Transcript ASCO ‘04 GI Highlights

ASCO ‘04 in Perspective
GI Highlights
George A. Fisher M.D. Ph.D.
Stanford University School of Medicine
ASCO ‘03 GI Highlights
A Tough Act to Follow
• First (+) adjuvant colon trial in >10 years
– Mosaic Trial: LV5FU2 vs. FOLFOX4
• “Targeted” therapies in metastatic colon
– First line: IFL + Bevacizumab
– Second line: Cetuximab + Irinotecan
• Encouraging early results Phase III pancreas
– GemOx vs Gem: response and DFS improvements
GEM vs GEMOX (Louvet et al #4008)
The GERCOR Pancreatic Trial
R
A
N
D
O
M
I
Z
A
T
I
O
N
Gemcitabine 1000 mg/m2 over 30 min
Weekly x 7, then 3 weeks of 4
Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1
Oxaliplatin 100 mg/m2 2 hour infusion day 2
Every 2 weeks
GEM vs GEMOX Efficacy
Response rate
Locally adv.
Metastatic
Prog. Free Surv.
Clinical Benefit
Overall Survival
1-yr survival
GEM
17.3%
14.9%
18.3
3.7 mos
26.9%
7.1 mos
27.8%
GEMOX
26.8%
27.4%
26.4%
5.8 mos
38.2%
9.0 mos
34.7%
p value
.044
.038
.03
ns
ns
Current ECOG Trial
Metastatic Pancreas Cancer
R
A
N
D
O
M
I
Z
A
T
I
O
N
Gemcitabine 1000 mg/m2 over 30 min
Weekly x 7, then 3 weeks of 4
Gemcitabine 1000 mg/m2 (10 mg/m2/min)
Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1
Oxaliplatin 100 mg/m2 2 hour infusion day 2
Every 2 weeks
Rectal Cancer ASTRO ‘03
The German pre-op vs. post-op trial
T3Nx
Rectal
R
A
N
D
O
M
I
Z
A
T
I
O
N
50.4 Gy
CI 5-FU
Surgery
Surgery
50.4 Gy
CI 5-FU
5-FU x 4
5-FU x 4
Rectal Cancer ASTRO ‘03
The German pre-op vs. post-op trial
Saur et al
ASTRO ‘03
5 yr Local Failure
Post-op
N= 394
12%
Pre-op
N= 405
6%
p value
5 yr survival
74%
74%
ns
Acute Toxicity
40%
28%
.005
Chronic Toxicity
23%
10%
.04
Sphincter
Preservation
20%
(17/85)
39%
(43/109)
.004
.006
Capecitabine vs. Infusional 5-FU
Concurrent with Neoadjuvant XRT
[Randomized Phase III NSABP R-04]
T3-4
or
N1
Rectal
R
A
N
D
O
M
I
Z
A
T
I
O
N
Capecitabine
+ radiation
(825/m2
bid)
5-FU infusion (225/m2 daily)
+ radiation
S
U
R
G
E
R
Y
Endpoints:
-path response
-local relapse
- down staging
- sphincter sparing
- quality of life
- biomarkers
Preoperative Chemoradiotherapy:
A Phase I/II Rectal Trial
Kuo et al. Stanford University
S
U
R
G
E
R
Y
Radiation therapy
Cetuximab q week
Capecitabine M-F
Oxaliplatin q 2wks
US T3/4
or N1
Rectal
Cancer
Biopsy
Day 0
Biopsy
Day 8
PET
PET
Endpoints:
-toxicity
-op morbidity
-path response
-downstaging
-sphincter
-molecular,
imaging and
circulating
cell correlates
Origin of FOLFOX
Bolus 400
LV5FU2
(1984)
200
Bolus 400
600
200
600
1997 (De Gramont et al. JCO): Better response rate
with less toxicity than bolus 5-FU (Mayo regimen)
Bolus 400
FOLFOX4
(1995)
200
85
Bolus 400
600
200
600
2000 (De Gramont et al. JCO):Better response rate
and DFS than LV5FU2
2004 (Goldberg et al. JCO): Better response rate /
DFS / OS with less toxicity than IFL (Saltz regimen)
Evolution of FOLFOX Regimens
Bolus 400
FOLFOX4
(1995)
200
85
Bolus 400
600
200
600
Bolus 400
FOLFOX6
(1997)
FOLFOX7
(1998)
400
100
2400-3000
400
130
2400
24 hr
Doses mg/m2: 5-FU, oxaliplatin, leucovorin
48 hr
FOLFOX4
Reasons for Discontinuation
• Reanalysis of Intergroup Study N9741
– 43% patients off study due to progressive disease
– 57% for “other” reasons”
•
•
•
•
•
•
23%
23%
7%
9%
29%
9%
neurotoxicity
myelosuppression
hypersensitivity
Complete response or secondary resection of mets
Patient refusal: unspecified
Other
Axel Grothey et al
Optimox I [De Gramont #3525]
Optimizing Oxaliplatin:
Concept of Intermittent Therapy
R
A
N
D
O
M
I
Z
A
T
I
O
N
FOLFOX4 to progressive disease or intolerance
Bolus 400
200
85
Bolus 400
600
FOLFOX7 x 6
400
130
200
LV5FU2 to PD
2400
600
FOLFOX7
Optimox 1 [De Gramont #3525]
Optimizing Oxaliplatin
Concept of Intermittent Therapy
Response rate
PFS (mos)
OS (mos)
G3/4 N-Tox
FOLFOX4
58.5%
9.0
20.0
18.7%
FOLFOX7
58.3%
9.2
21.6
13.3%
-more acute thrombocytopenia, N / V, cold sensitivity with
FOLFOX 7 vs. FOLFOX 4
-variable adherence to protocol by center (resuming FOLFOX7)
-protocol adherence correlated with improved survival
Optimox 2 Trial [using mFOLFOX7]
R
A
N
D
O
M
I
Z
A
T
I
O
N
FOLFOX7
400
130
2400
mFOLFOX7
400
100
3000
mFOLFOX7 x 6
mFOLFOX7 x 6
no rx until PD
LV5FU2
mFOLFOX7
mFOLFOX7
Oxaliplatin Neuropathy
Possible Protection by Ca/Mg
• Ca2+ gluconate + Mg2+ sulfate 1 gram each
before and after oxaliplatin
• Post-hoc analysis of 161 patients
– Gamelin et al, Clin Cancer Research 2004
– % pts stopping due to neurotoxicity
• 35% controls vs 5% for Ca / Mg treated
• No decrement in response rate
CONcePT: Optimization of
FOLFOX + Bevacizumab
2 x 2 randomization: 532 patients
mFOLFOX7 + Bevacizumab
Continued until treatment failure
+ placebo
mFOLFOX7 + Bevacizumab
Continued until treatment failure
+ Ca/Mg
mFOLFOX7 + Bevacizumab
Intermittent oxali therapy
placebo
mFOLFOX7 + Bevacizumab
Intermittent oxali therapy
Ca/Mg
*mFOLFOX7
400 (LV)
85 (Ox)
5 (Bev)
+
3000 (5-FU)
+
Integrating Parallel Successes
Bevacizumab: Role in first line
FOLFOX >> IFL
IFL + Bevacizumab > IFL
??FOLFOX + Bev > FOLFOX
FOLFOX ~ FOLFIRI
??FOLFIRI + Bev > FOLFIRI
Bevacizumab: Current
Cooperative Group Trials
Second Line ECOG Trial completed; results ASCO ‘05
FOLFOX4 + Bev
Results expected fall/winter ‘04; ASCO ‘05
First Line SWOG Trial: (underway)
[mFOLFOX6 vs. CAPOX] + Bevacizumab
Adjuvant NSABP Trial: (activation 10/04?)
Stage II / III colon cancer
mFOLFOX6 + Bevacizumab
EGFR Inhibition with First Line
FOLFOX Chemotherapy
ASCO
‘04
Fisher et al
#3514
Tabernero
et al #3512
Treatment
*Gefitinib +
FOLFOX 4
**Cetuximab
+ FOLFOX 4
Number of
Patients
36
Response
Rate
78%
42
81%
*Gefitinib at 500 mg; higher GI toxicity c/w FOLFOX
**Eligibility required EGFR(+) tumors
Proposed Intergroup Trial
R
A
N
D
O
M
I
Z
A
T
I
O
N
Investigator’s
Choice:
+ Bevacizumab
mFOLFOX6
CAPOX
+ Cetuximab
FOLFIRI
[CAPIRI]
+ Bevacizumab + Cetuximab
“Reasonable” Options for
Metastatic Disease
•
First line therapy
–
Good performance status
•
•
–
FOLFOX (n) vs CAPOX
+ Bevacizumab
FOLFIRI vs CAPIRI
+ Bevacizumab
Poor KPS
•
Capecitabine or 5-FU
+ Bevacizumab
– Liver mets only
•
• Second line therapy
– If first line irinotecan
•
•
•
•
Capecitabine
CAPOX or FOLFOX
Cetuximab (if EGFR +)
Cetuximab + irinotecan
– If first line oxaliplatin
• Irinotecan
• Irinotecan + cetuximab
Consider resection of
responders
ALWAYS CONSIDER CLINICAL TRIALS
Recently Completed Adjuvant
Trials for Colon Cancer
• Intergroup Stage III:
– IFL vs Roswell Park 5-FU/LV (Saltz #3500)
• NSABP Stage II/III:
– *Bolus 5-FU/oxali vs Roswell Park 5-FU/LV
• European Trials Stage II/III
– *FOLFIRI vs LV5-FU2
– UK Study: Continuous infusion 5-FU x 3 mos vs bolus
5-FU/LV x 6 months
– FOLFOX vs LV5-FU2
• Capecitabine vs bolus 5-FU Stage III (Cassidy #3509)
*no efficacy data available to date
Bolus 5-FU (Mayo) vs
Capecitabine for Stage III
X-ACT Trial (Cassidy # 3509)
Standard Mayo Clinic bolus 5-FU regimen x 6
versus
Capecitabine (1250 mg/m2 bid x 14 d q 3wks) x 8
Median follow-up 3.8 years
• Significantly decreased gr 3/4 diarrhea, stomatitis and
neutropenia
• 3 year DSF [HR = 0.87; p = 0.0526]
• 3 year Overall survival [HR = 0.84; NS]
“Reasonable” Options for
Adjuvant Therapy
• Stage II
– Assess risk
• Clinical parameters
• Molecular markers
• Stage III
– Good performance
status
• FOLFOX vs. CAPOX
– High risk
• FOLFOX vs CAPOX vs.
Capecitabine
– Low risk
• Observation vs.
capecitabine
– Poor performance
status
• Capecitabine vs.
observation
ALWAYS CONSIDER CLINICAL TRIALS
ASCO ‘03-04: Implications
• No role for IFL / Vanishing role for bolus 5-FU
• “Acceptable”, even “recommended” options include
regimens with no Phase II data
– FOLFOX or FOLFIRI + Bevacizumab first line colon
– Irinotecan + cetuximab after FOLFOX failure
• Consistently high activity with EGFR inhibitors and
fluoropyrimidine /oxali regimens
– Three phase II studies with > 75% response rates 1st line
• The Stage II dilemma continues
– Less toxic adjuvant options may shift risk-benefit
• Back to the drawing board:
– pancreas, gastric, esophageal and hepatocellular