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

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

Heme 46

Neuropathy 9

Vomiting 15

Diarrhea 13

Fatigue 24

GA

56

20

7

1

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: 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

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;136:187.

0

Years from randomization

1 2 3 4 5

5-fluorouracil

High adjusted HR = 0.68; 95% CI, 0.40-1.19; P=0.18Low adjusted HR = 0.90; 95% CI, 0.52-1.55; P=0.70

Years from randomization

High hENT1 (>50%)Low hENT1No staining

Gemcitabine

High adjusted HR = 0.34; 95% CI, 0.17-0.68; P=0.002Low adjusted HR = 0.47; 95% CI, 0.24-0.92; P=0.03

100

0

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atie

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rviv

ing

75

50

25

100

00

% o

f p

atie

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1 2 3 4 5

75

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High hENT1 (>50%)Low hENT1No 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.