Novel Biologics in the Treatment of Colorectal Cancer Howard S. Hochster, MD Professor of Medicine, NYU School of Medicine Director, GI Program NYU Cancer Institute
Current Therapies • Fluoropyrimidines • Oxaliplatin • Irinotecan • Bevacizumab; anti-angiogenic MoAB • Cetuximab; anti-growth factor MoAB
Multivariate analysis: Effect on OS P First-line doublet 0.69 All 3 drugs 0.005 Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients 22 21 20 19 18 17 16 15 14 13 12 First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 Median OS (mo) P =.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) OS (mos) = 13.2 + ([%3drugs] x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005 Source: Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005;23(36):9441-2. Adapted with permission from the American Society of Clinical Oncology.
Functions of Cell Surface Receptors The best targeted therapies may be those that mediate cell survival
AN INTERESTINGDILEMMA: Bevacizumab studied with bIFL; how will it be used with oxaliplatin-based Rx?
THE TREE TRIAL (2 cohorts)comparing oxaliplatin schedules TREE-1 Rationale • Given that: • 5-FU may be administered as an infusion, a bolus, or as an oral prodrug formulation • 3 oxaliplatin-fluoropyrimidine regimens would have: • Similar efficacy, if there were equivalent dose intensities • Variant AE profiles, related to the mode of fluoropyrimidine administration
RANDOMI ZAT ION RANDOMI ZAT ION TREE-1 and TREE-2: Treatment Schema TREE-1 (N=150) (Nov 2002-Oct 30, 2003) TREE-2 (N=223) (Nov 2003 – April 2004) mFOLFOX6 (q14 days) Oxaliplatin-85 mg/m2 LV-350 mg (fixed dose) 5-FU-400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hrs on D1 mFOLFOX6 + Bevacizumab (5 mg/kg q14 days) bFOL (every 28 days) Oxaliplatin - 85 mg/m2 IV x 2 hrs days 1,15 LV - 20 mg/m2 IV bolus on Days 1,8,15 5-FU - 500 mg/m2 IV bolus on Days 1,8,15 bFOL + Bevacizumab (5 mg/kg q 2 weeks) CapeOx Capecitabine 850 mg/m2 bid day 1-5 + Bevacizumab (7.5 mg/kg q21days) CapeOx (q21days) Oxaliplatin-130 mg/m2 over 2 hours on D1 Capecitabine-1000 mg/m2 twice daily on Days 1-15
TREE-1 vs. TREE-2: Demographics * ITT population
TREE-1: 5-FU/Capecitabine Dose Reductions • DSMB recommended that the capecitabine dose be reduced (to 850 mg/m2 b.i.d. x 14 days) in the CapeOX arm (30/10/03)
TREE-1 vs. TREE-2Comparative Grade 3/4 toxicities –First 12 weeks of treatment
TREE-2: Absolute Number of Patients with Specific Treatment-related Toxicities
TREE-1 vs. TREE-2Comparative Response Rate CapeOX bFOL FOLFOX • (p<0.004, from the pooled logistic regression analysis, likelihood ratio test)
TREE-1 vs. TREE-2Comparative Analysis Hochster et al., ASCO 2005 and GI ASCO 2006
TREE-2 Conclusions • Two sequential cohorts within same protocol, same investigators • CapeOX not tolerated at 1000 mg/m2 bid x 14 days; good tolerance at 850 mg/m2 bid • Addition of Bevacizumab to oxaliplatin plus fluoropyrimidines is safe with expected toxicities and overall gr 3-4 rates • Addition of Bevacizumab increases RR by approximately 10% • Also improves TTP • TTF is increased less by bevacizumab
All TKIs Are Not the Same • Chemical differences • PK differences • Differences in spectrum of activity • VEGFR and other receptors • Differences in toxicity
1st Generation PTK787 /ZK 22854 SU5416 SU6668 SU11248 Newer Inhibitors AAL993 CEP-7055 CP-547,632 GW654652 AMG 706 AZ 2171 Combined Inhibitors ZD6474 AEE788 BAY 43-9006 Small Molecule Inhibitors
PTK787/ ZK 225846 (Vatalanib) • Aminophthalazine • Well tolerated oral inhibitor of VEGFR-1,2,3 • Also inhibits c-kit and PDGFR • Promising phase I, II data • Inhibits blood flow on DCE-MRI • CONFIRM 1-2 trials
Phase III Trial of Vatalanib in First-Line MCRC (CONFIRM-1) RANDOMIZATION • Primary end point: PFS, OS • Secondary end points: TTP, TTF, ORR n=583 FOLFOX4 + placebo PD • Previously untreated MCRC • WHO PS 0-2 n=585 FOLFOX4 + Vatalanib 1250 mg po qd PD Hecht et al. ASCO, 2005. Abstract 3. Updated from oral presentation.
Phase III Renal Cell Cancer è Interim analysis positive Filed for market approval in RCC è July 2005 Phase III Hepatocellular Carcinoma è Started March 2005 Phase II/III Malignant Melanoma è Started May 2005 Sorafenib (BAY 43-9006)
Randomized Discontinuation Design represents an innovative approach for studying novel anticancer drugs Bayer and Onyx were the first to apply this design in a major oncology setting Tumor shrinkage ≥25% Sorafenib open label Sorafenib 12 weeks Sorafenib 12-week run-in Tumor growth/ shrinkage <25% % Progression free at 24 weeks Placebo* 12 weeks Tumor growth ≥25% Off study Randomized Discontinuation Study – Treatment Plan N= 79 N=32 N= 166 N=202 N=33 * Placebo patients who progressed could cross over to sorafenib Ratain MJ, et al. Presented at: ASCO; May 13-17, 2005; Orlando, Fla.
≥25% growth <25% change ≥25% shrinkage Data shown for 166 patients (12-week bidimensional measurements were not available for 36 patients). Tumor Size Changes After 12 Weeks of Treatment as Measured by Radiographic Measurements 125 100 Patients with increase in tumor size 75 50 25 % change from baseline in bidimensional tumor measurement 0 -25 -50 Patients with decrease in tumor size -75 -100 Source: With permission. Ratain MJ et al. Presentation. ASCO 2005. Abstract 4544
Sorafenib (n=32) Placebo (n=33) Censored Median Progression-Free Survival for Patients with Renal Cell Cancer Randomized to Placebo or Sorafenib 1.00 0.75 Median progression-free survival from randomization:Placebo=6 weeksSorafenib=24 weeksp=0.0087 Proportion of patients progression-free 0.50 0.25 0.00 -84 0 100 200 300 400 500 12-week run-in period Days from randomization Source: With permission. Ratain MJ et al. Presentation. ASCO 2005. Abstract 4544
AZD2171 Clinical Data • Extensive and innovative phase I program in a number of tumours: • 253 patients treated in monotherapy and combination studies • Program has led to a clear view of: • Pharmacokinetics • Evidence of inhibition of VEGF signalling in man • Initial evidence of anti-tumour activity • Tolerability profile • Dosing strategy
VEGF TrapPhase I experience • Phase I SQ administration • 25 ug/kg 800 q week 800 ug sq biw • 8/10 stable at 800 ug/kg q wk or biw; one PR in refractory BAL NSCLC • Toxicity: HTN, proteinuria • T ½ = 25 + 3 days • Phase I IV administration • 0.3 5 ug/kg iv q 2 wks • Usual toxicities • PR: ovarian (ascites), thymoma; 2 MRs
IV VEGF Trap Program:Summary of Ongoing Phase I and Phase II Studies • Phase I Single-Agent IV Study • Phase Ib Combination-Agent Studies • Phase Ib combination with oxaliplatin/5-FU/LV (FOLFOX4) • Phase Ib combination with LV5FU2-CPT11 • Phase Ib combination with docetaxel/cisplatin/ fluorouracil • Phase Ib combination with docetaxel, then docetaxel/cisplatin • Phase Ib combination with gemcitabine, then GEMOX • Phase II Single-Agent Studies • 3rd Line Non-Small-Cell Lung Adenocarcinoma • 3rd-Line Advanced Ovarian Cancer • Advanced Ovarian Cancer with Symptomatic Malignant Ascites
PropertiesCetuximab/IMC-C225 • IgG1 (chimerized antibody) • Exclusive for EGFR and its heterodimers • Prevents ligand binding to EGFR • Binds to EGFR with high affinity (Kd = 2.0 x 10–10 M) = ONE log higher than the natural ligand • Stimulates receptor internalization • Blocks receptor dimerization, tyrosine kinase phosphorylation, and signal transduction
Cetuximab ± Irinotecan in CRC Schema n=218 Irinotecan dose and schedule used during progression Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week Patients with CRC progressed on or within 3 months of irinotecan-based chemotherapy RANDOMIZATION Irinotecan dose and schedule used during progression Cetuximab 400 mg/m21st infusion, then 250 mg/m2/week Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week n=111 PD Cunningham D, et al. Proc Am Soc Clin Oncol. 2003;22:252. Abstract 1012 and oral presentation (slide 6).
Combination Antibody Therapy MCRCNCI 5844 (“BOND-2”) Bevacizumab + cetuximab Primary end point: Response rate Patients with MCRC who progressed with irinotecan (N=150) Bevacizumab + cetuximab + irinotecan At: http://ctep.cancer.gov/forms.
Efficacy Comparison (Historical Controls) “BOND” “BOND-2”
CALGB/SWOG Intergroup Trial 80405 Bevacizumab “Dealer’s Choice” FOLFOX or FOLFIRI Cetuximab R Bevacizumab +Cetuximab N=2289 Primary endpoint: OS HR 1.25 (22 vs 27.5 months)
PACCE Trial* Bevacizumab “Dealer’s Choice” FOLFOX or FOLFIRI R Bevacizumab +Panitumumab N=1000 Primary endpoint: PFS PACCE: Panitumumab Advanced Colorectal Cancer Evaluation; opened April 2005
Strategies for future developments • “Pile-on” Approach • Combo-chemo+bev • Combo-chemo + bev + cetuximab • Combo-chemo + bev + TKI + cetuximab • Combo-chemo + bev + cetuximab + novel biologic 1 + novel biologic 2 • Semi-STOP and GO • Biologic interludes • Avoid cytotoxics altogether
CONCLUSIONS • Combination Chemotherapy • Effective; “all 3-drugs” OS plateau • Platform for biologics • Angiogenesis Pathway • Validated target for combination with chemotherapy • Multiple approaches • Combinations of VEGF inhibitors? • Growth Factor Pathway • EGFR inhibitors validated • Can we use EGFR-TKIs in colorectal cancer
CONCLUSIONS • Studies underway combining dual-blockade with two antibodies plus chemotherapy • Future goals • Improved survival, decreased toxicity • Identifying the correct target • Confirming adequate inhibition of target