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Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148

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

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Discussion Pancreatic Cancer Abstracts 145, LBA146, 147, & LBA148

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  1. DiscussionPancreatic CancerAbstracts 145, LBA146, 147, & LBA148 Philip Agop Philip, MD, PhD, FRCP Karmanos Cancer Center Wayne State University Detroit, Michigan

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

  3. JASPAC 01 Surgery • Stratification • Center • R0/R1 • N0/N1 Randomization 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

  4. JASPAC 01 Surgery No Radiotherapy! • Stratification • Center • R0/R1 • N0/N1 Randomization 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

  5. 100 50 0 0 1 2 3 4 5 JASPAC 01 Overall SurvivalPrimary Endpoint • P<0.0001 for non-inferiority • P<0.0001 for superiority (%) • 70% S-1 GEM • 53% years

  6. Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;

  7. Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies

  8. 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

  9. 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

  10. Study Design nab-Paclitaxel 125 mg/m2IV 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

  11. IMPACT: Efficacy

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

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

  14. Tolerability:Selected Grade 3+ Toxicities, % Conroy et al, NEJM, 364:1817-1825, 2011

  15. Efficacy Conroy et al, NEJM, 364:1817-1825, 2011

  16. Study Populations Conroy et al, NEJM, 364:1817-1825, 2011

  17. IMPACT • Is an example of pre-clinicalto pilot testing to Phase III drugstepwisedevelopmental 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!)

  18. 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 Abstract LBA146

  19. 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 +RT50.4Gy Capecitabine 830mg/m2 bd + RT 50.4Gy

  20. 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 +RT50.4Gy Capecitabine 830mg/m2 bd + RT 50.4Gy

  21. 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 +RT50.4Gy Capecitabine 830mg/m2 bd + RT 50.4Gy

  22. Summary of Efficacy Data

  23. What do we learn from SCALOP? • Cape-RT is thecurrent 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

  24. 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

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

  26. 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)

  27. Thank you

  28. backup

  29. 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

  30. 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!

  31. Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;

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