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A Report from ASCO GI 2008 Up-to-Date Review of the Treatment of Metastatic Colorectal Cancer Edward Chu, MD Professor of Internal Medicine and Pharmacology Chief, Section of Medical Oncology Yale Cancer Center Yale University School of Medicine New Haven, CT Outline • Cytotoxic chemotherapy • FOLFOX and neurotoxicity • FOLFOX versus XELOX • Integration of biologics with cytotoxic chemotherapy • Bevacizumab • Bevacizumab plus panitumumab • Biomarker development for anti-EGFR antibodies Abstract 280 Effect of Intravenous Calcium and Magnesium vs Placebo on Response to FOLFOX+bevacizumab in the CONcePT Trial Hochster HS, Grothey A, Shpilsky A, Childs BH CONcePT : Schema 1° Endpoint: TTF for continuous vs. intermittent oxaliplatin Exclusion Criteria: • Prior exposure to bev and/or oxaliplatin • Peripheral neuropathy grade >1 R A N D O M I Z E mFOLFOX7/bev + placebo mFOLFOX7/bev + Ca2+/Mg2+ mFOLFOX7/bev + placebo mFOLFOX7/bev + Ca2+/Mg2+ Continuous Oxaliplatin Intermittent Oxaliplatin mFOLFOX7/bev: oxaliplatin 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr, 5-FU 2400 mg/m2 over 46 hours, bevacizumab 5 mg/kg over 30-90 minutes, Day 1 biweekly Ca2+/Mg2+: 1 g calcium gluconate/1 g magnesium sulfate over 30 min before and after oxaliplatin Intermittent: alternating between 8 cycles with oxaliplatin and 8 cycles with 5-FU/LV only CONcePT : Schema R mFOLFOX7/bev + placebo A TTF for continuous vs. N intermittent oxaliplatin mFOLFOX7/bev + Ca2+/Mg2+ D Study closed early due to negative Exclusion Criteria: O of Ca2+/Mg2+ on efficacy of impact mFOLFOX7/bev + placebo M • Prior exposure to bev mFOLFOX7/bev (int and cont) and/or oxaliplatin • Peripheral neuropathy foundI by IDMC during unplanned Z interim grade >1 mFOLFOX7/bev + Ca2+/Mg2+ analysis E 1° Endpoint: Continuous Oxaliplatin Intermittent Oxaliplatin mFOLFOX7/bev: oxaliplatin 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr, 5-FU 2400 mg/m2 over 46 hours, bevacizumab 5 mg/kg over 30-90 minutes, Day 1 biweekly Ca2+/Mg2+: 1 g calcium gluconate/1 g magnesium sulfate over 30 min before and after oxaliplatin Intermittent: alternating between 8 cycles with oxaliplatin and 8 cycles with 5-FU/LV only CONcePT : Clinical Efficacy Cont Placebo (N = 34) Cont Ca2+Mg2+ (N = 35) Int Placebo (N = 36) Int Ca2+Mg2+ (N = 35) 15.1 17.1 28.1 18.1 21 36 45 43 Adverse Event 16 13 8 12 Progression 9 5 8 8 Physician/Pt Decision 8 14 10 11 Other 1 2 10 4 Median Duration of Treatment ORR (evaluable), % Discontinuation of Treatment, N CONcePT: Conclusions • Two-factor logistic regression exploratory model of response data revealed no significant relationship between use of Ca2+/Mg2+ and response • Future reports of neuroprophylaxis await pending data Abstract 347 Diabetes Mellitus and the Incidence and Time to Onset of Oxaliplatin-Induced Peripheral Sensory Neuropathy (PSN) in Patients with Colorectal Cancer: A Pooled Analysis of Three Randomized Studies Ramanathan RK, André T, Rothenberg ML, de Gramont A, Tournigand C, Goldberg RM, Gupta S Pooled Analysis • Conducted pooled analysis of data from randomized clinical trials including FOLFOX4 treatment arm – EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC – EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC – EFC2962: Phase II/III study of LV5–FU2 + oxaliplatin • PSN data from the overall study population with or without diabetes were analyzed for: – Incidence and time to onset of PSN (Kaplan-Meier) – Trends indicating clinically relevant differences in the incidence and severity of PSN (Kaplan-Meier) Ramanathan et al, ASCO GI 2008, abstract 347. Incidence and Severity of PSN All Patients DM Patients (N = 1585) (N = 135) Grade 1 45.2 46.7 Grade 2 28.4 26.7 Grade 3 13.0 12.6 PSN Ramanathan et al, ASCO GI 2008, abstract 347. Conclusions • Patients with diabetes mellitus do not have an increased risk of developing cumulative neurotoxicity Abstract 341 XELOX vs. FOLFOX-4: Update of Efficacy Results from XELOX-1/NO16966, a Randomized Phase III Trial of First-Line Treatment for Patients with Metastatic Colorectal Cancer (MCRC) Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, A. Figer A, Wong R, Koski S, Sirzen F, Gilberg F, Saltz L Phase III NO16966 Trial Schema Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 XELOX XELOX + Placebo (N = 317) (N = 350) FOLFOX4 FOLFOX4 + Placebo (N = 317) (N = 351) Initial 2-arm open-label study (N = 634) XELOX + Bevacizumab (N = 350) FOLFOX4 + Bevacizumab (N = 349) Protocol amended to 2x2 placebocontrolled design after bevacizumab phase III data became available (N = 1400) Cassidy et al, ASCO GI 2008, Abstract 341. XELOX-1/NO16966 Trial Adverse Events FOLFOX-4 + Placebo (N = 649) XELOX + Placebo (N = 655) Diarrhea <12 20 Nausea 5 5 Stomatitis 2 1 Peripheral Neuropathy 4 4 Peripheral Sensory Neuropathy 3 3 Hand-foot syndrome 1 6 Fatigue <9 <6 Paresthesia 4 5 Neutropenia 43 <7 Febrile neutropenia 5 <2 Thrombocytopenia <4 7 Grade 3/4 Adverse Events, % Cassidy et al, ASCO GI 2008, Abstract 341. XELOX-1/NO16966 Trial Efficacy Results XELOX (N = 1,017) FOLFOX-4 (N = 1,017) Hazard Ratio (97.5% CI) Median PFS (All Patients) 8.0 months (886 events) 8.5 months (919 events) 1.01 (0.91-1.12) Median OS (All patients) 19.8 months (692 events) 19.6 months (695 events) 0.99 (0.88-1.12) Cassidy et al, ASCO GI 2008, Abstract 341. Abstract 340 Efficacy of Capecitabine vs. 5-FU in Colorectal and Gastric Cancer: Meta-analysis of Survival in 6 Clinical Trials Cassidy J, Rothenberg M, Saltz L, Twelves C, Van Cutsem E, Hoff P, Kang Y-K, Sirzen F, Gilberg F, Cunningham D Meta-Analysis: Capecitabine vs 5-FU • Included individual patient data from 6 phase III trials comparing the efficacy of capecitabine and 5-FU in metastatic colorectal and gastric cancers • Main endpoint was overall survival • Assessment completed with unstratified and stratified (by study) data • Included 6,171 patients (3,074 received 5-FU-based regimens and 3,097 received capecitabine-based regimens) • Unstratified data found a median OS of 23.1 and 22.4 months for patients who received capecitabine and 5-FU, respectively (HR = 0.96) Cassidy J et al, ASCO GI 2008, abstract 340. Meta-Analysis: Stratified OS Analysis Study 1. 2. 3. 4. 5. 6. N HR Range SO146951 605 1.01 0.86 - 1.19 SO147962 602 0.89 0.76 - 1.05 M660013 1,987 0.86 0.74 - 1.01 ML170324 316 0.89 0.69 - 1.15 NO169665 2,034 0.99 0.89 - 1.10 NO169676 627 1.02 0.86 - 1.21 Unstratified 6,171 0.96 0.90 - 1.02 Hoff PM et al. JCO 2001; 19:2282-92. Van Cutsem E, et al. JCO 2001; 19:4097-106. Twelves C, et al. N Eng J Med 2005; 352:2696-704. Kang YK, et al, ESMO 2006 (abstract 1072O). Cassidy J, et al. ASCO 2007 (abstract 4030). Rothenberg ML, et al. ASCO 2007 (abstract 4031). Cassidy J et al, ASCO GI 2008, abstract 340. Conclusions • Findings of meta-analysis suggest: – Equivalency of capecitabine and 5-FU in the treatment of adjuvant and metastatic colorectal cancer – Equivalency of capecitabine and 5-FU in the treatment of metastatic gastric cancer • Equivalency of capecitabine and 5-FU is supported by updated results of the NO16966 trial comparing capecitabine and 5-FU as treatment for metastatic colorectal cancer Abstract 342 Capecitabine and Oxaliplatin as First-Line Treatment in Patients with MCRC: A Meta-analysis of Randomized Phase II-III Trials Arkenau H-T, Arnold D, Diaz-Rubio E, Douillard J-Y, Martoni A, Grothey A, Hinke A, Schmiegel W, Schmoll H-J, Porschen R Meta-Analysis: Comparing PFS of Capecitabineand 5-FU-Containing Regimens N HR (fixed) Range 1,335 1.02 0.91 - 1.15 474 1.17 0.96 - 1.43 342 1.18 0.94 - 1.49 306 1.05 0.82 - 1.35 118 0.66 0.44 - 0.99 2,575 1.05 0.97 - 1.14 Study NO16966 Phase III1 XELOX vs. FOLFOX4 German AIO Phase III2 CAPOX vs. FUFOX Spanish TTD Phase III3 XELOX vs. FUOX French Phase III4 XELOX vs. FOLFOX6 Italian GOAM Phase II5 XELOX vs. PVIFOX All 1. Cassidy J, et al. ASCO 2007 (abstract 4030). 2. Porschen R, et al. J Clin Oncol 2007:4217-4223. 3. Díaz-Rubio E, et al. J Clin Oncol 2007:4224-4230. 4. Ducreux M, et al. ASCO 2007 (abstract 4029). 5. Martoni A, et al. Eur J Cancer 2006: 3161-3168. Arkenau HT, et al, ASCO GI 2008, abstract 342. Conclusions • Findings of meta-analysis suggest non-inferiority of capecitabine/oxaliplatin compared to 5-FU/oxaliplatin, based on PFS analysis and combination regimens. Abstract 350 Preliminary Efficacy of Bevacizumab with First-Line FOLFOX, XELOX, FOLFIRI and Fluoropyrimidines for MCRC: First BEAT Berry S, Cunningham D, Michael M, Kretzschmar A, Rivera F, DiBartolomeo M, Mazier M, Van Cutsem E, on behalf of the First BEAT investigators First BEAT: Study Schema First-line metastatic CRC (1,965) Bevacizumab + standard chemotherapy PD • Bevacizumab: 5 mg/kg Q2W or 7.5 mg/kg Q3W • Endpoints: safety and efficacy • Median follow-up 22.9 months Berry et al, ASCO GI 2008, abstract 350. Serious BEV-Related Adverse Events Event (%) Any AE or SAE (N = 1,914) CTC grade 3–5 or SAE* (N = 1,914) Hypertension 29.9 5.3 Proteinuria 10.4 1.1 Bleeding 31.0 3.4 Wound-healing complications 4.0 1.1 Arterial thromboembolic events 1.5 1.5 GI perforation 1.9 1.8 Berry et al, ASCO GI 2008, abstract 350. First BEAT: Clinical Efficacy (PFS) Overall (N = 1914) Median PFS 10.9 FOLFIRI (N = 503) 11.6 FOLFOX (N = 552) 11.2 XELOX (N = 346) 11.0 5-FU/Capecitabine (N = 300) 8.6 Berry et al, ASCO GI 2008, abstract 350. Abstract 363 First-line Irinotecan, Oxaliplatin and Infusional 5FU/LV (FOLFOXIRI) in Combination with Bevacizumab (BV) in MCRC Patients (pts): A Phase II Study by the GONO Group Masi G, Loupakis F, Baldi G, Fornaro L, Di Leo A, Ciarlo A, Amoroso D, Granetto C, Di Donato S, Falcone A Study Design • Phase II trial evaluating first-line therapy with FOLFOXIRI plus Bev in patients with initially unresectable mCRC • Primary endpoint: PFS rate at 10 months Masi et al, ASCO GI 2008, abstract 363. First-Line Bev/FOLFOXIRI: Safety Toxicity (N = 38) G1 G2 G3 G4 Nausea 42 18 5 0 Vomiting 24 21 0 0 Diarrhea 24 24 8 0 Stomatitis 42 13 3 0 Neutropenia 18 13 21 13 Thrombocytopenia 26 0 0 0 Anemia 42 24 5 0 Neurotoxicity 34 24 3 0 Hypertension 18 3 8 0 Deep venous thrombosis 0 0 5 0 Bleeding 32 0 0 0 Cardiac ischemia 0 0 5 0 Masi et al, ASCO GI 2008, abstract 363. Bev/FOLFOXIRI: Clinical Efficacy Efficacy, N (%) Complete Response (CR) N = 29 2 (7) Partial Response (PR) 20 (69) Stable Disease (SD) 7 (24) Progressive Disease 0 Disease Control Rate (CR + PR + SD) 29 (100) Resection Rates R0 4 (14) R1 1 (3) Masi et al, ASCO GI 2008, abstract 363. Bev/FOLFOXIRI: Conclusions • First-line therapy with bevacizumab/FOLFOXIRI associated with high response rates (76%) and 100% tumor control, in patients with MCRC • High response rates coincided with high R0 resection rate in initially unresectable patients • Grade 3/4 toxicities included nausea, diarrhea, stomatitis, neutropenia, anemia, neurotoxicity, hypertension, deep vein thrombosis, and cardiac ischemia Abstract 273 An Updated Analysis of Safety and Efficacy of Oxaliplatin (Ox)/bevacizumab (bev) +/Panitumumab (pmab) for First-line Treatment (tx) of MCRC from a Randomized, Controlled Trial (PACCE) Hecht J. R., Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, Shahin S, Griffin T PACCE Phase III Trial S C R E E N I N G Ox-based CT (e.g., FOLFOX) N = 800 Inv choice Iri-basedCT (e.g., FOLFIRI) N = 200 Inv choice R A N D O M I Z E 1:1 Panitumumab + Bevacizumab Bevacizumab Panitumumab + Bevacizumab 1:1 Bevacizumab Stratification Factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs Tumor assessments: Q12W until disease progression or intolerability FOLFOX Chemotherapy: Efficacy Pmab + Bev-Ox (N = 413) Bev - Ox (N = 410) CR 0 <1 PR 45 46 SD 29 34 PD 7 4 mPFS, mos 9.6 11.1 mOS, mos 19.4 NR Hecht et al, ASCO GI 2008, abstract 273. PACCE Trial: Grade 3/4 Toxicity Skin toxicity Diarrhea Dehydration Hypokalemia Hypomagnesemia Neutropenia Neuropathy Nausea Infections DVT Pulmonary embolism Pmab + Bev Bev (N = 401), % (N = 392), % Gr 3 33 21 14 8 3 12 9 10 16 6 0 Gr 3 1 12 4 3 0 17 10 4 7 7 0 Gr 4 <1 2 2 2 1 10 <1 0 2 0 6 Gr 4 0 1 1 1 0 7 <1 <1 2 0 4 Hecht et al, ASCO GI 2008, abstract 273. Abstract 279 Interim Results from PACCE: Irinotecan (Iri)/bevacizumab (bev) + Panitumumab (pmab) as First-line Treatment (tx) for MCRC Hecht J. R., Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, Suzuki S, Griffin T FOLFIRI Chemotherapy: Efficacy Pmab+ Bev-Iri (N = 115) Bev-Iri (N = 115) CR 0 0 PR 43 39 mut KRAS (N = 46) 30 38 WT KRAS (N = 57) 54 47 SD 27 38 PD 13 3 mPFS, mos 10.1 11.7 mOS, mos 20.7 20.5 Hecht et al, ASCO GI 2008, abstract 279. PACCE FOLFIRI Chemotherapy: Discontinuation of Treatment Reason for Discontinuation, N(%) Pmab+ Bev-Iri (N = 115) Bev-Iri (N = 115) Discontinued First-line 102 (89) 99 (86) Disease Progression 36 (35) 27 (27) 6 (6) 2 (2) 17 (17) 6 (6) 3 (3) 5 (5) 15 (15) 33 (33) Death Adverse Events Protocol Violation Consent Withdrawn Hecht et al, ASCO GI 2008, abstract 279. PACCE: Safety Analysis of FOLFIRI Arms Pmab+ Bev/Iri (N = 111) Adverse Event, % Bev/Iri (N = 113) Grade 3 Grade 4 Grade 3 Grade 4 Skin Toxicity 37 0 0 0 Diarrhea 27 1 9 0 Neutropenia 14 3 17 4 Dehydration 14 0 6 0 Infections 12 2 9 0 Nausea 10 2 6 0 Hypokalemia 9 2 4 0 Vomiting 8 2 7 0 Paronychia 4 0 0 0 Hypomagnesemia 3 2 0 1 Hypertension 2 0 3 0 Deep Vein Thrombosis 13 0 6 0 Pulmonary Embolism 0 11 0 5 Hecht et al, ASCO GI 2008, abstract 279. PACCE Trial: Conclusions • Addition of panitumumab to oxaliplatin-containing chemotherapy+bevacizumab worsened PFS and increased toxicity • Panitumumab added to irinotecan modestly increased response, although PFS and OS were similar for both treatment arms • Toxicity of panitumumab/bev-iri was considerable, additionally causing 2% grade 5 infections and gastrointestinal perforation, and 1% grade 5 pulmonary embolism • Most patients discontinued treatment for non-progressive events • Panitumumab/bev-iri improved response rates (54% vs. 47%) in patients with wild type KRAS tumor status • Evaluation of toxicity is ongoing Role of K-RAS Mutations as Predictive Biomarker • K-RAS: Downstream signalling molecule in EGFR signalling pathway1 • Lower response to erlotinib and gefitinib in NSCLC2,3 – erlotinib: 8% responders in patients with mutations vs 26% in wild-type K-RAS – gefitinib: 24% refractory tumors with K-RAS mutations vs 0% in drug-sensitive tumours (P = 0.02) • Lower response to cetuximab in CRC4 – 0% responders in patients with mutations vs 49% in non-mutated patients (P < 0.001) 1Calvo & Baselga, J Clin Oncol 2006; 14: 2158. et al, J Clin Oncol 2005; 23: 5900. 3Pao et al, PLoS Med 2005; 2: e17. 4Lièvre et al, AACR Annual Meeting 2007; Abstract 5671. 2Eberhard Abstract 278 Panitumumab Efficacy and Patient-Reported Outcomes in MCRC Patients with Wild-Type KRAS Tumor Status Amado R, Wolf M, Freeman D, Peeters M, Van Cutsem E, Siena S, Suggs S, Devercelli G, Woolley M, and Chang D KRAS Analysis of a Phase III Trial of Panitumumab as Salvage Therapy for MCRC R A N D O M I Z E Panitumumab 6.0 mg/kg Q2W + BSC PD BSC PD Optional Crossover Stratification • ECOG score (0-1 vs. 2) • Geographic region (Western EU vs. Central & Eastern EU vs. Rest of World) Van Cutsem E et al. J Clin Oncol 25:1658–1664, 2007. Molecular Composition of Treatment Arms Screened N = 1,040 Tumors screened for KRAS mutation status using DxS, LTD kit Randomized N = 463 Randomized to panitumumab + BSC N = 231 Randomized to BSC alone N = 232 Excluded from KRAS analyses (missing or unevaluable) N = 36 KRAS mutant N = 84 WT KRAS N = 124 KRAS mutant N = 100 Received P’mab in X-over protocol N = 77 BSC = Best supportive care; WT = wild-type WT KRAS N = 119 Received P’mab in X-over protocol N = 90 Amado 2008 ASCO GI abstract #278 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 Mutant PR (0%) SD (12%) PD (70%) PR (0%) SD (8%) PD (60%) % Change BSC Alone % Change Patient 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 Wild-Type PR (17%) SD (34%) PD (36%) % Change Pmab + BSC % Change Percent Decrease of Target Lesions in KRAS Evaluable Patients Patient BSC = Best supportive care; Pmab = panitumumab 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 Patient PR (0%) SD (12%) PD (75%) Patient Amado et al, ASCO GI 2008, abstract 278. KRAS Mutation Status and Efficacy of Single Agent Panitumumab BSC Pmab HR Median PFS, weeks mut KRAS wt KRAS 7.3 (N = 100) 7.4 (N = 84) 7.3 (N = 119) 12.3 (N = 124) 0.99 0.45 (P < .0001) Median OS, months mut KRAS 4.4 (N = 100) 4.9 (N = 84) NR wt KRAS 7.6 (N = 119) 8.1 (N = 124) NR BSC, basic supportive care; NR, not reported Amado et al, ASCO GI 2008, abstract 278. Conclusions • Salvage single agent panitumumab significantly (P < .0001) improved PFS in patients with KRAS wild type tumors with no benefit in those having mutant KRAS tumors • Only patients with wild type KRAS benefited from single agent panitumumab in the salvage setting • Long-term outcome of patients was primarily dictated by KRAS mutation status • Future studies will focus on prospective analysis of the efficacy of panitumumab-containing combination therapy in patients with wild type and mutant KRAS tumors Abstract 343 Panitumumab Efficacy in Patients with MCRC with Low or Undetectable Levels of Epidermal Growth Factor Receptor: Final Efficacy and KRAS Analysis Hecht JR, Mitchell EP, Baranda J, Richards D, Reiner M, Stout S, Amado RG Trial Design • Phase II single-arm, open-label study • Patients received panitumumab 6 mg/kg (Q2W) until disease progression or unacceptable toxicity • Previous analyses indicated that panitumumab efficacy is independent of tumor EGFR expression levels (Mitchell, ASCO 2007 abstract 4082, Hecht, ASCO GI 2007 abstract 350) • Exploratory analysis of KRAS mutation status – Total of 203 pts enrolled – EGFR expression levels available for 195 pts – KRAS mutation status available for 171 pts (55% wild type, 45% mutant) Hecht et al, ASCO GI 2008, abstract 343. Panitumumab in Low EGFR Expressors: KRAS and Efficacy EGFR Expression KRAS Status <1% 1%-9% Wild type Mutant (N = 81) (N = 111) (N = 94) (N = 77) Objective Response — — 12% 0 Stable Disease — — 47% 14% Median PFS, mos 8.1 8.1 15.0 7.1 Median OS, mos 41.6 37.4 54.0 29.1 Efficacy Measure Hecht et al, ASCO GI 2008, abstract 343. Conclusions • Patients received panitumumab 6 mg/kg (Q2W) until disease progression or unacceptable toxicity • EGFR expression levels, by immunohistochemistry, do not correlate with clinical benefit in treated patients • Response to panitumumab in treated patients correlates with wild-type KRAS status • Progression-free survival is doubled, and overall survival nearly doubled, when comparing clinical benefit in patients with wild type and mutant KRAS Hecht et al, ASCO GI 2008, abstract 343. Abstract 411 High Amphiregulin and Epiregulin Expression in KRAS Wild Type Colorectal Primaries Predicts Response and Survival Benefit After Treatment with Cetuximab and Irinotecan for Metastatic Disease Tejpar S, De Roock W, Biesmans B, De Schutter J, Piessevaux H, Humblet Y, Peeters M, Celik I, Van Cutsem E Study Design • Primary tumor specimens from patients treated on clinical trials with cetuximab and irinotecan for metastatic colorectal carcinoma • 152 patients with irinotecan-refractory disease were identified who had been treated with cetuximab • Tumors were analyzed for KRAS mutation status and amphiregulin and epiregulin mRNA levels Tejpar et al, ASCO GI 2008, abstract 411. Findings • mRNA levels of epiregulin and amphiregulin were significantly correlated (P < .0001) • KRAS was mutated in 43% (64/149) patients • Wild type KRAS and high EGFR ligand levels significantly correlated (P = .03 for amphiregulin and P = .02 for epiregulin) with each other • Response correlated with mutation status: ORR was 39.7% for patients with wild type KRAS and < 1% for those with mutant KRAS • Patients who achieved objective response were approximately 4 times more likely to have tumors with high (above median) levels of amphiregulin and epiregulin Tejpar et al, ASCO GI 2008, abstract 411. Findings KRAS Status All Wild-type Mutant Epiregulin Exp. Median PFS mos Median OS mos < 0.5233 12 26 > 0.5233 30 45.86 Overall 18 36 < 0.5233 12 31.57 > 0.5233 36 65.4 Overall 24.14 44.29 < 0.5233 12 22.86 > 0.5233 12 29.14 Overall 12 24.3 P < .001 P < .001 Tejpar et al, ASCO GI 2008, abstract 411. Conclusions • Patients with irinotecan-refractory disease who have mutant KRAS status received no benefit from cetuximab treatment in terms of response • Patients with tumors expressing above-median levels of epiregulin and amphiregulin, excluding those with mutant KRAS, have significantly longer progression-free and overall survival than those with below-median levels • This study supports the notion that response to cetuximab therapy depends upon KRAS status, and further suggests that patients with high expression of epiregulin and amphiregulin benefit the most from cetuximab therapy Tejpar et al, ASCO GI 2008, abstract 411. A Report from ASCO GI 2008 Up-to-Date Review of the Treatment of Metastatic Colorectal Cancer Thank You!