GI Highlights ASCO 2006 George A. Fisher MD PhD Stanford University Cancer Center.
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Transcript of GI Highlights ASCO 2006 George A. Fisher MD PhD Stanford University Cancer Center.
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