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Margaret Tempero, M.D. Professor of Medicine University of California, San Francisco

Debate: This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma. CONTRA. Margaret Tempero, M.D. Professor of Medicine University of California, San Francisco. Turning point for clinical research in pancreatic cancer

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Margaret Tempero, M.D. Professor of Medicine University of California, San Francisco

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  1. Debate: This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma. CONTRA Margaret Tempero, M.D. Professor of Medicine University of California, San Francisco

  2. Turning point for clinical research in pancreatic cancer FOLFIRINOX emerged as an effective non-gemcitabine containing regimen for metastatic pancreatic cancer ASCO 2010

  3. FOLFIRINOX Slide courtesy of Thierry Conroy

  4. Slide courtesy of Thierry Conroy

  5. Slide courtesy of Thierry Conroy

  6. Conroy T, et al. N Engl J Med 2011; 364:1817-25

  7. Conroy T, et al. N Engl J Med 2011; 364:1817-25

  8. Conroy T, et al. N Engl J Med 2011; 364:1817-25

  9. Study was unintentionally biased with low number of head of pancreas lesions and thus, fewer patients with biliary ductal obstruction and stents Toxicity is very concerning. 42.5% of patients in the experimental arm received G-CSF and almost 1/4 of the patients had grade 3/4 fatigue. 10 – 15% experienced grade 3/4 vomiting, diarrhea, or neuropathy Issues

  10. Is this a new worldwide standard of care for high performance status patients?

  11. FOLFIRINOX is a first-line option for patients with metastatic pancreatic cancer who are younger than 76 years and who have a good performance status (ECOG 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels. Conroy T, et al. N Engl J Med 2011; 364:1817-25

  12. What does a typical pancreatic cancer patient look like? • 41% are greater than 76 years old • 50% have biliary stents • 20% have co-existing heart disease • 30% do not receive any treatment • Proportion with PS 2 or worse is unknown (50%?)

  13. Clearly, FOLFIRINOX cannot be the standard of care for all

  14. Other options?

  15. Gemcitabine plus nab-Paclitaxel in Pancreatic Cancer Von Hoff , D.et al. J Clin Onc 29:34, 2011

  16. Comparison of % Grade 3/4 Toxicity FOLFIRINOX GA 56 20 7 1 27 Heme 46 Neuropathy 9 Vomiting 15 Diarrhea 13 Fatigue 24

  17. Conundrum Drug development, to be successful, must be done in patients with a good PS. Once established, useful regimens must be transportable to the average patient.

  18. Future regimens of choice for individuals or for studies will depend on several factors: Patient tolerability Predictive molecular signatures for chemotherapy Synergism with new agents, especially targeted therapeutics This is not a contest about what is best for everyone! It is very good to have these options!

  19. What is the best way to modify FOLFIRINOX? Delete Bolus 5Fu? Reduce doses? Does modification affect efficacy? Could you alternate FOLFOX and FOLFIRI? Is interrupted therapy feasible? How will a validated predictive test for gemcitabine effectiveness change the landscape? Lots of Questions

  20. Gemcitabine: activation and mechanism of action • Gemcitabine: a deoxycytidine analogue • Requires intracellular uptake followed by sequential phosphorylation to active metabolite form • Gem Gem Gem-MP Gem-DP Gem-TP • Blocks DNA synthesis/replication at several steps inhibition of RR * NT incorporation into DNA * Deoxycytidine kinase (rate limiting step)

  21. A Retrospective Analysis of RTOG9704 Confirmed hENT1 as a Predictive Biomarker for Gemcitabine Response • RTOG 9704 trial compared gemcitabine with bolus 5-fluorouracil as adjuvant chemotherapy after pancreatic cancer resection • In a cohort of patients who received gemcitabine (N=91), hENT1 expression was associated with increased survival • There was no association between hENT1 expression and response to 5-fluorouracil • hENT1 is not a prognostic biomarker Gemcitabine 5-fluorouracil 100 100 High hENT1 (>50%) Low hENT1 No staining High hENT1 (>50%) Low hENT1 No staining 75 75 50 50 % of patients surviving % of patients surviving 25 25 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years from randomization Years from randomization High adjusted HR = 0.34; 95% CI, 0.17-0.68; P=0.002 Low adjusted HR = 0.47; 95% CI, 0.24-0.92; P=0.03 High adjusted HR = 0.68; 95% CI, 0.40-1.19; P=0.18 Low adjusted HR = 0.90; 95% CI, 0.52-1.55; P=0.70 1. Farrell, et al. Gastroenterology. 2009;136:187.

  22. Stay Tuned • 40% of patients have hENT1 positive tumors • Clovis is validating an IHC assay for hENT1 as a predictor for gemcitabine benefit • hENT1 may be the first useful predictive biomarkers for selection of gemcitabine based treatment

  23. Drug resistance Drug delivery Issues in Pancreas Cancer Therapy

  24. Hanahan and Weinberg, Cell, 2011

  25. Enrichment Subclasses Pathways Biology Stringent criteria for target validation Prioritization of targets Explore stromal targets Can we be strategic?

  26. Thank you.

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