Evolving Paradigms in the Adjuvant therapy of Colon Cancer: Disappointment, Yet Opportunity ********** Howard S. Hochster, MD Professor of Medicine, Yale School of Medicine Associate Director, Yale Cancer Center

Is the addition of Oxaliplatin beneficial in treating stage II Colon Cancer? (Yothers, et.al. abst #3507)

Combined analysis of 4 sequential NSABP trials 2.5 without and 1.5 with oxaliplatin –Direct randomization in one trial only Trials included both stage II and III –N = 8671 but for stage II = 3000 Stage II patients included both: – high risk (N= 1542) & conventional risk (N= 1458)

Oxali Hazard Ratio by Stage OS DFS TTR Stage II Stage III Overall Pooled Stage II Stage III Overall Pooled Stage II Stage III Overall Pooled 4 HR < 1.0 Favors Oxali

Does the effect of Oxali vary by stage (II vs III)? Strong effect overall for Oxali including stages II & III on all 3 endpoints (OS, DFS, TTR) Oxali-Stage interaction not statistically significant: OS P=0.38, DFS P=0.20, TTR P=0.32 No definitive evidence that the relative effect of Oxali (hazard ratio) varies by stage of disease 5

Observed 5 year Adjusted* Kaplan-Meier Estimates by Risk Group Endpoint – Risk Group5-FU/Lv 5-FU/Lv + Oxali Increase with Oxali OS – HiRisk – LoRisk DFS – HiRisk – LoRisk TTR – HiRisk – LoRisk *Adjusted for age, gender, and race

Oxaliplatin for stage II Colon Cancer - conclusions Combined analysis – not randomized N = ~ 3000 (~1000 oxali) No statistical evidence of interaction by disease stage HR ~ 0.80 (DFS) and 0.95 (OS) Absolute benefit of 3-4%, but not statistically significant Analysis is underpowered for this degree of benefit

What about the high risk patients? Is there a role for oxaliplatin given a higher expected relapse rate? ECOG approach (18q- and MSS) Oncotype Colon Coloprint

QUASAR Results: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer Kerr et al., ASCO 2009, #4000 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% Recurrence Score Risk of recurrence at 3 years T3 and MMR deficient (11%) T4 and MMR proficient (13%) T3 and MMR proficient (76%) NB. 17 patients had both T4 and MMR Deficient tumors and had recurrence risks that were similar to those for patients with T3 and MMR proficient tumors and were not included in the plot

ColoPrint 18 gene panel (RNA) Confirmatory study of 233 patients, 135 stage II (Klinik rechts der Isar, Munich) Low Risk (73%) vs. High Risk (27%) 5 year DFS = 95% v 80% Rosenberg, et al, Proc ASCO 2010 HR 4.13 (95%CI , p=0.009)

Conclusion Combined analysis is not statistically significant for benefit of adding oxaliplatin in stage II colon cancer Study is underpowered, however Supports 3-4% absolute benefit for use of oxaliplatin Consider using FOLFOX for high risk stage II colon cancer with appropriate discussion

Another comment Though not statistically significant (inadequate sample size) the added absolute survival benefit may be 2-3% This level of curative benefit is acceptable to patients despite added treatment and toxicity –Jansen, Otten, Stiggelbout. JCO 22, 3181, 2004 Compare with threshold for breast cancer adjuvant therapy interventions

Bevacizumab adjuvant therapy in stage III colon cancer Results of C-08 (Allegra, et al, abst# 3508) and AVANT (Andre, et al, abst #3509)

NSABP C-08: Grade 3+ Toxicities Increased with Bevacizumab (%) <0.001 < P Wound Comp Proteinuria Pain Hypertension mFF6+BmFF6

NSABP

NSABP C-08 HR Wolmark, et al Proc ASCO 2009

NSABP

AVANT: Summary of Results For DFS (ITT Stage III) FOLFOX4 (N=955) FOLFOX4 + Bev (N=960) XELOX + Bev (N=952) Lost to follow-up, n (%)67 (7)48 (5)57 (6) Patients with event, n (%)237 (25)280 (29)253 (27) P-value for global hypothesis p= year DFS rate, %767375

AVANT: DFS (ITT Stage III) Data Cut-off Date: 30 June 2010 (3-Year Minimum Follow-Up) FOLFOX4 (N=955) FOLFOX4 + Bev (N=960) XELOX + Bev (N=952) HR (95% CI) 1.17 (0.98, 1.39) 1.07 (0.90, 1.28) FOLFOX4 FOLFOX4 + Bev XELOX + Bev Number at risk FOLFOX4 FOLFOX4 + Bev XELOX + Bev Event-free rate Time (months)

AVANT: DFS by N Stage (ITT Stage III) FOLFOX4 III N1 FOLFOX4 III N2 FOLFOX4 + Bev III N1 FOLFOX4 + Bev III N2 XELOX + Bev III N1 XELOX + Bev III N2 Number at risk N2 N Time (months) Event-free rate FOLFOX4 (N1) FOLFOX4 (N2) FOLFOX4 + Bev (N1) FOLFOX4 + Bev (N2) XELOX + Bev (N1) XELOX + Bev (N2) 60% 40%

AVANT: DFS: Cumulative Hazard Ratio (ITT Stage III) Time from randomization (years) FOLFOX4 + Bev XELOX + Bev Hazard ratio

ANGIOGENESIS & CRC ADJUVANT THERAPY Why didn’t bevacizumab work in this setting?

Folkman, NEJM, 1971 Folkman J. N Engl J Med 1971;285: Fig 2. Illustration of the Concept That Most Solid Tumors May Exist Early as Tiny Cell Populations Living by Simple Diffusion in the Extracellular Space (Further Growth Requires Vascularization, and the Tumor Then Maintains Itself by Perfusion).

Tumor is dormant Somatic mutation Small avascular tumor Folkman. N Engl J Med. 1971;285:1182; Hanahan and Folkman. Cell. 1996;86:353; Griffioen and Molema. Pharmacol Rev. 2000;52:237. Activators (eg, VEGF, bFGF, IL-8) Inhibitors Rapid tumor growth The Angiogenic Switch (a more contemporary illustration)

Angiogensis is complex; bevacizumab only binds one isoform of VEGF Ellis L, Hicklin, et al Nat Rev Cancer 2008

C-08 and AVANT: findings FOLFOX/CapeOX with bevacizumab is not more effective than same chemotherapy alone for endpoint of 3 year DFS In both studies, bevacizumab given with chemotherapy and for 6 more months alone is very effective at reducing recurrence (HR 0.6) WHILE RECEIVING BEVACIZUMAB Following discontinuation of bevacizumab recurrence rate increases and DFS is same –C-08 slightly lower and AVANT slightly higher – not statistically significant –OS =same in C-08 and slightly lower in AVANT (not mature) AVANT – greater benefit for N2 disease?

Comparative Results C-08/Avant (HR values) C-08AVANT N y y y DFS (3y) OS * *95% CI excludes 1.0 for FOLFOX+bev arm; all others = NS

SCIENTIFIC OBSERVATIONS Micrometastases – yes, studies consistent with theory Dormancy – yes, consistent Delay in recurrence while on anti-angiogenic– yes Cytotoxicity - no Increase in patients cured – no “Anti-angiogenesis” – yes!! Folkman – yes and no

CONCLUSIONS Anti-VEGF antibodies apparently inhibit growth of dormant metastases –2 large randomized clinical trials remarkably consistent with this theory Effect is transient –Cytostatic, not cytotoxic therapy Angiogenic switch is not stochastic; recurrence delayed but not prevented No change in cure rate Failed agent, but not failed strategy

ADJUVANT THERAPY of COLON CANCER 2011: A DECADE OF DISAPPOINTMENT Bevacizumab = NO (C-08, AVANT) Cetuximab = NO (Kras wt – N0147) Irinotecan = NO (PETACC3) Trials in unselected populations (mostly) Adjuvant trials based on advanced disease results –Could they be done based on lesser data? Compelling Biology? New paradigms needed –Biologically selected population –Trial of targeted agents in appropriate populations

Current trial: IDEA (International Duration Evaluation in Adjuvant) colon cancer Worldwide effort to address duration question of oxaliplatin (3 vs 6 mos) R 3 mos 6 mos Common question Group-specific question e.g. +/- BEV +/- Celecoxib +/- Agents X/Y/Z FOLFOX or XELOX

IDEA: International Duration Evaluation in Adjuvant colon cancer Participating groups: –GISCAD/GONO (Italy – TOSCA) – (bevacizumab) –SCOT (UK, Australia) – only 3 vs 6 –CALGB/SWOG (US - C80702) – celecoxib –GERCOR/PRODIGE (France) – only 3 vs 6 –HORG (Greece) – only 3 vs 6 Pooling only stage III colon cancer Total numbers of patients pooled: >10,500 –Non-inferiority margin of 2.5% Extension to stage II patients ongoing

Opportunities in Adjuvant Therapy of CRC Profiling and selecting patients for risk –Node positive and node negative Biomarkers for angiogenesis More specific anti-angiogenics –Role of other signaling molecules –Pan-receptor blockade –Agents suitable for prolonged use and potentially less toxicity