GI HighlightsASCO 2006
George A. Fisher MD PhD
Stanford University Cancer Center
ASCO ‘06 GI HighlightsLess 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
• 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 1-14, oxali 130/m2 d 1 and Bev 7.5 mg/kg q 3 weeks
Infusional vs Bolus vs Oral Fluoropyrimidine based Therapies
THE TREE TRIALS(Hochster et al #3510)
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)
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: Feasibility of Metastatectomy in Patients Treated with Bevacizumab
[Michael et al]
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 InhibitorsFOLFIRI 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
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 (CALGB 80203: Venook et al #3509)
FOLFIRI FOLFIRI
+ Cetux
FOLFOX FOLFOX + Cetux
Response rate
36% 44% 40% 60%
• 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
FOLFIRI vs FOLFOX + Cetuximab CALBGB 80203: Conclusions
Cooperative Group Trial for Metastatic Colorectal Cancer
RANDOMIZATION
Investigator’s Choice:
mFOLFOX6
or
FOLFIRI
+ 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 2322 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
11 8 39
Response Rate
2
(18%)
1
(8%)
3
(8%)
Stable Disease
4
(36%)
3
(25%)
8
(21%)
*Hecht et al #3547**Berlin et al #3548
Chemotherapy Free IntervalsWhen 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
OPTIMOX 2
FOLFOX 4 until “treatment failure”
FOLFOX 7for 6 cycles
LV5FU2Until progression
FOLFOX 7
mFOLFOX 7for 6 cycles
*ObservationUntil progression
FOLFOX 7
R
R
mFOLFOX 7for 6 cycles
LV5FU2Until progression
FOLFOX 7
OPTIMOX-Trials: DDC
t
T size
FOLFOX FOLFOX
PFS 1
PD Baseline progression
PFS 2
Progressionat reintroduction
DDC=PFS1+PFS2
Tournigand JCO 2006
?
OPTIMOX Results(Maindrault-Goebel et al #3504)
OPTIMOX 1 OPTIMOX 2
# patients 100 102
Response rate 61% 61%
Reintroduction
of oxaliplatin
32% 52%
Response rate to second oxaliplatin
13% 31%
Progression Free Survival (PFS)
8.7 mos 6.9 mos (p < .05)
Duration Disease Control (PFS1+PFS2)
12.9 mos 11.7 mos (p = .4)
Median chemo free intervals:– Non-responders (SD): 3.9 mos– Responders: 5.1 mos– Overall: 4.6 mos– *favorable patients: 8.0 mos
OPTIMOX Subset Analysis(Maindrault-Goebel et al #3504)
*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
337 patientsrandomized
FOLFIRIQ 2 weeksX 2 mos
FOLFIRI q 2 weeks until treatment failure
ChemoVacationX 2 mos
FOLFIRIQ 2 weeksX 2 mos
etc.
Alternating vs. Continuous FOLFIRI in Metastatic Colorectal Cancer
(Labianca et al #3505)
Intermittent Continuous
Response rate 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
* 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
• 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
ASCO ‘06: Pancreas Cancer
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 wksGemcitabine (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%
[Poplin et al ASCO ‘06]*reasons cited to go off study
• 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)
Gem vs FDR Gem vs FDR Gem + Oxaliplatin: Results
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 CancerTepper 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
CRT f/b Surgery
Surgery alone P value
Median OS 4.5 yrs 1.8 yrs =.02
5 yr OS 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 CancerFLP (cisplatin) vs. FLO (oxaliplatin)
FLP: 5-FU 2000/m2 (24 hr CI) q wkleucovorin 200/m2 q wkcisplatin 50/m2 q 2 wks
FLO: 5-FU 2600/m2 (24 hr CI) q 2 wksleucovorin 200/m2 q 2 wksoxaliplatin 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
[Al-Batran ASCO ‘06: #LBA4016]
*statistically significant
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
# patients 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%
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 HighlightsConclusions
• 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