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

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

Slide courtesy of Thierry Conroy FOLFIRINOX

Slide courtesy of Thierry Conroy

Conroy T, et al. N Engl J Med 2011; 364:

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: 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 Heme46 Neuropathy 9 Vomiting15 Diarrhea13 Fatigue24 GA

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

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 1. Farrell, et al. Gastroenterology. 2009;136: Years from randomization fluorouracil High adjusted HR = 0.68; 95% CI, ; P=0.18 Low adjusted HR = 0.90; 95% CI, ; P=0.70 Years from randomization High hENT1 (>50%) Low hENT1 No staining Gemcitabine High adjusted HR = 0.34; 95% CI, ; P=0.002 Low adjusted HR = 0.47; 95% CI, ; P= % of patients surviving % of patients surviving High hENT1 (>50%) Low hENT1 No staining

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.