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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 ASCO 2010 • Turning point for clinical research in pancreatic cancer • FOLFIRINOX emerged as an effective non-gemcitabine containing regimen for metastatic pancreatic cancer FOLFIRINOX Slide courtesy of Thierry Conroy Slide courtesy of Thierry Conroy Slide courtesy of Thierry Conroy Conroy T, et al. N Engl J Med 2011; 364:1817-25 Conroy T, et al. N Engl J Med 2011; 364:1817-25 Conroy T, et al. N Engl J Med 2011; 364:1817-25 Issues • 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 Is this a new worldwide standard of care for high performance status patients? Conroy T, et al. N Engl J Med 2011; 364:1817-25 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. 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%?) Clearly, FOLFIRINOX cannot be the standard of care for all Other options? Gemcitabine plus nab-Paclitaxel in Pancreatic Cancer Von Hoff , D.et al. J Clin Onc 29:34, 2011 Comparison of % Grade 3/4 Toxicity FOLFIRINOX GA Heme 46 56 Neuropathy 9 20 Vomiting 15 7 Diarrhea 13 1 Fatigue 24 27 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. This is not a contest about what is best for everyone! 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 It is very good to have these options! Lots of Questions • 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? Gemcitabine: activation and mechanism of action •Gemcitabine: a deoxycytidine analogue •Requires intracellular uptake followed by sequential phosphorylation to active metabolite form inhibition of RR Gem Gem NT Gem-MP * Gem-DP Gem-TP incorporation into DNA * Deoxycytidine kinase (rate limiting step) •Blocks DNA synthesis/replication at several steps A Retrospective Analysis of RTOG9704 Confirmed hENT1 as a Predictive Biomarker for Gemcitabine Response – – There was no association between hENT1 expression and response to 5-fluorouracil hENT1 is not a prognostic biomarker Gemcitabine 100 5-fluorouracil 100 High hENT1 (>50%) Low hENT1 No staining 75 % of patients surviving • 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 % of patients surviving • 50 25 High hENT1 (>50%) Low hENT1 No staining 75 50 25 0 0 0 1 2 3 4 5 0 Years from randomization 1 2 3 4 5 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. 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 Issues in Pancreas Cancer Therapy • Drug resistance • Drug delivery Hanahan and Weinberg, Cell, 2011 Can we be strategic? Enrichment • Subclasses • Pathways Biology • Stringent criteria for target validation • Prioritization of targets • Explore stromal targets Thank you.