A Report from ASCO 2007 First-Line Metastatic Colorectal Cancer Edward Chu, MD Professor, Medicine & Pharmacology Chief, Section of Medical Oncology Deputy Director, Yale Cancer Center Yale Cancer Center Yale University School of Medicine New Haven, CT

CRC Treatment Review Chemotherapy for advanced disease –Oral vs. IV 5-FU –Sequential vs. combination –Continuous vs. intermittent Targeted therapies –Anti-angiogenesis inhibitors Bevacizumab –EGFR inhibitors Cetuximab

Chemotherapy for Advanced Disease

Abstract 4029 Efficacy and Safety from a Phase III, Randomized Study of Capecitabine plus Oxaliplatin (XELOX) vs. Infusional 5-FU/LV plus Oxaliplatin (FOLFOX6) as First-Line Treatment for Metastatic Colorectal Cancer M. Ducreux, J. Bennouna, M. Hebbar, M. Ychou, G. Lledo, T. Conroy, A. Adenis, R. Faroux, C. Rebischung, J. Douillard

Phase III Study of XELOX vs. FOLFOX6 as First-Line Treatment of mCRC Primary Endpoint: Non-inferiority of XELOX to FOLFOX on best RR Secondary Endpoints: PFS; OS; Safety; QoL; Pharmacoeconomics FOLFOX6 12 cycles (N = 150) Metastatic/advanced colorectal cancer, previously untreated by chemotherapy (N = 306) RANDOMIZERANDOMIZE XELOX 8 cycles (N = 156) Ducreux M, et al. ASCO Abstract #4029.

Phase III Study of XELOX vs. FOLFOX6 as First-Line Treatment of mCRC Grade 3/4 Hematologic Toxicity Ducreux M, et al. ASCO Abstract #4029.

Phase III Study of XELOX vs. FOLFOX6 as First-Line Treatment of mCRC Clinical Activity Response (%) XELOX (N = 156) FOLFOX6 (N = 150) ORR (independent review)4246 ORR (investigator)44 PFS8.8 mos.9.3 mos. OS19.9 mos.20.5 mos. Ducreux M, et al. ASCO Abstract #4029.

Abstracts 4028 and 4030 Bevacizumab in Combination with XELOX or FOLFOX4: Updated Efficacy Results from XELOX-1/NO16966, a Randomized Phase III Trial in First-Line Metastatic Colorectal Cancer Abstract 4028: L. Saltz et al. Abstract 4030: J. Cassidy et al.

XELOX + Placebo (N = 350) FOLFOX4 + Placebo (N = 351) XELOX + Bevacizumab (N = 350) FOLFOX4 + Bevacizumab (N = 350) XELOX (N = 317) FOLFOX4 (N = 317) Initial 2-arm open-label study (N = 634) Protocol amended to 2x2 placebo- controlled design after bevacizumab phase III data became available (N = 1,401) Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± Bevacizumab

Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± Bevacizumab Study Objectives Main endpoint: progression-free survival (PFS) Two primary objectives –XELOX is non-inferior to FOLFOX –Bevacizumab + chemotherapy is superior to placebo + chemotherapy Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

XELOX vs. FOLFOX: PFS 2-Arm Study Only (ITT) FOLFOX N = 317; 294 events XELOXN = 317; 285 events HR = 0.96 [97.5% CI: 0.80–1.16] (ITT) HR = 0.98 [97.5% CI: 0.81–1.18] (EPP) Survival Months Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

XELOX/BV vs. FOLFOX/BV: PFS (ITT) FOLFOX + bevacizumab N = 349; 255 events XELOX + bevacizumabN = 350; 258 events HR = 1.01 [97.5% CI: 0.83–1.23] (ITT) HR = 1.04 [97.5% CI: 0.84–1.27] (EPP) PFS Estimate Months Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

FOLFOX vs. XELOX: Safety Profile FOLFOX (N = 649) XELOX (N = 655) Grade 3/4 AEs 78.3%71.5% Diarrhea grade 3/4 11.2%20.2% Neutropenia grade 3/4 43.8% 7.0% Febrile neutropenia grade 3/4 4.8% 0.9% Hand-foot syndrome grade 3 1.2% 6.1% Neurosensory toxicity grade 3/4 16.5%17.4% Venous thromboembolic events grade 3/4 6.3% 3.8% Cardiac disorders grade 3/4 1.4% 0.9% Discontinuations due to AE24.8%26.0% All-cause 60-day mortality 2.3% 3.4% Treatment-related mortality up to 28 days after last dose 1.7% 2.1% Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

XELOX vs. FOLFOX: Conclusions XELOX and FOLFOX are equivalent in terms of clinical efficacy (RR, PFS, and OS) Safety profiles of XELOX and FOLFOX are similar –Increased grade 3/4 myelosuppression and neutropenic fever with FOLFOX –Increased incidence of hand-foot syndrome with XELOX XELOX should be considered a standard treatment option in first-line setting Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

Capecitabine-Based Regimens Issues to Consider What is the optimal dose of capecitabine when used in combination with oxaliplatin? –1,000 mg/m 2 bid 2 weeks on / 1 week off –Lower doses, mg/m 2 bid –Fixed dose What is the optimal schedule for capecitabine-based regimens? –2 weeks on / 1 week off (every 3 weeks) –1 week on / 1 week off (every 2 weeks)

Capecitabine Dosing U.S. vs Europe European trials –Capecitabine 1,000-1,250 mg/m 2 bid (d1-14, q3w) United States trials –Capecitabine 1,250 mg/m 2 bid dose too toxic (d1-14, q3w) –1,000 mg/m 2 bid more tolerable, but still toxic –Lower doses more tolerable in U.S. (850 mg/m 2 bid) Reasons for discrepancy? –United States diet fortified with folic acid –Vitamin/nutritional supplements Folic acid exacerbates capecitabine toxicity –Pharmacogenetic differences in folate metabolism, DPD? –Other?

Abstract 4012 Sequential Compared to Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer: A Dutch Colorectal Caner Group (DCCG) Phase III Study C. J. Punt, M. Koopman, J. Douma, J. Wals, A. H. Honkoop, F. L. Erdkamp, R. S. de Jong, C. J. Rodenburg, L. Mol, N. F. Antonini

CAIRO Study Design Primary Endpoint: Survival Secondary Endpoints: PFS, RR, Safety, QoL Sample Size: 1,298 patients in 221 centers CAPIRI (N = 378) Capecitabine (N = 397) mCRC No prior therapy (N = 820) CAPOX (N = 213) Irinotecan (N = 251) CAPOX (N = 143) Punt CJ, et al. ASCO Abstract #4012.

CAIRO Study Clinical Efficacy CombinationSequenceP-value OS (mos.) n.s. 1-yr Survival67%64%n.s. PFS (mos.) RR (%)41%20%< Punt CJ, et al. ASCO Abstract #4012.

CAIRO Study Conclusions Median OS equivalent between sequential and combination strategies Highlights the role of effective salvage treatments in mCRC Sequential therapy is a reasonable treatment option for patients with mCRC –Consider in good risk patients –Role of biologics in improving clinical efficacy and maintaining safety profile Punt CJ, et al. ASCO Abstract #4012.

Abstract 4013 Final Results of OPTIMOX2, a Randomized Phase II Study of Maintenance Therapy of Chemotherapy-Free Intervals (CFI) after FOLFOX in Patients with Metastatic Colorectal Cancer F. Maindrault-Goebel, G. Lledo, B. Chibaudel, L. Mineur, T. Andre, M. Bennamoun, M. Mabro, P. Artru, C. Louvet, A. de Gramont

OPTIMOX1 Study Tournigand et al, JCO x FOLFOX7 → 12x sLV5FU2 → 6x FOLFOX7 FOLFOX4 620 pts R Cum. Oxaliplatin7801,560 (%) FOLFOX4 FOLFOX7 RR PFS DDC OS G3/4 N-Tox Primary endpoint

OPTIMOX Trials: DDC T size FOLFOX PFS1 PDBaseline progression PFS2 Progression at reintroduction DDC = PFS1 + PFS2

OPTIMOX Studies OPTIMOX1 FOLFOX 4 until TF FOLFOX7 sLV5FU2 OPTIMOX2 mFOLFOX7 sLV5FU2 mFOLFOX7 CFI CFI: Chemotherapy-Free Interval

OPTIMOX2 Study Continuous vs. Intermittent Chemotherapy mFOLFOX7: no bolus 5-FU, 100 mg/m 2 oxaliplatin Comparison: maintenance therapy vs. chemotherapy- free intervals (CFI) Primary endpoint: Duration of disease control (DDC) Planned trial size, N = 600 –After bevacizumab approved downsized to a randomized phase II trial (N = 200) Maindrault-Goebel F, et al. ASCO Abstract #4013.

FOLFOX Regimens 600 FOLFOX4 B 400 FOLFOX6 2,400 FOLFOX7 200 B ,400-3, B 400 mFOLFOX ,000 Maindrault-Goebel F, et al. ASCO Abstract #4013.

OPTIMOX2 Clinical Efficacy OPTIMOX Maintenance 5-FU/LV Chemo-Free Interval P-value RR (%)6061n.s. PFS (mo) DDC (mo) n.s. OS (mo) Maindrault-Goebel F, et al. ASCO Abstract #4013.

OPTIMOX2 Conclusions Stop-and-go with maintenance is associated with prolonged OS and DDC vs. chemotherapy-free interval Incidence of grade 3 neurotoxicity similar between 2 arms Break in chemotherapy not recommended –May consider for patients with “good” tumor biology –Role of biologics in maintenance strategy needs to be explored in phase III trials (Dream Study) Maindrault-Goebel F, et al. ASCO Abstract #4013.

Targeted Therapy VEGF Inhibitors

Abstracts 4028 and 4030 Bevacizumab in Combination with XELOX or FOLFOX4: Updated Efficacy Results from XELOX-1/NO16966, a Randomized Phase III Trial in First-Line Metastatic Colorectal Cancer Abstract 4028: L. Saltz et al. Abstract 4030: J. Cassidy et al.

XELOX + Placebo (N = 350) FOLFOX4 + Placebo (N = 351) XELOX + Bevacizumab (N = 350) FOLFOX4 + Bevacizumab (N = 350) XELOX (N = 317) FOLFOX4 (N = 317) Initial 2-arm open-label study (N = 634) Protocol amended to 2x2 placebo- controlled design after bevacizumab phase III data became available (N=1,401) Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± Bevacizumab

XELOX/BV vs. FOLFOX/BV: PFS (ITT) FOLFOX + bevacizumab N = 349; 255 events XELOX + bevacizumabN = 350; 258 events HR = 1.01 [97.5% CI: 0.83–1.23] (ITT) HR = 1.04 [97.5% CI: 0.84–1.27] (EPP) PFS Estimate Months Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

XELOX vs. FOLFOX4 ± Bevacizumab Safety Profile FOLFOX/XELOX + Placebo (N = 675) FOLFOX/XELOX + Bevacizumab (N = 694) Grade 3/4 AEs 74.8%80.0% Gastrointestinal perforations grade 3/4 0.3% 0.6% Bleeding grade 3/4 1.2% 1.9% Arterial thromboembolic events grade 3/4 1.0% 1.7% Hypertension grade 3/4 1.2% 3.7% Proteinuria grade 3/4 – 0.6% Wound-healing complication grade 3/4 0.3% 0.1% Discontinuations due to AE 20.7%30.7% All-cause 60-day mortality 1.6% 2.0% Treatment-related mortality up to 28 days after last dose 1.5% 2.0% Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

Effect of Bevacizumab on PFS XELOX + Placebo (X+P) FOLFOX-4 + Placebo (F+P) XELOX + Bevacizumab (X+A) FOLFOX-4 + Bevacizumab (F+A) VS. HR = 0.83 [97.5% CI 0.72–0.95] P = Months PFS Estimate

Effect of Bevacizumab on PFS XELOX and FOLFOX Subgroups XELOX subgroup HR = 0.77 [97.5% CI 0.63–0.94] (ITT) P = Months PFS Estimate XELOX + Placebo N = 350; 270 events XELOX + Bevacizumab N = 350; 258 events FOLFOX subgroup HR = 0.89 [97.5% CI 0.73–1.08] (ITT) P = FOLFOX + Placebo N = 351; 277 events FOLFOX + Bevacizumab N = 349; 255 events Months

Phase III NO16966 Trial Conclusions First study to show that XELOX and FOLFOX regimen are clinically equivalent Provides first evidence that bevacizumab confers clinical benefit to FOLFOX chemotherapy Safety profile in line with previous trial results in CRC Supports the use of bevacizumab in combination with standard first-line chemotherapy Saltz L, et al. ASCO Abstract #4028. Cassidy J, et al. ASCO Abstract #4030.

Abstract 4027 Updated Results of BICC-C Study Comparing First-Line Irinotecan/Fluoropymidine Combinations with or without Celecoxib in mCRC C. Fuchs, J. Marshall, E. Mitchell, R. Wierzbicki, V. Ganju, M. Jeffery, J. Schultz, D. A. Richards, R. Soufi-Mahjoubi, J. Barrueco

Phase III Study of Three Irinotecan Regimens in First-Line mCRC (BICC-C) Fuchs C, et al. ASCO Abstract #4027. Original Design (Period 1: 2/03-4/04) Irinotecan 180 mg/m 2 D 1 q 2wk 5-FU 400 mg/m 2 (bolus) D1 q 2 wk LV 400 mg/m 2 D 1 q 2 wk 5-FU 400 mg/m 2 bolus/2.4 g/m 2 (46 hr infusion) D 1 q 2 wk ARM B: Modified Saltz Irinotecan: 125 mg/m 2 5-FU: 500 mg/m 2 LV: 20 mg/m 2 D 1, 8, q 3 wks Irinotecan: 250 mg/m 2 d1 q 3 wks Capecitabine: 1,000 mg/m 2 bid d1-14 q 3 wks ± Celecoxib 400 mg bid N = 1,000 (430) 3 x 2 design RANDOMIZATIONRANDOMIZATION ± Celecoxib 400 mg bid ± Celecoxib 400 mg bid ARM A: FOLFIRI ARM C: XELIRI

Phase III Study of Three Irinotecan Regimens in First-Line mCRC (BICC-C) N = x 2 design Fuchs C, et al. ASCO Abstract #4027. ARM B: Modified Saltz IFL + BV This arm was discontinued Amended Design (Period 2: 5/04-12/04) ARM C: XELIRI ± Celecoxib 400 mg bid ARM A: FOLFIRI + BV ± Celecoxib 400 mg bid RANDOMIZATIONRANDOMIZATION

BICC-C Study Clinical Efficacy FOLFIRI + Bevacizumab mIFL + Bevacizumab P-value Median PFS11.2 mos.8.3 mos.0.28 Median OSNot reached19.2 mos.0.01 Fuchs C, et al. ASCO Abstract #4027.

BICC Study Update on Clinical Efficacy TTP (months) OS (months) FOLFIRI + BV ≤ 65 > Not reached FOLFIRI ≤ 65 > Barrueco J, et al, ASCO 2007, Abstract #4076.

FOLFIRI + BV vs. FOLFOX + BV Clinical Efficacy FOLFIRI + BV OSNR PFS11.2 mos. RR54% FOLFOX + BV 21.3 / 26 mos. 9.4 / 9.9 mos. 47% / 53% BICC-C Trial NO16966 / TREE-2 Trials

Bevacizumab Therapy Conclusions Bevacizumab can be safely and effectively used in combination with 5-FU-, irinotecan-, and oxaliplatin- based chemotherapy for the first-line treatment of mCRC VEGF and the VEGF-signaling pathway are rational targets for anticancer therapy Agents in clinical development target the VEGF ligand, VEGF receptors, and VEGFR-TK

Bevacizumab Therapy Arterial Thromboembolic Events Chemotherapy alone Bevacizumab + Chemotherapy Arterial TE events*2.0% (15/741)4.5% (45/1004) Risk factors for arterial thromboembolic events* included: –History of prior arterial thromboembolic events such as stroke or heart attack –Age of 65 years or older *Pooled analysis of 5 randomized trials

Bevacizumab Recommendations Recommended dose is 5 mg/kg every 14 days as an IV infusion until disease progression Bevacizumab therapy should not be initiated for at least 28 days following surgery Bevacizumab should be permanently discontinued in patients who develop: –Gastrointestinal perforation –Wound dehiscence requiring medical intervention –Serious bleeding –Nephrotic syndrome –Hypertensive crisis

Bevacizumab Therapy Issues Should bevacizumab be continued at time of disease progression? What dose of bevacizumab should be used in second- line and disease refractory setting? What are the biomarkers of response to bevacizumab therapy?

Targeted Therapy EGFR Inhibitors

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 E. Van Cutsem, M. Nowacki, I. Lang, S. Cascinu, I. Shchepotin, J. Maurel, P. Rougier, D. Cunningham, J. Nippgen, C. Köhne

CRYSTAL Trial Study Design FOLFIRI q2w FOLFIRI q2w + Cetuximab mCRC EGFR positive (N = 1,217) PFS Primary Endpoint: PFS Secondary Endpoints: ORR, OS, QoL, Safety Van Cutsem E, et al. ASCO Abstract #4000.

CRYSTAL Trial Grade 3/4 Toxicity FOLFIRI N = 602, % Cetuximab + FOLFIRI N = 600, % Any Neutropenia Febrile neutropenia Diarrhea Vomiting Fatigue Skin reactions Infusion-related reactions Van Cutsem E, et al. ASCO Abstract #4000.

Progression-Free Survival (months) PFS Estimate HR = 0.851; 95% CI = [ ] Log-rank P-value = mos. 8.0 mos. FOLFIRI (N = 608) Cetuximab + FOLFIRI (N = 609) 1-year PFS rate 34% vs. 23% Van Cutsem E, et al. ASCO Abstract #4000. CRYSTAL Trial Progression-Free Survival

FOLFIRI (N = 609) Cetux + FOLFIRI (N = 608) P-value PFS PFS, grade 0/1 ST-5.4 (N = 244) PFS, grade 2 ST-9.4 (N = 243) PFS, grade 3 ST-11.3 (N = 112) ORR, % R0 resection, % R0, liver mets only, %4.5 (N = 134)9.8 (N = 122)- Van Cutsem E, et al. ASCO Abstract #4000. CRYSTAL Trial Clinical Efficacy

CRYSTAL Trial Surgery with Curative Intent Van Cutsem E, et al. ASCO Abstract #4000. P = odds ratio = 3.0 Surgery with curative intent N = 599 No residual tumor after resection N = 599 Cetuximab + FOLFIRIFOLFIRI

CRYSTAL Trial Conclusions Cetuximab can be safely and effectively combined with FOLFIRI in the first-line setting Addition of cetuximab to FOLFIRI improves RR and PFS Skin reactions correlate with clinical activity Significant 3-fold increase in R0 resection rate for patients with initially unresectable disease QoL and biomarker analysis is ongoing Cetuximab should be considered for first-line and neoadjuvant therapy, esp. in liver-limited disease Van Cutsem E, et al. ASCO Abstract #4000.

Phase III CALGB/SWOG Trial First-Line mCRC Primary endpoint: OS Secondary endpoint: PFS, RR RANDOMIZATIONRANDOMIZATION FOLFOX FOLFIRI N = 2,289 (600+ enrolled) Bevacizumab + Cetuximab Bevacizumab Cetuximab

Anti-EGFR Abstract Conclusions Cetuximab has been safely and effectively combined with irinotecan and oxaliplatin for first-, second-, and third-line treatment Cetuximab is a reasonable treatment alternative to bevacizumab in the first-line and neoadjuvant setting (liver-limited disease) CALGB/SWOG currently enrolling patients to confirm role of cetuximab, bevacizumab, and cetuximab/bevacizumab in first-line setting Panitumumab active in the disease refractory setting Panitumumab can not be reasonably substituted for cetuximab in combination with chemotherapy –Await further clinical studies