Transcript Systemic Therapy of Metastatic Colorectal Cancer

GI Highlights
ASCO 2006
George A. Fisher MD PhD
Stanford University Cancer Center
ASCO ‘06 GI Highlights
Less impressive than ‘03-05
• Metastatic colon
– Bevacizumab update
– EGFR inhibition
– Chemo vacations
• Pancreas
– Metastatic
• Gem v. Fixed dose rate
gemcitabine v. gemox
– Adjuvant
• 5-FU-radiation + (5-FU
vs Gem)
• Esophageal
– Neoadjuvant CRT vs
surgery alone
• Advanced Gastric
– Alternatives to 5-FU and
cisplatin
• Anal squamous cell
– Cisplat/5-FU induction
and concurrent vs.
mitomycin/5-FU
concurrent with radiation
Bevacizumab Update
• TREE Trial: Final Analysis (Hochster et al)
– (FOLFOX vs bFOL vs CAPOX) + Bev
• BEAT Trial (Michael et al)
– Feasibility of Metastatectomy in Bev treated
patients
Infusional vs Bolus vs Oral
Fluoropyrimidine based Therapies
THE TREE TRIALS
(Hochster et al #3510)
• Randomized Phase II Study in first line
metastatic colorectal cancer
– TREE 1 = FOLFOX vs bFOL vs CAPOX
– TREE 2 = same plus bevacizumab
Infusional vs Bolus vs Oral
Fluoropyrimidine based Therapies
THE TREE TRIALS
(Hochster et al #3510)
• TREE 2 (223 patients)
• mFOLFOX 6 + Bev at 5 mg/kg q 2 weeks
• bFOL (bolus 5-FU weekly x 3 with oxali q 2
weeks) and Bev at 5 mg/kg q 2 weeks)
• CAPOX: with 825 mg/m2 capecitabine d 114, oxali 130/m2 d 1 and Bev 7.5 mg/kg q 3
weeks
Tree 2 Trial : Efficacy
(Hochster et al #3510)
mFOLFOX
+ Bev
bFOL
+ Bev
CAPOX
+ Bev
P value
Response
Rate
53%
41%
48%
ns
Time to
Progression
9.9 mos
8.3 mos
10.3 mos
ns
Overall
Survival
26.0 mos
20.7 mos
27.0 mos
ns
TREE 2 Trial: Conclusion
• CAVEAT
– randomized Phase II: not powered for small
differences in effect
• Bolus 5-FU + oxaliplatin + Bevacizumab
– probably inferior with greater toxicity and trend
toward lower efficacy
• FOLFOX + Bev vs CAPOX + Bev
– “comparable” efficacy / toxicity when capecitabine
dose reduced to 825 mg/m2 bid
– “equivalence” of efficacy not yet established
BEAT Trial: Feasibility of Metastatectomy in
Patients Treated with Bevacizumab
[Michael et al ASCO ‘06]
• 1,927 Metastatic chemo-naïve patients
from 41 countries
• FOLFOX (37%) or FOLFIRI (28%) or
CAPOX (19%) with Bev q 2 or 3 weeks
• 43 pts (2.4%) underwent metastatectomy
– 91% liver / 5% lung / 2% nodal / 2% peritoneal
– 57% no residual dz / 20% residual / 23% ??
– Median time from last bev dose: 67 days
• Protocol specified minimum of 6 weeks (42 days)
BEAT Trial: Feasibility of Metastatectomy in
Patients Treated with Bevacizumab
[Michael et al]
Results:
• No complications: 67%
• Complications: 30%
– Bleeding / wound healing: 0%
– Operative site infection: 12%
– Gastric perf / portal vein thrombus / MI: 6%
– Ascites / pleural effusion / fever / bowel
obstruction: 2% each
BEAT Trial Conclusion
• No significant bleeding or wound
healing complications when
bevacizumab held for minimum of 6
weeks before elective metastatectomy
• Only 2.4% (44 patients) of entire study
group reported metastatectomy
Michael et al (ASCO ‘06)
Update on EGFR Inhibition
• First line trials
• New inhibitors
• Efficacy in EGFR (-) patients
EGFR Inhibitors
• Antibodies:
– Cetuximab
– Panitumumab: Fully humanized
• EGFR specific Tyrosine Kinase Inhibitors
– e.g. Gefitinib / Erlotinib
• Multi-targeted Tyrosine Kinase Inhibitors
– e.g. ZD 6474 / XL647 / others…
First Line EGFR Inhibitors
FOLFIRI vs FOLFOX + Cetuximab
(CALGB 80203: Venook et al #3509)
• Originally randomized phase III study in
first line metastatic colorectal cancer
with accrual goal of 2200 pts
• Accrual slowed with approval of first line
bevacizumab
• Study closed at 238 pts and redesigned
as randomized Phase II trial
FOLFIRI vs FOLFOX + Cetuximab
(CALGB 80203: Venook et al #3509)
Response
rate
FOLFIRI
FOLFIRI
+ Cetux
FOLFOX
FOLFOX
+ Cetux
36%
44%
40%
60%
All Patients (combined FOLFIRI + FOLFOX)
- Response rate: 38% vs. 52% with Cetuximab
(p = .02)
- Progression free and overall survival too
premature to present
FOLFIRI vs FOLFOX + Cetuximab
CALBGB 80203: Conclusions
• Difficult to complete Phase III trials
when “standard of care” changes
• Usual caveat of randomized Phase II
comparisons (small numbers)
• Activity of EGFR inhibitors in first line
chemotherapy supported
• Underscores importance of current
national Phase III first line trial
Cooperative Group Trial for
Metastatic Colorectal Cancer
Investigator’s
Choice:
mFOLFOX6
or
FOLFIRI
R
A
N
D
O
M
I
Z
A
T
I
O
N
+ Bevacizumab
+ Cetuximab
+ Bevacizumab
+ Cetuximab
Panitumumab in Metastatic
Colorectal Cancer
• Patients with documented progression on irinotecan
and oxaliplatin regimens
• Panitumumab 6 mg/kg q 2wk vs BSC
• Response rate 8%; median duration 4.2 mos
Panitumumab
BSC
# patients
231
232
2 month PFS
49%
30%
4 month PFS
18%
5%
Peters M. et al AACR 2006
Efficacy of EGFR Inhibitors: No
Correlation with EGFR Expression
(Hecht # 3547 ASCO ‘06)
• Multicenter phase II study of panitumumab
• Metastatic colorectal cancer with disease
progression after oxali and irinotecan
regimens
• EGFR membrane staining in <1% or 1-9%
of evaluated tumor cells by IHC
• Interim analysis of 23 patients presented
Panitumumab Efficacy in low or
no EGFR expressing tumors
*< 1%
*1-9%
**>10%
Number of
Patients
Response
Rate
11
8
39
2
(18%)
1
(8%)
3
(8%)
Stable
Disease
4
(36%)
3
(25%)
8
(21%)
*Hecht et al #3547
**Berlin et al #3548
Chemotherapy Free Intervals
When Less is More
• OPTIMOX Trials: (“optimal use of oxaliplatin”)
– minimizing oxaliplatin neurotoxicity
– testing the idea of a “chemotherapy vacation”
• Alternating Therapy: (2 months on - 2 months off)
– decreasing the dose density of FOLFIRI
Entry criteria for both studies: “unresectable” metastatic disease
OPTIMOX Trial Designs
(Maindrault-Goebel et al #3504)
OPTIMOX 1
FOLFOX 4 until “treatment failure”
R
FOLFOX 7
for 6 cycles
LV5FU2
Until progression
FOLFOX 7
mFOLFOX 7
for 6 cycles
LV5FU2
Until progression
FOLFOX 7
mFOLFOX 7
for 6 cycles
*Observation
Until progression
FOLFOX 7
OPTIMOX 2
R
OPTIMOX-Trials: DDC
Tournigand JCO 2006
T size
PFS 1
DDC=PFS1+PFS2
?
PFS 2
t
FOLFOX
FOLFOX
PD
Baseline
progression
Progression
at reintroduction
OPTIMOX Results
(Maindrault-Goebel et al #3504)
# patients
Response rate
Reintroduction
of oxaliplatin
Response rate to
second oxaliplatin
Progression Free
Survival (PFS)
Duration Disease
Control (PFS1+PFS2)
OPTIMOX 1
100
61%
32%
OPTIMOX 2
102
61%
52%
13%
31%
8.7 mos
6.9 mos (p < .05)
12.9 mos
11.7 mos (p = .4)
OPTIMOX Subset Analysis
(Maindrault-Goebel et al #3504)
Median chemo free intervals:
– Non-responders (SD): 3.9 mos
– Responders: 5.1 mos
– Overall: 4.6 mos
– *favorable patients: 8.0 mos
*performance status, 1 site of metastatic disease,
LDH and Alkaline Phos < 3x upper limit of normal
OPTIMOX Conclusions
• Presumed quality of life advantage
associated with median ~5 month
chemo vacation may offset diminished
progression free survival
• Next study will include targeted therapy
administered as maintenance during
chemo free interval
Alternating vs. Continuous FOLFIRI
in Metastatic Colorectal Cancer
(Labianca et al #3505)
Study Schema
FOLFIRI
Q 2 weeks
X 2 mos
Chemo
Vacation
X 2 mos
337 patients
randomized
FOLFIRI q 2 weeks
until treatment failure
FOLFIRI
Q 2 weeks
X 2 mos
etc.
Alternating vs. Continuous FOLFIRI
in Metastatic Colorectal Cancer
(Labianca et al #3505)
Intermittent
Continuous
33.6%
36.5%
Progression Free
Survival (PFS)
6.2 mos
*6.5 mos
Overall Survival
16.9 mos
*17.6 mos
2nd line therapy
56%
55%
Median # cycles
8
8
Response rate
* Hazard Ratio = 1.0
Studies of Chemotherapy Free
Intervals: Conclusions
• Diminishing dose density does not
appear to impact duration of disease
control
• Presumption of improved quality of life
• New trials need to confirm and extend
these observations incorporating
targeted therapies
Celecoxib: No Benefit
• [FOLFIRI vs IFL vs CAPIRI] + celecoxib
(Fuchs et al #3506 ASCO ‘06)
– The death of IFL (?)
• Inferior efficacy with higher toxicity
– Caution with capecitabine substitutions
• Dose reductions necessary in combination regimens
• [FOLFIRI vs CAPIRI] + celecoxib
(De Greve et al #3577 ASCO ‘06)
– Another Phase III trial suspended early
– Chemo + celecoxib vs chemo + placebo response
rates 26 vs 46% favoring placebo…??
Where to Go from Here…
• New targets / new agents
– Death pathway agonists
– mTOR inhibitors
• Molecular predictors of response
– EGFR activation (?)
– VEGF polymorphisms
– LDH (?)
• Combining targeted therapies
Where to Go from Here…
• Novel trial designs to incorporate
chemo-free intervals
• Identifying who among metastatic colon
cancer patients can be “cured”
– Aggressive multidrug therapy with
resection / ablations for the potentially
curable
– Chemo-free intervals to prolong quality
living during disease control
And finally, extending successes
beyond metastatic disease
• Incorporating targeted therapy into
multimodality care of rectal cancer
• Improving cure rates in early stage II/III
• Applying gains to other tumor sites
• Finding a way to pay for it all…
CapOxIriBevacizutux = ~$$$ / month
ASCO ‘06: Pancreas Cancer
• Metastatic disease
– ECOG 6201: fixed dose rate gemcitabine
vs FDR gem + oxaliplatin vs standard gem
• Adjuvant therapy
– RTOG 9704:
• Gem x 3 wks - 5-FU / radiation - gem x 3 mos
• 5-FU x 3 wks - 5-FU / radiation - 5-FU x 3 mos
Phase III Study in Advanced Disease
ECOG 6201
(Poplin ASCO ‘06: #LBA4004)
• “standard” gemcitabine
(1000 mg/m2 over 30 min)
• Fixed Dose Rate gemcitabine
(1500 mg/m2 at 10 mg/m2/min [150 minutes]
• Gemcitabine (FDR) + oxaliplatin q 2 wks
Gemcitabine (1000 mg/m2 over 100 min) day 1
Oxaliplatin (100 mg/m2 over 2 hours) day 2
E6201: Gem vs FDR Gem vs
FDR Gem + Oxaliplatin
• Patients:
– 12% Performance status 2
– 12% with locally advanced (88% mets)
– Medium f/u 12.2 months
• Statistics
– Goal: improvement in median survival from
6 mos (control gem) to 8 mos in either
experimental arm (p<.025 and 81% power)
[Poplin et al ASCO ‘06]
Gem vs FDR Gem vs FDR
Gem + Oxaliplatin: Results
Gem
FDR Gem FDR Gem + Ox
# patients
279
277
276
*Progression
49%
51%
40%
*Toxicity
15%
20%
24%
Response
5%
10%
9%
Median OS
4.9 mos
6.0 mos
5.1 mos
1 yr survival
17%
21%
21%
*reasons cited to go off study
[Poplin et al ASCO ‘06]
Gem vs FDR Gem vs FDR
Gem + Oxaliplatin: Results
• Hazard ratio of FDR Gem vs Gem
– HR = .83 (.69 -1.0) p = .05
• Hazard ration of FDR Gem + Ox vs Gem
– HR = .88 (.73 - 1.05) p = .16
• Conclusion: Single agent Gemcitabine remains
standard of care in metastatic pancreas cancer
• Caveat: ?? role for FDR gem or gem + platinum
analogue when response rate is clinically
important (offset by increase in cytopenia / N /
V / neuropathy)
Phase III Trial in Resected
Pancreas Cancer: RTOG 904
– 492 pts stratified by nodes / margins / tumor size
(< 3 cm vs > 3 cm)
• Gem x 3 wks - 5-FU / radiation - gem x 3 mos
• 5-FU x 3 wks - 5-FU / radiation - 5-FU x 3 mos
– Primary endpoint overall survival
• Pancreatic head only (86% of patients)
• All patients
– Slight imbalance in study arms
• T3/4 disease: 81% in gem arm; 70% in 5-FU (p=.06)
RTOG 9704: Head of
Pancreas Tumors Only
RTOG 9704: All Patients
RTOG 9704: Conclusions
• Addition of gemcitabine to post-op
radiation / 5-FU improves survival in
tumors of the pancreatic head
• Reason for lack of statistical benefit for
entire group unclear
• Role of radiation remains controversial
and not addressed in this study
ASCO ‘06 Esophageal Cancer
Tepper et al #4012
• CALGB 9781 Phase III planned 500
patients with resectable esophageal ca
– Chemoradiation f/b surgery vs surgery alone
• Chemo (cisplat 100/m2 + 5-FU 1000/m2 d1-4)
• Chemo on weeks 1 and 5 with radiation
– Trial closed early due to poor accural
– Results of 56 patients reported
Trimodality Therapy vs Surgery
Alone for Esophageal Cancer
(Tepper et al #4012 ASCO ’06)
• Primary endpoint: overall survival
– Expected surgery control arm: 20%
– Goal: 40% increase in 5 year OS
– Median follow-up 6 years
Median OS
5 yr OS
CRT f/b
Surgery
4.5 yrs
Surgery alone
P value
1.8 yrs
=.02
39%
16%
<.008
Trimodality Therapy vs.
Surgery Alone in Esophageal
Cancer: Conclusions
• Poor accrual limits statistical power; yet
magnitude of difference statistically significant
despite small numbers
• Many questions still unanswered
– Accuracy of clinical staging
– Selection criteria for surgery candidates
– Role of newer agents
ASCO ‘06: Gastric Cancer
Two Phase III trials in metastatic disease
• 5-FU/cisplatin vs. mFOLFOX6
– (Al-Batran et al #LBA4016)
• Epirubicin + (cisplatin vs oxaliplatin) +
(5-FU vs capecitibine)
– (Cunningham et al #LBA4017)
Metastatic Gastric Cancer
FLP (cisplatin) vs. FLO (oxaliplatin)
FLP:
5-FU 2000/m2 (24 hr CI) q wk
leucovorin 200/m2 q wk
cisplatin 50/m2 q 2 wks
FLO:
5-FU 2600/m2 (24 hr CI) q 2 wks
leucovorin 200/m2 q 2 wks
oxaliplatin 85/m2 q 2 wks
Statistical Goal: Improve TTP from 3.6 to 5.1 months
[Al-Batran #LBA4016]
FLP vs. FLO in Gastric Cancer
(# patients)
FLP (112)
FLO (108)
Median time on therapy
3.0 mos
4.3 mos
Response
25%
34%
Time to Progression
3.8 mos
*5.7 mos
Time to Treatment Failure 3.1 mos
*5.3 mos
*statistically significant
[Al-Batran ASCO ‘06: #LBA4016]
Phase III Gastric Trial: Comparing
capecitabine with 5-FU and oxaliplatin
with cisplatin (Cunningham #LBA4017)
• Bifactorial design with all patients receiving
epirubicin (50/m2 q 3 wks)
• Randomized to capecitabine 625/m2 b.I.d.
continuously vs. 5-FU 200/m2 daily by
continuous infusion
• Second randomization to oxaliplatin (130/m2)
or cisplatin (60/m2) q 3 weeks
• Four arms: ECF / ECX / EOF / EOX
• Primary endpoint: non-inferiority in overall
survival (cap vs 5-FU / ox vs cisplatin)
Phase III Gastric Trial: capecitabine (X)
vs 5-FU and oxaliplatin vs cisplatin
(Cunningham #LBA4017)
ECF
ECX
EOF
EOX
263
250
245
244
Median # cycles 6
6
6
6
Response
41%
46%
42%
48%
1 yr survival
39.4% 44.6%
43.9%
40.1%
# patients
Hazard ratio: FU vs Xeloda (0.86); Oxali vs cisplatin (0.92) ns
ASCO ‘06: Randomized
Gastric Trial Conclusions
• Oxaliplatin may be substituted for cisplatin in
metastatic gastric cancer
– Improved outcomes in one study
– Non-inferior outcome in other
– Less toxicity in both
• Capecitabine may be substituted for
infusional 5-FU
• Treatment choices may be made based on
toxicity / convenience
ASCO ‘06: Phase III Trial in
Anal Cancer RTOG 98-11
[Ajani #4009]
• 682 patients (598 evaluable to date)
– 5-FU 1000/m2 daily CI x 4 days +
mitomycin 10/m2 week 1 and 4 of radiation
– 5-FU 1000/m2 daily CI x 4 days + Cisplatin
75/m2 q 4 wks starting 2 months prior to
radiation
– Primary objective: improve DFS @ 5 yrs
from 63% to 73% or decrease HR by 33%
Phase III Trial in Anal Cancer
[Ajani #4009]
ASCO ‘06 GI Highlights
Conclusions
• Prospective incorporation of chemo holidays
– concept of “duration of disease control”
• Phase III studies closed early
– When the “standard of care” is a moving target
• Capecitabine v 5-FU; oxali v cisplatin
– Picking your poisons…
• Dilemmas in Phase III Interpretations
– Statistical vs clinical significance
• Second generation targeted therapies in GI cancers
– Phase II ASCO ‘07 / ‘08