Download folfirinox

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.