Clinical Review of Current Treatment Strategies for Colorectal Cancer Oncology Journal Club Clinical Review of Current Treatment Strategies for Colorectal Cancer John L. Marshall, MD Chief, Division Hematology and Oncology Director, Developmental Therapeutics and GI Oncology Lombardi Cancer Center Georgetown University Washington, DC

Management of mCRC: An Evolving Treatment Algorithm Diagnosis of mCRC Resectable Unresectable Adjuvant therapy Surgery Neo-adjuvant/ Pre-operative therapy First-line Second-line Third-line Borderline/ Potentially Fourth-line Treatment continuum

Advances in the Treatment of Colorectal Cancer 1980 1985 1990 1995 2000 2005 Therapeutic concepts Palliative chemotherapy Adjuvant chemotherapy Neoadjuvant chemotherapy Capecitabine Oxaliplatin Cetuximab Bevacizumab Irinotecan 5-FU Panitumumab Targeted Therapies {

News from ASCO 2008 EGFR/KRAS: Colon Cancer is split in two Trials close to re-tool MSI-H: Colon Cancer is split again? 5-FU harmful in adjuvant setting VEGF/EGFR: Dual inhibition may be bad PACCE CAIRO-2

Management of mCRC: An Evolving Treatment Algorithm Diagnosis of mCRC Resectable Unresectable Adjuvant therapy Surgery Neo-adjuvant/ Pre-operative therapy First-line Second-line Third-line Borderline/ Potentially Fourth-line Treatment continuum

NCCN Guidelines: Advanced mCRC Good Tolerance to Intensive Therapy Poor Tolerance to Intensive Therapy First-line Second-line Third- or Fourth-line FOLFOX + BEV or CapeOx + BEV FOLFIRI + BEV 5-FU/LV + BEV Cape ± BEV or 5-FU + LV ± BEV FOLFIRI or Irinotecan FOLFIRI + cetuximab or Cetuximab + irinotecan FOLFOX or CapeOx Cetuximab or panitumumab or cetuximab + irinotecan Improvement in functional status No improvement in functional status Cetuximab or panitumumab or cetuximab + irinotecan Clinical trial or best supportive care Irinotecan or FOLFIRI Best supportive care Therapy after first progression as above NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. v2.2007.

Arm A – Camptosar + infusional BICC-C Trial N = 900 Arm A – Camptosar + infusional + Celecoxib or Placebo 400 mg bid RANDOMI ZAT ION Camptosar: 180 mg/m2 D 1 q 2wk LV: 400 mg/m2 over 2hr D 1 q 2 wk 5-FU: 400 mg/m2 (bolus) D1 q 2 wk 5-FU: 2,400 mg/m2 (46 hr infusion) D 1 q 2 wk + Bevacizumab Metastatic Disease Arm B – D1, D8 bolus + Celecoxib or Placebo 400 mg bid Camptosar: 125 mg/m2 5-FU: 500 mg/m2 LV: 20 mg/m2 D 1, 8, q 3 wks Arm C - Campcape Camptosar: 250 mg/m2 d1 q 3 wks Capecitabine: 1,000 mg/m2 bid d1-14 q 3 wks

Period 1: Progression Free Survival Data thru March 1, 2006 (ITT) Months Proportion of PFS FOLFIRI mIFL CapeIRI Regimen Median PFS (Months) HR (95% CI) P Value FOLFIRI 7.6 -- mIFL 5.8 1.55 (1.2, 2.0) 0.0009 CapeIRI 5.5 1.47 (1.1, 1.9) 0.0049

Period 2: Overall Survival Data Thru March 1, 2006 (ITT) Regimen Median OS (Months) 1 Year HR (95% CI) P Value FOLFIRI+ BEV Not Reached 87% -- mIFL + BEV 18.7 61% 2.5 (1.3,5.0) 0.01 Proportion of Patients Who Survived Survival Time (months) mIFL + bevacizumab FOLFIRI + bevacizumab

FOLFOX4 + bevacizumab N=350 Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC Study Design and Drugs Protocol amended to 2x2 placebo-controlled design after bevacizumab Phase III data1 became available (N=1,401) 1Hurwitz H., et al. Proc ASCO 2003;22 (Abstract 3646) XELOX + placebo N=350 FOLFOX4 + placebo N=351 XELOX + bevacizumab N=350 FOLFOX4 + bevacizumab N=350 XELOX N=317 FOLFOX4 N=317 Recruitment June 2003–May 2004 Recruitment Feb 2004–Feb 2005 Initial 2-arm open-label study (N=634) OX = oxaliplatin; LV = leucovorin; BV = bevacizumab; PL = placebo; 5-FU = 5-fluorouracil XELOX + bevacizumab/placebo: 21-day cycle D1 D2 D15 Rest Oral capecitabine 1,000 mg/m2 BID BV or PL 7.5mg/kg IV 30–90 min OX 130mg/m2 IV 2 h D21 FOLFOX4 + bevacizumab/placebo: 14-day cycle OX 85mg/m2 IV 2 h 5mg/kg IV 30–90 min 5-FU 600mg/m2 IV 22 h D3 LV 200mg/m2 5-FU 400mg/m2 IV bolus Cassidy et al. ESMO 2006. Oral Presentation

Primary Objective Achieved Based on ITT Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC PFS XELOX Non-inferiority FOLFOX/FOLFOX + placebo/FOLFOX + bevacizumab N = 1,017; 826 events XELOX/XELOX + placebo/XELOX + bevacizumab N = 1,017; 813 events Primary Objective Achieved Based on ITT Roche Medical Affairs. All rights reserved. Cassidy et al. ESMO 2006. Oral Presentation

Phase III Trial of XELOX vs Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC PFS Superiority of Bevacizumab + CT HR = 0.83 [97.5% CI 0.72–0.95] (ITT) P = 0.0023 Primary Objective Achieved XELOX Subgroup FOLFOX Subgroup HR = 0.77 [97.5% CI 0.63–0.94] (ITT) P = 0.0026 XELOX + placebo N = 350; 270 events XELOX + bevacizumab N = 350; 258 events HR = 0.89 [97.5% CI 0.73–1.08] (ITT) P = 0.1871 FOLFOX + placebo N = 351; 277 events FOLFOX + bevacizumab N = 349; 255 events FOLFOX + placebo/XELOX + placebo N = 701; 547 events FOLFOX + bevacizumab/XELOX+ bevacizumab N = 699; 513 events Roche Medical Affairs. All rights reserved. Cassidy et al. ESMO 2006. Oral Presentation

Maindrault-Goebel F, et al. ASCO 2007, Abstract 4013 Final Results of OPTIMOX-2 - A Large Randomized Phase II Study of Maintenance Therapy or Chemotherapy-free Intervals (CFI) After FOLFOX in Patients with Metastatic Colorectal Cancer (Mrc): A GERCOR Study Maindrault-Goebel F, et al.

OPTIMOX Studies OPTIMOX-1: OPTIMOX-2: Maintenance therapy (N = 620) FOLFOX 4 until progression FOLFOX 7 sLV5FU2 OPTIMOX-2: Chemotherapy-free interval (N = 202) mFOLFOX 7 Tournigand et al. J Clin Oncol. 2006;24:394. Maindrault-Goebel et al. ASCO 2007. Abstract 4013.

Progression-free Survival 10 20 30 40 50 60 70 80 90 100 0.0 0.2 0.4 0.6 0.8 1.0 OPTIMOX1 median 36 weeks OPTIMOX2 median 29 weeks Weeks Probability P = 0.08

Overall Survival 10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0 OPTIMOX1 median 26 months OPTIMOX2 median 19 months P = 0.0549 Months Probability

ASCO 2008, Abstract 4010 Intermittent Oxaliplatin (Oxali) Administration and Time-to-Treatment-Failure (TTF) in Metastatic Colorectal Cancer (mCRC): Final Results of the Phase III CONcePT Trial Grothey A., et al.

CONcePT Trial Design Patients with mCRC (N = 140) Continuous Oxaliplatin* mFOLFOX7 + bevacizumab +placebo (N = 34) mFOLFOX7 + bevacizumab +Ca2+/Mg2+ (N = 35) Intermittent Oxaliplatin† mFOLFOX7 + bevacizumab + placebo (N = 36) mFOLFOX7 + bevacizumab + Ca2+/Mg2+ *Treat to failure. †8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin. Grothey A, et al. ASCO 2008. Abstract 4010.

CONcePT: Kaplan-Meier Estimate of TTF Proportion of Patients 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months N at risk CO: 68 63 58 46 36 28 20 11 6 4 4 4 2 2 1 1 0 IO: 71 65 61 56 52 43 32 28 21 18 12 12 10 7 4 1 1 TTF (mos) 95% CI CO IO 4.2 5.6 3.7–5.5 4.7–7.0 Unstratified (IO relative to CO), P = .002* Stratified by CaMg (IO relative to CO), P = .003* * Log rank test Continuous Oxaliplatin (CO) Intermittent Oxaliplatin (IO) Censored data Grothey A, et al. ASCO 2008. Abstract 4010.

CONcePT: Kaplan-Meier Estimate of PFS 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Proportion of Patients 1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months N at risk CO: 68 64 46 39 29 24 13 7 3 3 3 1 0 0 0 0 0 IO: 71 64 55 51 43 38 27 24 18 15 10 9 8 3 2 1 1 Unstratified (IO relative to CO), P = .044* Stratified by CaMg (IO relative to CO), P = .030* * Log rank test CO PFS (mos) 95% CI IO 7.3 12.0 6.9–NE 8.2–NE Continuous Oxaliplatin (CO) Intermittent Oxaliplatin (IO) Censored data Grothey A, et al. ASCO 2008. Abstract 4010.

ASCO 2007, Abstract 4000 Randomized Phase III Study of Irinotecan and 5-FU/FA With or Without Cetuximab in the First-line Treatment of Patients with Metastatic Colorectal Cancer (mCRC): The CRYSTAL Trial Van Cutsem E, et al.

Irinotecan and 5-FU/FA ± Cetuximab The CRYSTAL Trial Study Design Cetuximab + FOLFIRI Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks EGFR-expressing Metastatic CRC R Stratification factors: Regions ECOG PS Populations Randomized patients: N = 1,217 Safety population: N = 1,202 ITT population: N = 1,198 FOLFIRI Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks Van Cutsem E, et al. ASCO 2007. Abstract 4000.

CRYSTAL Trial Progression Free Survival Van Cutsem E, et al. ASCO 2007. Abstract 4000.

Cell Response to Signaling What is the Role of the Epidermal Growth Factor Receptor (EGFR) in Cancer? Proliferation Metastasis Angiogenesis Apoptosis Resistance Shc PI3-K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 Cell Membrane EGFR Signaling Proteins Cell Response to Signaling

Pathway vs. Network Signaling Network “Chaotic” Pathway “Newtonian” A. Friedman and N. Perrimon, Cell 128, January 26, 2007

ASCO 2008, Abstract 2 KRAS Status and Efficacy in the First-line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) Treated with FOLFIRI With or Without Cetuximab: The CRYSTAL Experience Van Cutsem E, et al.

CRYSTAL PFS in Patients with KRAS Wild-type 0.0 0.2 0.4 0.6 0.8 1.0 4 8 12 Months PFS Estimate 18 Cetuximab + FOLFIRI FOLFIRI KRAS wild-type (N = 348) HR = 0.68: P = .017 2 6 10 14 Median PFS Cetuximab + FOLIFIRI: 9.9 months Median PFS FOLIFIRI: 8.7 months 0.1 0.3 0.5 0.7 0.9 16 1-year PFS rate: 43% 1-year PFS rate: 25% Van Cutsem E, et al. ASCO 2008. Abstract 2. Reproduced with permission.

Relating KRAS Status to Efficacy Progression Free Survival Cetuximab + FOLFIRI HR = 0.63; P = 0.007 mPFS wild-type (N = 172): 9.9 months mPFS mutant (N = 105): 7.6 months FOLFIRI HR = 0.97; P = 0.87 mPFS wild-type (N = 176): 8.7 months mPFS mutant (N = 87): 8.1 months 0.5 1.0 0.4 0.3 0.2 0.1 0.0 0.6 0.7 0.8 0.9 8 2 4 6 10 16 PFS Estimate Months Cetuximab + FOLFIRI wild-type Cetuximab + FOLFIRI mutant 12 14 FOLFIRI wild-type FOLFIRI mutant

ASCO 2008, Abstract 4000 KRAS Status and Efficacy of First-line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) with FOLFOX With or Without Cetuximab: The OPUS Experience Bokemeyer C. et al.

Cetuximab + CT in KRAS Wild-Type: Data Consistency Response rate (%) 59 37 10 20 30 40 50 60 70 CRYSTAL (N = 540) OPUS1 (N = 233) 43 61 FOLFIRI FOLFOX Cetuximab + FOLFIRI Cetuximab + FOLF0X CRYSTAL - KRAS wild-type: HR = 0.68 P = 0.017 32% risk reduction for progression OPUS - KRAS wild-type: HR = 0.57 P = 0.016 43% risk reduction for progression 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 12 14 16 18 Months PFS estimate 1Bokemeyer C. et al, ASCO 2008. Abstract 4000.

ECCO 2007, Abstract 0007 Analysis of KRAS Mutations in Patients with Metastatic Colorectal Cancer Receiving Panitumumab Monotherapy Amado RG, et al.

KRAS as a Biomarker for Panitumumab Response in mCRC Pts with mutant KRAS receiving panitumumab had 0% RR and SD similar to BSC alone (12% vs 8%) PFS log HR significantly different depending on K-ras status (P < .0001) Percentage decrease in target lesion greater in patients with wild-type KRAS receiving panitumumab Patients With Mutant KRAS Mean in Wks Stratified log rank test: P < .0001 115/124 (93) Patients With Wild-type KRAS 1.0 0.9 Proportion With PFS 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 2 4 6 8 10 Events/N (%) Median in Wks Pmab + BSC BSC alone 114/119 (96) 12.3 7.3 19.0 9.3 HR: 0.45 (95% CI: 0.34-0.59) 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks 76/84 (90) 95/100 (95) 7.4 9.9 10.2 HR: 0.99 (95% CI: 0.73-1.36) Amado RG, et al. ECCO 2007. Abstract 0007.

Q: Is More Always Better?

3 Drugs: 5-FU/LV, irinotecan, oxaliplatin Correlation Between Survival and Percentage of Patients Receiving Three Drugs in Phase III Trials 3 Drugs: 5-FU/LV, irinotecan, oxaliplatin . Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

FOLFOXIRI vs. FOLFIRI JCO 2007

Open-label, Phase II-III Trial of Irinotecan or Oxaliplatin-based CTX + Bevacizumab ± Panitumumab in First-line mCRC: PACCE Trial Discontinued 3/2007 due to significantly inferior PFS in planned interim analysis OS significantly inferior in unplanned analysis ECOG score Prior adjuvant TX Disease site Oxaliplatin doses/ Irinotecan regimen Number of metastatic organs Oxaliplatin-based CTXa Irinotecan-based CTXa Oxaliplatin/CTX + Bevacizumab + Panitumumab N = 407 Oxaliplatin/CTX + Bevacizumab N = 405 Irinotecan/CTX + Bevacizumab + Panitumumab N = 68 Irinotecan/CTX + Bevacizumab N = 67 Phase III Phase II RANDOM I Z A T I ON aThe choice of either Ox/CTX or Irino/CTX was at the oncologist’s discretion Hecht et al. World Congress on GI Cancer, 2007

ECCO 2007, Abstract 3000 Randomised Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) With or Without Cetuximab in Advanced Colorectal Cancer (ACC), The CAIRO-2 Study of the Dutch Colorectal Cancer Group (DCCG) an Interim Safety Analysis Tol J, et al.

Capecitabine Oxaliplatin Bevacizumab CAIRO-2 Study Design Arm A Arm B Randomization Capecitabine Oxaliplatin Bevacizumab Capecitabine Oxaliplatin Bevacizumab Cetuximab Dutch Colorectal Cancer Group (DCCG)

CAIRO-2 Interim Safety Analysis Adverse Event, % Arm A: Capecitabine, Oxaliplatin, Bevacizumab (N = 197) Arm B: Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab (N= 192) Gastrointestinal, grade 3/4 Diarrhea 20 23 Nausea 9 6 Vomiting 8 Cardiovascular, grade 3/4 Hypertension 7 4 Thromboembolic event Grade 3/4 neurotoxicity Grade 3/4 allergic reaction 3 Grade 3/4 bleeding 2 1 Tol J, et al. ECCO 2007. Abstract 3000.

Progression-free Survival Arm A (without cetuximab) 10.7 months (9.7-12.5) Arm B (with cetuximab) 9.6 months (8.5-10.7) HR: 1.21 P = 0.018 6 12 18 24 30 Months from randomization 0.0 0.2 0.4 0.6 0.8 1.0 Progression free survival probability Arm A (without cetuximab) Arm B (with cetuximab) Dutch Colorectal Cancer Group (DCCG)

KRAS Genotyping (N = 501) Wildtype N = 305 (61%) Mutation P value Arm A 152 (50%) 103 (53%) Arm B 153 (50%) 93 (47%) Median PFS (months) 10.7 12.5 0.92 10.5 8.6 0.47 0.10 0.043 Dutch Colorectal Cancer Group (DCCG)

CALGB/Intergroup Front-line Trial FOLFOX or FOLFIRI Bevacizumab Cetuximab Bevacizumab/

Adjuvant Oxaliplatin Mosaic Trial (3-year Data) FOLFOX-4 (1,100 pts) LV5FU2 (1,100 pts) T3, T4 N0 = 40% (87% vs 84%) Tx, N1, N2 = 60% (72% vs 65%) 77.8% 72.9% P < 0.01 R A N D OM I Z A T I O DFS Endpoint

ASCO 2008 Abstract LBA4005 A Phase III Trial Comparing FULV to FULV + Oxaliplatin in Stage II or III Carcinoma of The Colon: Survival Results of NSABP Protocol C-07 Wolmark N, et al.

Survival Results of NSABP C-07 FULV 5-FU 500 m2 IV bolus weekly x 6; LV 500 mg/m2 IV weekly x 6, each 8-week cycle x 3 (N = 1,209) FLOX FULV + oxaliplatin 85 mg/m2 IV on Weeks 1, 3, and 5 of each 8-week cycle x 3 (N = 1,200) Patients with stage II or III carcinoma of the colon stratified by number of positive lymph nodes N = 2,409 Primary endpoint: DFS Wolmark N, et al. ASCO 2008. Abstract LBA4005.

C-07: Disease-Free Survival 20 40 60 80 100 2 4 6 3-years 5-years 1 3 5 7 10 30 50 70 90 P = .002 HR: 0.81 [0.70-0.93] FLOX 76.1% 69.4% FULV 71.5% 64.2% ∆ 4.6% 5.2% FLOX (N = 1,200) FULV (N = 1,209) Years Proportion of Patients (%) Wolmark N, et al. ASCO 2008. Abstract LBA4005.

C-07: Overall Survival P = .06 HR: 0.85 [0.72-1.01] FLOX (N = 1,200) 20 40 60 80 100 2 4 6 D(n) 3y 5y 1 3 5 7 10 30 50 70 90 FLOX 259 80.3% 77.7% FULV 301 78.3% 73.5% ∆ 42 2.0% 4.2% P = .06 HR: 0.85 [0.72-1.01] FLOX (N = 1,200) FULV (N = 1,209) Years Proportion of Patients (%) Wolmark N, et al. ASCO 2008. Abstract LBA4005.

C-07: Overall Survival Hazard Ratios FLOX Better FULV Better 0.5 0.75 1 1.25 1.5 1.75 Overall < 65 yr ≥ 65 yr Stage II Stage III Wolmark N, et al. ASCO 2008. Abstract LBA4005.

ASCO 2008 Abstract 4008 Confirmation of Deficient Mismatch Repair (Dmmr) as a Predictive Marker for Lack of Benefit from 5-FU Based Chemotherapy in Stage II and III Colon Cancer (CC): A Pooled Molecular Reanalysis of Randomized Chemotherapy Trials Sargent D. J., et al.

MSI-H and Adjuvant 5-FU Sargent, ASCO 2008

MSI-H and Adjuvant 5FU Sargent, ASCO 2008

E5202: Stage II Colon Cancer mFOLFOX6 vs. mFOLFOX6 + bevacizumab qow Tumor block risk assessed based on biology (18q/MSI) High risk (MSS and 18q LOH) Low risk (MSI + or no loss 18q) Observation Surgery Accrual goal: 3,125

Where We Are Today Adjuvant First-line Second-line Third-line 5-FU/LV FOLFOX Capecitabine First-line CPT-11 Oxaliplatin Bevacizumab Second-line Cetuximab Third-line Cetuximab/ CPT-11 Panitumumab

Colon Cancer is More than One Disease 50-60% 40-50% KRAS Wild Type KRAS mutant + EGFR Agents 15-20% – EGFR Agents 80-85% MSI-High MSS ? No 5-FU

Clinical Review of Current Treatment Strategies for Colorectal Cancer Oncology Journal Club Clinical Review of Current Treatment Strategies for Colorectal Cancer Closing Comments