 00844649 Gem +/- Nab-Paclitaxel 630 Tubulin, Cytotoxic Abraxis/Celgene 00662688 Gem +/- Capecit +/- Dalteparin 136 Cytotoxic/ LMWH GERCOR 00541021 Gem +/- Sorafenib 104 Raf-1, Antivascular Institut Paoli- Calmettes 01231347 Gem +/- AMG 479/placebo 825 IGF1R Amgen Gem +/- EndoTag-1 Tubulin, Antivasc. Medigene www.clinicaltrials.gov (accessed 12-30-2010)

The Future in Pancreas Cancer Enhanced understanding of inherited susceptibility Improved molecular classification Improved screening Incremental therapeutic improvements Profiling tumors, e.g., wild-type ras, SPARC+, SMAD4 retained, etc.