Adjuvant Matters Richard M Goldberg MD UNC Lineberger Comprehensive Cancer Center Chapel Hill, NC

Disclosures  I have been a paid consultant to sanofi-aventis sanofi-aventis Genentech Genentech Pfizer Pfizer  Memberships NSABP (Wolmark, Allegra abstracts) NSABP (Wolmark, Allegra abstracts) ACCENT (de Gramont abstract) ACCENT (de Gramont abstract)  Coauthor Ribic NEJM paper upon which some of the presentation by Sargent is based Ribic NEJM paper upon which some of the presentation by Sargent is based

NSABP Protocol C-07: A Phase III Trial Comparing FU/LV to FU/LV + Oxaliplatin in Stage II or III Colon Cancer: Survival Data Wolmark, Wieand, Kuebler, Colangelo, O'Connell, Yothers and the NSABP Investigators

Questions  Answered Does oxaliplatin add to PFS and OS? Does oxaliplatin add to PFS and OS? Does 5-FU schedule matter? Does 5-FU schedule matter? Is 5 years of follow-up adequate for OS? Is 5 years of follow-up adequate for OS?  Unanswered What’s the optimal adjuvant therapy duration? What’s the optimal adjuvant therapy duration? How much total oxaliplatin is optimal? How much total oxaliplatin is optimal? How do we best manage Stage II patients? How do we best manage Stage II patients?

Stage ll + lll FLOXFU/LV Randomize

Critical Statistics  5.5 year median follow-up  Outcomes better than projected Expected # deaths 700 Expected # deaths 700 Actual # deaths 560 Actual # deaths 560 Consequent reduction in power Consequent reduction in power  % Stage II: C-07 28% C-07 28% MOSAIC 40% MOSAIC 40%

p = HR: 0.81 [0.70 – 0.93] 19% risk reduction C-07 DFS 3y 5y FLOX 76.1% 69.4% FULV 71.5% 64.2% Δ 4.6% 5.2%

D(n) 5y 6y FLOX % 77.7% FULV % 73.5% Δ % 4.2% p = 0.06 HR: 0.85 [0.72 – 1.01] 15% risk reduction C-07 Survival

Median FLOX 17.6 FULV 22.2 P = 0.02 HR: 1.24 C-07 Survival after Recurrence

Questions  Answered Does oxaliplatin add to PFS and OS? Yes Does oxaliplatin add to PFS and OS? Yes Does 5-FU schedule matter? No Does 5-FU schedule matter? No Is 5 years of follow-up adequate for OS? No Is 5 years of follow-up adequate for OS? No  Unanswered What’s the optimal adjuvant therapy duration? 3 versus 6 versus other? What’s the optimal adjuvant therapy duration? 3 versus 6 versus other? How much total oxaliplatin is optimal? May differ in different patients How much total oxaliplatin is optimal? May differ in different patients How do we best manage Stage II patients? TBD No treatment, 5-FU alone, or FOLFOX How do we best manage Stage II patients? TBD No treatment, 5-FU alone, or FOLFOX

Initial Safety Report of NSABP C-08 Allegra, Yothers, Sharif, O’Connell, Wolmark and the NSABP Investigators

NSABP C-08 Schema Stage II or III Colon Cancer Stratification Number of + Lymph Nodes Randomization mFOLFOX6 mFOLFOX6 + Bevacizumab Disease-free survival: primary endpoint

Questions  Answered Is the frequency of early deaths different? Is the frequency of early deaths different? What are the relative toxicities of FOLFOX +/- bevacizumab? What are the relative toxicities of FOLFOX +/- bevacizumab? Were there any surprises? Were there any surprises?  Unanswered Does bevacizumab add to FOLFOX in the adjuvant setting? Does bevacizumab add to FOLFOX in the adjuvant setting? Does bevacizumab have any long term toxicity (or benefit)? Does bevacizumab have any long term toxicity (or benefit)?

Early Mortality with Adjuvant Regimens C-08 within 18 months of randomization C-08 within 18 months of randomization FOLFOX 1.33%FOLFOX 1.33% FOLFOX + bev 1.42%FOLFOX + bev 1.42% MOSAIC data within 7 months of randomization MOSAIC data within 7 months of randomization LV5FU2 0.5%LV5FU2 0.5% FOLFOX 0.5%FOLFOX 0.5% C89803 data within 6 months of randomization C89803 data within 6 months of randomization 5-FU/LV 1%5-FU/LV 1% IFL 2.8%IFL 2.8%

Toxicities (Grade 3+) Significantly Increased with Bevacizumab (%) mFOLFOX6mFOLFOX6 + Bev p-value Hypertension1.812 (5 pts Gr 4) < Any Pain < Proteinuria0.82.7<0.001 Wound Complications (all Gr 3) <0.001

mFOLFOX6(%) mFOLFOX6 + Bev (%) p-value Wound Complications Hypertension < Sensory Neuropathy (Grade 2+) <0.001 Depression <0.01 Dizziness Proteinuria0.21.6<0.001 Pain - Any <0.001 Toxicities (Grade 3+) After Chemotherapy

Questions  Answered Is the frequency of early deaths different? No Is the frequency of early deaths different? No What are the relative toxicities of FOLFOX +/- bevacizumab? BP, pain, wounds, proteinuria What are the relative toxicities of FOLFOX +/- bevacizumab? BP, pain, wounds, proteinuria Were their any surprises? Pain, a bit more oxaliplatin delivered, no major increase in wound complications Were their any surprises? Pain, a bit more oxaliplatin delivered, no major increase in wound complications  Unanswered Does bevacizumab add to FOLFOX in the adjuvant setting? No data Does bevacizumab add to FOLFOX in the adjuvant setting? No data 28 months median time on study28 months median time on study Efficacy analysis: 592 events or 4 years after last entry (DMC evaluation every 6 months, latest October 2010)Efficacy analysis: 592 events or 4 years after last entry (DMC evaluation every 6 months, latest October 2010) Does bevacizumab have any long term toxicity (or benefit)? No data Does bevacizumab have any long term toxicity (or benefit)? No data

Association between 3 year DFS and OS is delayed with improved survival after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Findings from the 20,898 patient ACCENT dataset de Gramont for the ACCENT collaborative group

Questions  Answered Do we need to extend adjuvant trial follow-up beyond 5 years? Do we need to extend adjuvant trial follow-up beyond 5 years? Is a survival advantage that is apparent after 5 years still meaningful? Is a survival advantage that is apparent after 5 years still meaningful? Should trial design be continuously reevaluated? Should trial design be continuously reevaluated?  Unanswered Do we need to change surveillance plans? Do we need to change surveillance plans?

MOSAIC Update: OS with 6 Years Minimum Follow-up FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Overall survival (months) Probability HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.1% 4.4% p=0.996 p=0.029 ASCO 2007

R 2 = 0.80 ACCENT: 3yr DFS vs 5yr OS May 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer

Hypothetical – 3yr DFS v. 7yr OS R 2 = 0.75

Why Was 6 Years Required for MOSAIC to Become Positive for OS?  Previous analyses with 5FU/LV showed excellent association between 3 yr DFS & 5 yr OS ACCENT: Median time from recurrence to death: 12 months ACCENT: Median time from recurrence to death: 12 months MOSAIC: Median ~ 24 months MOSAIC: Median ~ 24 months Improved imaging to detect recurrence earlierImproved imaging to detect recurrence earlier Enhanced treatment post-recurrenceEnhanced treatment post-recurrence Secondary resections in selected patientsSecondary resections in selected patients

Impact of longer survival following recurrence on clinical trials  Longer follow-up for OS required to observe benefit improved post-recurrence treatments improved post-recurrence treatments  DFS even a more important endpoint  Treatments that delay rather than prevent recurrence may send misleading DFS signals

Questions  Answered Do we need to extend adjuvant trial follow-up beyond 5 years? Yes Do we need to extend adjuvant trial follow-up beyond 5 years? Yes Is a survival advantage only apparent after 5 years still meaningful? Absolutely Is a survival advantage only apparent after 5 years still meaningful? Absolutely Should trial design be continuously reevaluated? Absolutely, by clinician & statistician teams Should trial design be continuously reevaluated? Absolutely, by clinician & statistician teams  Unanswered Do we need to change surveillance plans? Probably Do we need to change surveillance plans? Probably

Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer Sargent, Marsoni, Thibodeau, Labianca, Hamilton, Torri, Monges, Ribic, Grothey, Gallinger

Questions  Answered Should MMR testing be considered prior to 5- FU based Rx for stage II pts? Should MMR testing be considered prior to 5- FU based Rx for stage II pts?  Unanswered Should MMR testing be considered prior to 5- FU based Rx for stage III pts? Should MMR testing be considered prior to 5- FU based Rx for stage III pts? Should other agents be used in MSI-H pts? Should other agents be used in MSI-H pts? Why are MSI-H different then MSS tumors? Why are MSI-H different then MSS tumors?

Biology  15% of CRC pts have MSI-H tumors Most hypermethylation, not mutation Most hypermethylation, not mutation  MSI-H cells have a growth advantage in the presence of 5-FU Carrethers, Gastro, 1999 MMR cells unable to bind 5-FU modified DNA MMR cells unable to bind 5-FU modified DNA  MSI-H cell lines are more sensitive to irinotecan Bras-Goncalves, BJC, 2000 are more sensitive to irinotecan Bras-Goncalves, BJC, 2000 are not resistant to oxaliplatin Sergent, Canc Chemo Pharmacol 2002 are not resistant to oxaliplatin Sergent, Canc Chemo Pharmacol 2002

Pooled data (N=1027) TrialTreatmentN % Stage II % dMMR FU/LEV11730%14% INT FU/LEV21550%18% FU/LV6619%12% GIVIO5FU/LV18352%16% FFCD5FU/LV15466%19% NCIC5FU/LV29261%15% Total102752%16%

DFS By MMR Status, Pooled Data HR: 0.79 ( ) p=0.30 HR: 0.51 ( ) p=0.009 Treated (N=512)Untreated (N=515) dMMR 70% pMMR 67% 5 yr DFS dMMR 80% pMMR 56% 5 yr DFS

Overall Survival By Treatment, Stage II dMMR Patients HR: 3.15 ( ) p=0.03 N = 55 N = 47 Untreated 93% Treated 75% 5 yr OS P-value = for treatment by MMR status interaction

Conclusions  dMMR validated as a prognostic marker in untreated patients  No suggestion of benefit from 5-FU based treatment in dMMR patients  Significant OS decrement to 5-FU based treatment in stage II patients

Take Home Message When considering a Stage II patient for 5-FU-based therapy, mismatch repair status, by MSI or IHC, should be used to determine whom not to treat

CALGB 89803: 5-FU/ LV +/- Irinotecan  854/1264 tumors evaluated for MSI Patients with samples no different from overall population Patients with samples no different from overall population 153 (18%) MSI-H by DNA microsatellite analysis 153 (18%) MSI-H by DNA microsatellite analysis PFS (p=0.04) advantage and OS trend (p=0.17) for IFL over FL treated MSI-H patients PFS (p=0.04) advantage and OS trend (p=0.17) for IFL over FL treated MSI-H patients No PFS or OS advantage for MSS patients Bertagnolli, submitted No PFS or OS advantage for MSS patients Bertagnolli, submitted

p= p = p = p = Disease free survivalOverall survival MSI-H tumors Non- MSI-H tumors

Questions  Answered Should MMR testing be considered prior to 5-FU based Rx for stage II pts? Yes Should MMR testing be considered prior to 5-FU based Rx for stage II pts? Yes  Unanswered Should MMR testing be considered prior to 5-FU based Rx for stage III pts? Unclear Should MMR testing be considered prior to 5-FU based Rx for stage III pts? Unclear Should other agents be used in MSI-H pts? Needs verification Should other agents be used in MSI-H pts? Needs verification Irinotecan and oxaliplatin cell line dataIrinotecan and oxaliplatin cell line data CALGB clinical dataCALGB clinical data Why are MSI-H different then MSS tumors? TBD Why are MSI-H different then MSS tumors? TBD

Conclusions Adjuvant Matters  5-FU/Oxaliplatin standard for adjuvant Rx of Stage III colon cancer Should be considered in high-risk stage II Should be considered in high-risk stage II No advantage over 5-FU/LV in pooled stage II No advantage over 5-FU/LV in pooled stage II  Bevacizumab is not standard adjuvant Rx  Adjuvant trials need to be bigger and longer  MSI status appears relevent to likelihood of benefit from 5-FU and possibly other agents  At last we have useful markers of heterogeneity K-ras and MSI appear to be prognostic and predictive K-ras and MSI appear to be prognostic and predictive