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