Colorectal Cancer Treatment Future irections Margot F. Sweed CRNP Fox Chase Cancer Center M_Sweed Sweed@FCCC. @FCCC.edu April 2005 What s the Target? Agents in clinical trials PTK 787/ZK SUO11248 Panitumumab Mapatumumab Sorafemib Pharmacogenomics what s the best treatment? Agents Targeting the VEGF Pathway Anti-VEGF antibodies (bevacizumab) Ribozymes (Angiozyme) P P P P VEGFR-1 VEGF P P P P VEGFR-2 Endothelial cell Soluble VEGF receptors (VEGF-Trap) Anti-VEGFR antibodies (IMC-1121b) Small-molecule VEGFR inhibitors (PTK-787) The VEGF Family of Angiogenic Factors VEGFs are a family of angiogenic factors secreted by tumors in response to hypoxia and other stimuli Five members of the VEGF family play important roles in angiogenesis:, VEGF-B,,, VEGF-E VEGFs induce endothelial cell division and migration resulting in the formation of new blood vessels vorak HF, et al. Curr Top Microbiol Immunol. 1999;237:97-132. VEGFs Bind and Activate VEGF Receptors on Endothelial Cells Extracellular Intracellular VEGF-B VEGFR-1/Flt-1 VEGF-E VEGFR-2/KR Adapted from vorak HF. J Clin Oncol. 2002;20(21):4368-4380. Tyrosine Kinase VEGFR-3/Flt-4 Lymphangiogenesis Tumor metastasis Signal Transduction Receptor-ligand interactions at the cell- surface trigger messaging pathways within the cell that direct tumor cell survival, proliferation and differentiation. The systems that convey cell surface signals to the cytoplasm and nucleus are mediated through protein-protein communication. signal transduction Cross talk between pathways Cohen SJ, Cohen RB, Meropol NJ, 2005 1
PTK/ZK A multi-vegf Receptor Inhibitor PTK/ZK inhibits activation of VEGF receptors: VEGFR-1, VEGFR-2, and VEGFR-3 Binds and Inhibits A Only Extracellular VEGF-B VEGF-E Complete inhibitor of the VEGF receptor tyrosine kinases that are critical for tumor angiogenesis and metastasis 1,2 PTK/ZK is being codeveloped by Pharma AG and Schering AG, Germany 1. Wood JM, et al. Cancer Res. 2000;60:2178-2189. 2. Bold G, et al. J Med Chem. 2000;43(12):2310-2323. Intracellular VEGFR-1/Flt-1 VEGFR-2/KR VEGFR-3/Flt-4 Adapted from vorak H. J Clin Oncol. 2002;20(21):4368-4380. Hsei V, et al. Pharm Res. 2002;19(11):1753-1756. Lymphangiogenesis Tumor metastasis PTK/ZK Phase III CONFIRM Trials Two multinational, randomized, double-blind, blind, placebo-controlled controlled trials in patients with metastatic colorectal cancer 1,250 mg PTK/ZK administered orally once daily in combination with oxaliplatin in the FOLFOX4 regimen CONFIRM 1: Previously untreated patients Endpoint: Progression-free survival and overall survival CONFIRM 2: Patients who have failed Irinotecan/5 FU Endpoints: Overall survival Previously untreated patients CONFIRM-1 Multinational, randomized, phase III trial R A N O M I Z E PTK/ZK 1,250 mg/day p.o. Placebo 0 Interim safety Final analysis: analysis Progression-free and overall survival Patients who have failed irinotecan/5-fu based therapy CONFIRM-2 Multinational, randomized, phase III trial R A N O M I Z E PTK/ZK 1,250 mg/day p.o. Placebo 0 Interim safety Final analysis: analysis Overall survival PTK/ZK + Oxaliplatin-based Chemotherapy is Generally Well Tolerated in Patients with Metastatic Colorectal Cancer PTK/ZK + FOLFOX4 (N=35) Grade 3 / 4, adverse events >5% N(%) Neutropenia 9 (26) izziness/lightheadedness 6 (17) Fatigue 4 (11) iarrhea 5 (14) Common mild adverse events of the combination include nausea (69%), neuropathy (77%), vomiting (54%) and diarrhea (54%) Steward WP, et al. Presented at the 40th Annual Meeting of ASCO 2004. 2
SU11248 is a tyrosine kinase inhibitor that blocks activation of receptor tyrosine kinases (RTKs( RTKs) ) on tumor cells and tumor vasculature. Image not available SU11248 Overview A Selective RTK inhibitor Small molecule Good oral bioavailability Inhibits multiple receptor tyrosine kinases (RTKs) expressed on iverse tumor cells VEGFR, PGFR, KIT, FLT3 Endothelium, pericytes, and stroma VEGFR, PGFR Potential to both directly and indirectly (through antiangiogenesis) inhibit growth of multiple tumor types Sun et al. J Med Chem. 2003;46:1116-1119. Mendel et al. Clin Cancer Res. 2003;9:327-337. PGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor. Sugen Phase II -SUO11248 in Metastatic CRC that has not responded to previous treatment w/ Irinotecan, Oxaliplatin, and fluoropyrimidine with or w/o Oral SUO11248 days 1-28. 1 Repeat every 42 days. Side effects- HTN, hand-foot syndrome, dysesthesias, diarrhea, fatigue The EGFR signaling pathway regulates cell differentiation, proliferation, migration, angiogenesis and apoptosis. In cancer cells, this can all be deregulated. EGFR (HER-1) is a transmembrane glycoprotein. The extracellular domain of EGFR is a ligand-binding site for transforming growth factor (TGF) and EGF. Blockade downstream results in : 1. Inhibition of cell growth 2. Promotes apoptosis 3. Inhibits angiogenesis Potentiates chemotherapy/xrt Harari. CCR, 2000; Ciardeiello & Tortora. CCR, 2001. Cetuximab shows activity in CRC patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. Chung KY, 2005 N=16 pts EGFR negative 4 had PR (greater than 50% reduction in measurable disease) EGFR positivity has little/no predictive value to response Higher EGFR higher response rate Inconsistent / imperfect IHC methodology: Archived/ stored tissue- decline in staining intensity Interobserver variability in definitions of expression Chung KY, et al. (2005) J Clin Oncol vol 23; no 9 pp1-8 EGFR Staining Intensity vs. Response Cunningham et al. NEJM 2004 Is EGFR expression predictive of response? Cetuximab + Irinotecan Cetuximab Alone EGFR Staining Intensity N RR N RR Faint Weak- Moderate Strong 53 21% 21 5% 89 25% 55 13% 75 23% 34 12% 3
Skin Reaction-Efficacy Cetuximab +/- Irinotecan Is rash predictive of response? RR% Cetux/I Cetux Surv (mo.) RR% Surv (mo.) none 6.3 3.0 0 2.5 Grade 1-21 20.4 11.6 Grade 3-43 55.2 33.3 any 25.8 9.1 13.0 8.1 An Exploratory Pharmacogenomic Study of Cetuximab Monotherapy in Metastatic CRC (IRB 04-002; 002; BMS CA 225045) Examine protein and mrna profiles in many different genes which are involved in regulation and activation of the EGFR pathway in order to predict response to Erbitux treatment. To evaluate the relationship between grade >2 skin rash and tumor response rates. Feasibility of escalating the weekly dose. Explore whether additional genes can be identified that are predictive of response to Erbitux. Allows EGFR negative patients Cunningham NEJM 2004 Panitumumab (ABX-EGF) Fully human monoclonal antibody that is directed against the epidermal growth factor receptor. Only rare serious allergic reaction reported. In phase II trial. Binds with higher affinity to the EGFR than Cetuximab. Mapatumumab (HGS-ETR1) Agonistic human monoclonal antibody that binds to the TRAIL receptor 1 protein, and induces apoptosis (programmed cell death). TRAIL (tumor necrosis factor apoptosis inducing ligand) receptor -11 is often called the death receptor. This antibody stimulates the TRAIL receptor-1 protein to trigger cell death like native TRAIL but with a longer ½ life and specificity for TRAIL receptor 1. phase II in Germany Human Genome Sciences, 2005 Sorafemib (BAY 43-9006 9006) Small molecule (intracellular signaling) targets VEGFR-2, VEGFR-3, PGFR, c-c KIT and Raf kinase. Signaling pathway to inhibit cell proliferation and the signaling cascade to inhibit tumor angiogenesis. Preclinical data show additive activity when sorafenib is combined with chemotherapy. Combination studies in CRC underway. Adjuvant Therapy Phase III (NSABP C-08) C Flourouracil,, Leucovorin, and Oxaliplatin with or without bevacizumab in treating patients undergone surgery for stage II or stage III colon cancer. Phase III (NCCTG-N0147) N0147) Irinotecan and/or Oxaliplatin plus 5-Fluorouracil 5 /Leucovorin with or without Cetuximab after curative resection for patients with colon cancer Cohen SJ, Cohen RB, Meropol NJ, 2005 4
WHAT WORKS Vesell ES: Advances in pharmacogenetics & pharmacogenomics. J Clin Pharmacol 40: 930-938,2000. Evans WE, McLeod HL: Pharmacogenomics-rug disposition, drug targets and side effects. N Engl J Med 348: 538-549, 2003. Genetic determinants are involved in 20% to 95% of differences in drug pharmacokinetic and pharmacodynamic processes. These determinants are polymorphisms (changes) in genes directing drug transport and metabolism, cellular targets, signaling and response pathways that remain constant throughout the lifetime. Pharmacogenomics Thymidylate Synthase (TS) expression Microsatellite Instability (MSI) Microsatellites are repeating NA sequences. MSI is demonstrated when the length of NA sequences in a tumor differs from that in nontumor tissue. 5 - FU inhibits Thymidylate Synthase (TS) enzyme = decreased NA synthesis 5-FU attacks Increased expression of TS=low chance response to 5 FU based therapy. Polymorphisms (changes) in TS gene may predict for how individuals will respond to 5FU based regimen thymidylate synthase deoxyuriylate thymidylate thymidine triphosphate NA synthesis and repair Thymidylate Synthase etermination By IHC ECOG 4203 High TS Low TS R a n d o m i z e IROX + FOLFOX + FOLFOX + *Tissue block from metastatic site required for all patients Microsatellite Instability (MSI) is a feature of Hereditary Nonpolyposis CRC (HNPCC) MSI is a NA abnormality present in >90% of HNPCC-associated colorectal tumor tissue MSI indicates an increased likelihood of HNPCC MSI is not diagnostic of HNPCC; also seen in 15% of sporadic colorectal cancer tissue MSI analysis requires access to slides of archival paraffin-embedded colorectal tumor specimen Nat Med 1996;2:169-74 2001 Myriad Genetic Laboratories HNPCC Results From Failure of Mismatch Repair (MMR) Genes Base pair mismatch T C T A C A G C T G Normal NA repair efective NA repair (MMR+) T C G A C A G C T G Τ C Τ A C A G C T G T C T A C A G A T G 5
Mismatch Repair Failure Leads to Microsatellite Instability (MSI) Normal MICROSATELLITE INSTABILITY 10% 15% 15% of sporadic tumors have MSI 95% of HNPCC tumors have MSI Microsatellite instability Addition of repeated NA Electrophoresis gel Normal MSI tumor Surgery ECOG 5202: Stage II Colon Cancer Tumor block risk assessment based on biology (18q/MSI) Accrual Goal: 3,125 High-risk (MSS and 18q Loss) Low-risk (MSI + or no loss 18q) Arm A: Leucovorin 500 mg/m 2 + 5-FU 5 500 mg/m 2 q 1 wk x 6 x 4 cycles Arm B: Leucovorin 500 mg/m 2 IV bolus + 5-FU 5 500 mg/m 2 IV bolus + Observation Implications for practice CRC cancer is complex. All colon cancers are not genetically identical. Targeted therapy still has side effects. eveloping new agents is important, but we must also learn how best to match those we have with the patients and tumors most likely to benefit. HIT THE TARGET!!! Slide not available 6