EGFR Inhibitors in Colorectal Cancer

EGFR Inhibitors in Colorectal Cancer John L. Marshall, MD Lombardi Comprehensive Cancer Center Ligand Binding and Dimerization Results in TK Activation EGF TGF Homodimer Heterodimer High affinity binding ATP ATP ATP Ligand Binding Dimerization Phosphorylation and Activation Source: With permission from Amgen Inc. EGFR Activation and Signaling Pathways Ligand Ligand EGFr dimer Grb-2 Shc Grb-2 P13K MAPK = mitogen-activated protein kinase P13k = phosphatidylinositol 3-kinase mTOR Transcription Factors SOS Ras SOS Signal Adapters and Enzymes PTEN Akt Raf MEK 1/2 FKHR GSK-3 BAD MAPK Signal Cascade Jun FOS Myc p27 Cyclin D-1 Source: With permission from Amgen Inc. EGFR Activation Mediates Several Processes EGFr Activation Tumor Spread of cancer cells Blood Vessel Metastatic Spread Cell Survival Tumor Blood Vessel Angiogenesis Proliferation Source: With permission from Amgen Inc. EGFR Expression Correlates With Poor Prognosis in Selected Solid Tumors Tumor Type EGFR Expression (%) •NSCLC •40-80 •SCCHN •Colorectal •Glioblastoma •Breast •95 •25-77 •40-60 •14-91 •Prostate •Ovarian •Esophageal •Pancreatic •41-100 •35-70 •35-88 •30-50 *Responses observed in various solid tumors for gefitinib, erlotinib, and cetuximab. SCCHN = squamous cell carcinoma head and neck. Arteaga C. Semin Oncol. 2003;30(suppl 7):3-14. Anti-EGFr Monoclonal Antibodies Monoclonal Antibody Cetuximab (C-225) Description Status Approved: Colorectal cancer Submitted: Head and Neck (H&N) cancer Phase 2: NSCLC, Others Phase 2 Trials: Recurrent ovarian cancer, NSCLC Phase I-2 Trials: Colorectal cancer Phase 2-3 Trials: Colorectal cancer, NSCLC, Others Chimeric IgG1 Matuzumab (EMD 72000) Panitumumab (ABX-EGF) Humanized IgG1 Fully human IgG2 Mendelsohn J. J Clin Oncol. 2002;20(suppl 18):1s-13s. Sridhar SS, et al. Lancet Oncol. 2003;4:397-406. www.clinicaltrials.gov Tewes M, et al. Proc Am Soc Clin Oncol. 2002. Abstract 378. Vanhoefer U, et al. J Clin Onc 2004;22(1):175-184 Properties of Cetuximab  IgG1 MAb (chimerized)  Binds specifically to EGFR and its heterodimers  Binds to EGFR with high affinity (Kd = 2.0 x 10–10 M): 1 log higher than the natural ligand  Following the recommended dose regimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), the mean half-life was 114 hours (range 75-188 hours)  Competitively inhibits ligand binding to EGFR  Stimulates receptor internalization  Blocks receptor dimerization, tyrosine kinase phosphorylation, and signal transduction Shitara K, et al. Cancer Immunol Immunother. 1993;36:373-380. LoBuglio AF, et al. Proc Natl Acad Sci U S A. 1989;86:4220-4224. ERBITUX Package Insert, June 2004. Data on file. ImClone Systems Incorporated and Bristol-Myers Squibb Company; 2004. Cetuximab Randomized Pivotal Trial in Metastatic Colorectal Cancer Randomized Phase II Study Design Patients with EGFR-expressing metastatic CRC progressed after receiving irinotecan-based chemotherapy CETUXIMAB with irinotecan n = 218 RANDOMIZATION CETUXIMAB as a single agent n = 111 ERBITUX Package Insert, June 2004. Cetuximab Randomized Pivotal Trial in Metastatic Colorectal Cancer Patient Baseline Demographics Characteristic Gender, % Male Female Age, y Median Range Karnofsky Performance Status, % < 80  80 Prior oxaliplatin treatment, % ERBITUX Package Insert, June 2004. All Patients (n = 329) 63 37 59 26-84 12 88 63 Cetuximab/C225 in Colon Cancer RR TTP CPT-11 + C225 2:1 OS 8.6 22.9 4.1 54 pts crossover C225 alone 10.8 1.5 6.9 Source: Cunningham D et al. N Engl J Med 2004;351:337-45. The “Bond” Trials C225 Alone C225 + Bev P Value C225 + CPT-11 C225 + P Value CPT-11 + Bev PR TTP OS 11% 23% 0.05 23% 38% 0.03 1.5 mo 6.9 mo 5.6 mo NR >0.01 4.1 mo 8.6 mo 7.9 mo NR >0.01 - - Sources: Cunningham D et al. N Engl J Med 2004;351:337-45. Saltz L et al. Presentation. ASCO GI Symposium 2005. Abstract 169b Cetuximab in the first line? • FOLFIRI + Cetuximab – 59% PR (13/22) 36% SD (8/23) • Raoul et al ECCO 2003 • FOLFOX + Cetuximab – 81% PR • ASCO 2004 – 82% CR/PR, 12.5 median PFS • ASCO 2005 Sources: Raoul et al. Proc ECCO 2003;Abstract 289. Tabernero JM et al. Proc ASCO 2004;Abstract 3512. Rubio ED et al. Proc ASCO 2005. Abstract 3535 Monoclonal Antibodies as Targeted Therapy: Evolution to Fully Human Antibody Chimeric Mouse Humanized Fully Human 100% Mouse Protein 34% Mouse Protein 10% Mouse Protein 100% Human Protein mouse human cetuximab matuzumab panitumumab Panitumumab Phase 2 Study: Monotherapy for CRC - Methods • Eligibility requirements: – Metastatic colorectal carcinoma, ECOG 0-1 – Measurable disease – Failed prior therapy with a fluoropyrimidine +/- leucovorin, and either irinotecan, oxaliplatin or both – EGFr overexpression by immunohistochemistry • Cohort A: 2+ or 3+ in > 10% of tumor cells • Cohort B: 2+ or 3+ in < 10%, but 1+, 2+ or 3+ in >10% of tumor cells Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511. - poster Panitumumab Phase 2 Study: Monotherapy for CRC - Methods • Dose: 2.5 mg/kg – Infused over 1 hour – No loading dose – Administered without premedication – Given weekly until disease progression or unacceptable toxicity • Assessments: – Toxicity assessed weekly – Tumor assessment every 8 weeks Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511. - poster Panitumumab Phase 2 Study: Monotherapy for CRC – Toxicity (Treatment-related Adverse Events) Toxicity Rash Fatigue Diarrhea Vomiting All Grade 140 (95%) 34 (23%) 30 (20%) 10 (7%) Grade 3 5 (3%) 3 (2%) 1 (1%) 2 (1%) Grade 4 0 0 0 0 Selected Treatment-emergent adverse events reported through cycle 2 as possibly, probably, or definitely related to panitumumab Events starting before cycle 1 or after the first infusion in cycle 3 are excluded. Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511, poster. Data on file. Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study: Methods • Multicenter, open-label, single-arm study consisting of 2 parts: – Part 1: Patients (N=19) received 1st line panitumumab/IFL therapy: • Panitumumab 2.5 mg/kg/week administered intravenously over 1 hour in 6-week courses (days 1, 8, 15, 22, 29 and 36), immediately followed by: • IFL regimen: irinotecan (IR) 125 mg/m2, leucovorin (LV) 20 mg/m2, 5-fluorouracil (5FU) 500 mg/m2 on days 1, 8, 15 and 22 • Enrollment for Part 1 is closed – Part 2: Patients received 1st line panitumumab/FOLFIRI therapy • Part 2 is ongoing with enrollment closed (N=24); patients are continuing therapy Berlin J, et al. ESMO 2004. a265 Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study, Part 1: Skin Toxicity Skin Toxic Worst Severity All Patients (N=19) Mild Moderate Severe Life-Threatening 9 (47%) 7 (37%) 3 (16%) 0 ( 0%) Median (95% CI) Time to Onset, days 11.0 (7.0, 15.0) Berlin J, et al. ESMO 2004. a265 Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study, Part 1: Efficacy All Patients (N=19) Overall Response Partial Response Complete Response Stable Disease Progressive Disease No Assessment 9 (47%) 8 (42%) 1 ( 5%) 6 (32%) 1 ( 5%) 3 (16%) Treated pts received at least 1 dose of panitumumab or 1 dose of IFL Berlin J, et al. ESMO 2004. a265 Randomized Controlled Phase 3 Trial in mCRC R A N D O M I Z E 1:1 Panitumumab 6.0 mg/kg Q2W + BSC PD Follow-up BSC PD Optional Panitumumab Crossover Study Follow-up Randomization stratification • ECOG score: 0-1 vs. 2 • Geographic region: Western EU vs. Central & Eastern EU vs. Rest of World Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Study Endpoints Primary • Progression-free survival (per blinded central radiology assessment of modified-RECIST criteria) Secondary • Overall survival time and best overall objective response (central radiology) - co-secondary • Duration of and time to response Safety • Incidence of adverse events (including all, grade 3/4, treatment related events), antibody formation Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Key Eligibility Criteria • Metastatic colorectal adenocarcinoma (mCRC) • ECOG score 0 to 2 • Radiologic documentation of disease progression after fluoropyrimidine, irinotecan, and oxaliplatin – During or within 6 months following most recent chemotherapy regimen – Failure after prespecified doses of irinotecan and oxaliplatin • EGFr membrane staining on ≥ 1% tumor cells (IHC, central laboratory) • Adequate hematologic, renal, and hepatic function Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Demographics and Disease Characteristics Panitumumab Plus BSC (N=231) Sex – n (%) Men Women Median (range) age – years ECOG status – n (%) 0-1 ≥2 Number of metastatic sites – n (%) 1-2 3-5 Prior adjuvant chemotherapy – n (%) Prior chemotherapy – n (%) At least 2 lines At least 3 lines Mean (SD) % of tumor cells with EGFr membrane staining Intensity of EGFr staining – n (%) 3+ (strong) 2+ (moderate) 1+ (weak) 0 (none) 47 (20) 122 (53) 60 (26) 2 (1) 41 (18) 113 (49) 78 (34) 0 (0) 146 (63) 85 (37) 62 (27, 82) 201 (87) 30 (13) 161 (70) 70 (30) 86 (37) 230 (100) 84 (36) 32.5 (29.3) BSC Alone (N=232) 148 (64) 84 (36) 63 (27, 83) 195 (84) 37 (15) 161 (70) 69 (30) 78 (34) 232 (100) 88 (38) 27.5 (26.1) Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Progression-Free Survival 1.0 0.9 Event-free Probability 0.8 0.7 Hazard ratio=0.54 (95% CI: 0.44, 0.66) Stratified log-rank test p < 0.000000001 Panitumumab BSC 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 8 118 75 16 49 17 Patients at risk: Panitumumab 231 BSC 232 24 32 40 Weeks from Randomization 31 7 13 3 5 1 48 1 1 56 Primary Analysis, All Randomized Analysis Set, Central Radiology Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Kaplan- Meier Progression-Free Survival Rates at Prespecified Time Points % Progression Free (95 % CI) 60% 49% Panitumumab (N=231) BSC (N=232) 35% 30% 26% 30% 18% 20% 10% 0% Wk 8 Patients at risk: Panitumumab BSC 118 75 50% 40% 14% 9% 5% 10% 4% 4% 1% Wk 40 5 1 1%1% Wk 48 1 1 Wk 12 76 31 Wk 16 49 17 Wk 24 31 7 Wk 32 13 3 Primary Analysis, All Randomized Analysis Set, Central Radiology Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Overall Survival – Interim Analysis (All Randomized Analysis Set) 1.0 Panitumumab (N=231) BSC (N=232) Hazard ratio=0.93 (95% CI 0.73, 1.19) Stratified log-rank p = 0.6065 0.9 0.8 % Surviving 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 21 16 20 18 11 12 6 8 5 7 3 5 0 3 0 1 0 0 0 0 Patients at risk: Panitumumab 231 219 204 170 136 103 81 60 232 221 199 175 139 98 76 60 BSC Note: There were 250 events Months from Randomization 47 31 41 29 Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Overall Survival: Censored BSC Patients Who Subsequently Responded After Crossing Over 1.0 Panitumumab BSC HR= 0.78 (95% CI: 0.61, 1.01) 0.9 Survival Probability 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 Patients at risk: Panitumumab 231 219 204 170 136 103 81 60 47 BSC 232 219 194 149 113 71 51 38 26 7 8 9 10 11 12 13 14 15 16 17 18 19 Months from Randomization 31 21 16 17 10 8 11 5 6 2 5 2 3 2 0 2 0 0 0 0 0 0 Note: BSC patients censored at the time that they received their first dose of panitumumab; Included confirmed and unconfirmed responses by investigator (RECIST criteria) Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Safety – Grade 3/4 Adverse Events Panitumumab (N = 229) Patients with any grade 3 or 4 event Abdominal pain Fatigue Dyspnea Anorexia Jaundice Asthenia Vomiting Ascites Diarrhea Intestinal obstruction Paronychia Deep vein thrombosis Pulmonary embolism Grade 3 75 (33) 17 (7) 10 (4) 9 (4) 7 (3) 7 (3) 6 (3) 5 (2) 3 (1) 3 (1) 3 (1) 3 (1) 2 (1) 0 (0) Grade 4 4 (2) 0 (0) 0 (0) 2 (1) 0 (0) 1 (0) 1 (0) 0 (0) 1 (0) 0 (0) 4 (2) 0 (0) 1 (0) 1 (0) BSC (N = 234) Grade 3 41 (18) 8 (3) 7 (3) 8 (3) 5 (2) 3 (1) 5 (2) 2 (1) 2 (1) 0 (0) 2 (1) 0 (0) 0 (0) 0 (0) Grade 4 4 (2) 3 (1) 0 (0) 0 (0) 0 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) MedDRA version 8.0 preferred terms; graded per NCI CTCAE version 2.0 Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Overall Survival by Worst Grade of Skin Toxicity in the Panitumumab Patients 1.0 0.9 0.8 Survival Probability 0.7 0.6 0.5 0.4 Grade 2-4 Grade 1 Hazard ratio = 0.61a (95% CI: 0.40, 0.95) p = 0.0278 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months from Randomization 39 8 29 5 17 4 13 3 9 2 6 0 5 0 1 0 0 0 0 0 Patients at risk: Grade 2-4 Grade 1 a 152 150 138 120 99 71 58 57 55 47 34 24 20 12 Hazard ratio for Grade 2-4 relative to Grade 1, stratified by ECOG and geographic region Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1 Conclusions and Questions • EGFR antibodies are active in colon cancer • Skin rash toxicity is the biggest barrier to more widespread use • Approval(s) in “last line” therapy – Role in 1st line or adjuvant to be determined