Individualizing Therapy for Gastrointestinal Malignancies 2010 Update Thomas J. Semrad MD, MAS Assistant Professor of Medicine UC Davis Cancer Center

Disclosure Consulting or Advisory: Genomic Health, Inc

Individualizing Therapy in Colorectal Cancer Tumor MSI KRAS, BRAF, and others Host Pharmacogenetics

Colon Cancer Is More Than One Disease Chromosome Instability: 85% Microsatellite Instability: 15% KRAS Mutation: 40% BRAF Mutation: 10% CIMP Watch this Space!!!

Microsatellite Instability (MSI) Defective DNA Mismatch Repair (dMMR) Nature Reviews Cancer 2004;4,769-780.

MSI Identifies a Subset of Stage II and III Colon Cancer with a Lower Risk of Relapse MSS Untreated Patients JCO 2010;28:3219-3226

MSI Predicts for Lack of Benefit from Adjuvant 5FU Stage II Stage III MSI MSS JCO 2010;28:3219-3226

Tumor Block Risk Assessed Based on MSI / 18q LOH mFOLFOX6 High Risk (MSS and 18qLOH) R Tumor Block Risk Assessed Based on MSI / 18q LOH mFOLFOX6 + bevacizumab Surgery Low Risk (MSI or no loss 18q) Observation Accrual Goal 3,125

Adjuvant 5FU: QUASAR Lancet 2007;370:2020-2029

RT-PCR for RNA Quantification from Fixed Paraffin-Embedded Tumor Tissue Strand Displacement and Cleavage of Probe Polymerization Completed R Q Forward Primer Reverse Probe Reporter Quencher Clark-Langone, BMC Genomics: 2007; 8:279. Cronin et al. Am J Pathol. 2004;164:35-42.

QUASAR: Pre-Specified Primary Endpoint: Recurrence Risk Is there a significant relationship between the risk of recurrence and the pre-specified continuous Recurrence Score in stage II colon cancer patients randomized to surgery alone? STROMAL FAP INHBA BGN CELL CYCLE Ki-67 C-MYC MYBL2 REFERENCE ATP5E GPX1 PGK1 UBB VDAC2 GADD45B RECURRENCE SCORE Calculated from Tumor Gene Expression Kerr et al., ASCO 2009, #4000

QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711) Kerr et al., ASCO 2009, #4000

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

Nature Reviews Cancer 2009; 9, 489-499

Mutated KRAS Predicts Absence of Benefit From EGFR-Targeted Antibodies Wild-type KRAS N Engl J Med 2008;359:1757-65

What We Thought We Knew: CRYSTAL N Engl J Med 2009;360:1408-17

Cetuximab Does Not Improve DFS in Stage III CRC JCO 28:15s, 2010 (suppl; abstr 3508)

MRC COIN Cetuximab and Oxaliplatin 5FU or capecitabine Oxaliplatin Second Line Therapy: Irinotecan based Primary Endpoint: Overall Survival in KRAS wild-type Secondary Endpoints: OS in KRAS mutant OS in “all wild-type” PFS, RR QOL Health Economics Advanced Colorectal Cancer, first line therapy No Prior Chemotherapy for Metastatic Disease PS 0-2 Good Organ Function No prior EGFR IHC A 5FU or capecitabine Oxaliplatin Cetuximab B 5FU or cap Oxaliplatin 5FU or cap Oxaliplatin C 12 Weeks OxMdG: mFOLFOX6 with slightly different LV CapOx: Oxaliplatin 130mg/m2 D1; Capecitabine 1000mg/m2 D1-14 every 21 days, reduced to 850mg/m2 July 2007 due to toxicity CapOx or OxMdG chosen before randomization; N=815 per arm JCO 28:15s, 2010 (suppl; abstr 3502)

JCO 28:15s, 2010 (suppl; abstr 3502)

Biomarkers Total 1316 Population N Arm A Arm B ITT 1630 815 All WT 581 KRAS 565 Population N Arm A Arm B ITT 1630 815 Assessed for mutation 1316 (81%) 648 668 KRAS mutated 565 (43%) 268 297 BRAF mutated 102 (8%) 57 45 NRAS mutated 50 (4%) 18 32 KRAS wild-type 729 (55%) 367 362 “All wild-type” 581 (44%) 289 292 BRAF 102 NRAS 50 KRAS & NRAS 11 JCO 28:15s, 2010 (suppl; abstr 3502)

COIN: Survival by Subgroup Median Overall Survival (Months) JCO 28:15s, 2010 (suppl; abstr 3502)

COIN: Response Rates KRAS WT KRAS Mutated Arm A Arm B N 367 362 268 297 ORR at 12 weeks 50% 59% 41% 40% Odds Ratio (B vs. A) OR 1.44 P = 0.015 OR 0.97 P = 0.877 Overall Response 57% 64% 46% 43% OR 1.35 P = 0.049 OR 0.88 P = 0.449 JCO 28:15s, 2010 (suppl; abstr 3502)

CAUTION: CROSS TRIAL COMPARISONS!! ??? Front Line Chemotherapy Plus EGFR-Targeted Antibody - KRAS Wild Type Trial Arm RR (%) OR P-value PFS (months) HR OS (months) MRC COIN ASCO 2010 N = 1630 OxFdG / XELOX 57 1.44 0.015 8.6 0.959 0.60 17.9 1.037 0.68 + cetuximab 64 17.0 CRYSTAL ASCO GI 2010 N = 1198 FOLFIRI 40 2.07 <0.0001 8.4 0.696 0.0012 20.0 0.796 0.0093 9.9 23.5 OPUS JCO 2009 N = 337 FOLFOX4 37 2.544 0.011 7.2 0.570 0.0163 NR NA 61 7.7 PRIME N = 1183 48 0.07 8.0 0.80 0.02 19.7 0.83 + panitumumab 55 9.6 23.9 CAUTION: CROSS TRIAL COMPARISONS!!

BRAF Mutation: Prognostic and/or Predictive? BRAF Mutated Trial Arm RR (%) OR P-value PFS (months) HR OS (months) CRYSTAL FOLFIRI 15 NR 0.9136 5.6 0.934 0.8656 10.3 0.908 0.7440 + cetuximab 19 8.0 14.1 Combined CRYSTAL & OPUS Chemotherapy 13 1.6 0.4606 3.7 0.69 0.267 9.9 0.63 0.079 22 7.1 KRAS and BRAF Wild Type Combined CRYSTAL & OPUS Chemotherapy 49 2.27 <0.001 7.7 0.64 21.1 0.84 0.041 + cetuximab 61 10.9 24.8 JCO 28:15s, 2010 (suppl; abstr 3506)

www.abcam.com

Predictors of Benefit from Bevacizumab in Colon Cancer ?? VEGF Pathway Polymorphisms

JCO 2005; 23: 7342-7349

JCO 2009; 27: 5519-5528

N9741 JCO 2010; 28: 3227-3233

Pharmacogenetic Hypotheses Can Be Tested in Cooperative Group Trials JCO 2010; 28: 3227-3233

Conclusions: I MSI KRAS mutations BRAF mutation Prognostic in Stage II and III Predicts lack of benefit from 5FU in Stage II KRAS mutations Predict lack of benefit from cetuximab BRAF mutation May NOT be a good predictor for lack of benefit from cetuximab Suggests an awful prognosis

Conclusions: II No evidence for benefit of either bevacizumab or cetuximab in adjuvant setting Does cetuximab combine better with irinotecan than oxaliplatin? Pharmacogenetic data is needed from cooperative group trials