margaret tempero, m.d. professor of medicine university of california, san francisco debate: this...
TRANSCRIPT
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
% o
f p
atie
nts
su
rviv
ing
75
50
25
100
00
% o
f p
atie
nts
su
rviv
ing
1 2 3 4 5
75
50
25
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.