Pancreatic Cancer: Current Therapies, Clinical Trials & Future Directions

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1 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

2 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

3 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)

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

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

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

7 Resected PC Survival (MSKCC) , N= 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

8 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

9 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

10 CT Pancreas Angiogram Borderline Resectable Hypovascular pancreas head tumor SMV SMA

11 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, Single Arm Phase II Trials ACOSOG Z05041 Gemcitabine/erlotinib neoadjuvant Endpoint: Survival 2 yrs 90

12 US Intergroup/RTOG 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

13 Inoperable Pancreas Cancer

14 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

15 Overall Survival CALGB by Performance Status (Pooled Data) Proportion Surviving 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= p= M onths from S tudy E ntry Kindler, et al. J Clin Oncol, 2010

16 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, Sultana, et al. J Clin Oncol, 2007

17 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

18 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.

19 Targeted Therapy in Pancreatic Adenocarcinoma: Is There a Role?

20 Phase III Anti-Vascular Trials in PC Drug N RR Med OS Reference Gemcitabine + Bevacizumab Gemcitabine + Placebo % 10% 5.8 mths 6.1 mths Gemcitabine + Erlotinib + Bevaciz. 13.5% 7.1 mths Gemcitabine + Erlotinib % 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 Van Cutsem AViTA Kindler Rougier Kindler, HJ. J Clin Oncol, Van Cutsem, E. J Clin Oncol, Kindler, HJ. Lancet Oncology Rougier, P. ESMO, GI, 2010

21 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

22 PA.3 Overall Survival Survival Distribution Function G + Erlotinib (N= 261) G + Placebo (N= 260) 1-Year Survival 23% 17% Tumor Control 57% 49% HR= 0.82 ( ) p= 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

23 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

24 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)

25 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

26 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

27 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 R 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

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

29 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)

30 J. Natl. Cancer Inst. 91: , 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

31 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

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

33 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

34 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

35 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)

36 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

37 FOLFIRINOX vs Gemcitabine: Overall Survival 1.00 FOLFIRINOX Gemcitabine Probability Median 11.1 mo HR = 0.57 P < Median 6.8 mo 0.00 Number at risk Gemcitabine FOLFIRINOX Months Conroy T, et al. J Clin Oncol. 2010;28(18s). Abst #4010

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

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

40 CT Angiogram Locally Advanced PC

41 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: Blackford, et al. Clin Can Res, 2009

42 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: ; Krishnan S, et al. Cancer. 2007;110:47-55; Ko A, et al. Int J Rad Biol Oncol, Phys. 2007;68: ; Mukherjee S, et al. Clin Oncol. 2008;20:

43 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)

44 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

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

46 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.