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What New Drugs are on the way? Dr Goldberg

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Two new drugs for colorectal cancer may offer new hope for late stage patients, and they might hit the market in 2013. ...

Two new drugs for colorectal cancer may offer new hope for late stage patients, and they might hit the market in 2013.

Dr. Rich Goldberg, physician-in-chief of the Ohio State University Medical Center and a leader in colorectal cancer research is going to give you the straight facts about these drugs:

* What hope might they offer?
* What side effects do they cause?
* Will either be the right drug for you?

About Dr. Goldberg:
Dr. Richard Goldberg is an internationally renowned gastrointestinal oncologist and the physician-in-chief at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Institute (OSUCCC-James). He is a member and former chair of the National Cancer Institute Colorectal Task Force and an international leader in evaluating new agents for the treatment of colorectal cancer and researching inherited colorectal cancer syndromes

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What New Drugs are on the way? Dr Goldberg What New Drugs are on the way? Dr Goldberg Presentation Transcript

  • Welcome! What New Drugs Are On the Way for Colorectal Cancer? Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series Our webinar will begin shortlywww.FightColorectalCancer.org877-427-2111
  • 1. Tonight’s speaker: Dr. Richard Goldberg 2. Archived webinars: Link.FightCRC.org/Webinars3. Follow up survey to come via email. Get a free BlueStar of Hope pin when you tell us how we did tonight4. Ask a question in the panel on the right side of your screen5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111
  • Dr. Richard Goldberg Physician-in-chief at The Ohio State University Comprehensive Cancer CenterA member and former chair of the National Cancer Institute Colorectal Task ForceAn international leader in evaluating new agents forthe treatment of colorectal cancer and researching inherited colorectal cancer syndromes
  • New Agents inColorectal CancerManagementRichard GoldbergWexner Medical Center atThe Ohio State University
  • Heterogeneity: Incidence of Selected Mutations in Advanced Colorectal Cancers Study N KRAS NRAS BRAF PI3K Overlapping Mutation Mutation Mutation Mutation Mutations Rate Rate Rate Rate De 747 40% 2.6% 4.7% 14.5% 20% of MT-KRAS Roock had MT-PI3KCAIRO 2 559 39.4% N/A 8.7% 9.9% 51% MT-KRAS had MT-PI3K COIN 1316 43% 4% 8% N/A 2% MT-KRAS had MT-NRAS The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • In MCRC: Cytotoxics Remain the Nucleus First Line:  5-FU/capecitabine +/- bevacizumab  FOLFOX +/- bevacizumab  FOLFIRI +/- bevacizumab  FOLFIRINOX +/- bevacizumab  ? Role for EGFR targeted therapy in first line: 80405 Second Line  Reciprocal of first line +/- bevacizumab or an EGFR monoclonal AB Third Line:  KRAS wt: EGFR monoclonal +/- irinotecan  KRAS mt: no standard therapy The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Drug Development: The Spotlight is on Biologics Repackaging cytotoxics  Liposome encapsulation: irinotecan or SN-38  Platinum analogues: pico- or satroplatin Exploiting biologics  Pinpoint a single driving mutation (imatinib & c-kit)  Drug multiple targets  Discover a “dirty drug”: exs: regorafinib, BIBF1120  Combine biologics: ex. Bond 2  Combine biologics and cytotoxics: ex. Bond 2 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Expression Center – S. Siena, et al, JNCI, 2009 The Ohio State University Comprehensive Cancer Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Expression Center – S. Siena, et al, JNCI, 2009 The Ohio State University Comprehensive Cancer Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Expression Brivinib Ramucirumab BIBF 1120 Regorafinib Perifosine Center – S. Siena, et al, JNCI, 2009 The Ohio State University Comprehensive Cancer Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Expression Brivinib Ramucirumab BIBF 1120 Regorafinib Perifosine Center – S. Siena, et al, JNCI, 2009 The Ohio State University Comprehensive Cancer Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Expression Brivinib Ramucirumab BIBF 1120 Regorafinib Perifosine Center – S. Siena, et al, JNCI, 2009 The Ohio State University Comprehensive Cancer Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Targeted Agents On the formulary Target  Bevacizumab VEGF  Cetuximab EGFR receptor  Panitumumab EGFR receptor On the way to ODAC?  Regorafenib VEGF, RAF, RET, KIT, PDGFR  Aflibercept (VEGF trap) VEGF  Perifosine Akt, JNK, MAPK On the radar screen  Brivinib FGF & VEGF  Pertuzumab HER-2  Rilotumumab c-Met (hepatocyte GF)  Ramucirumab VEGF-2  BIBF1120 VEGF1-3, PDGF, FGFR The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • A drug that worksat the cell surface AFLIBERCEPT The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Large molecule VEGF inhibitors PlGF VEGF-A VEGF-C, VEGF-B VEGF-D Bevacizumab RamucirumabAflibercept(VEGF Trap) Functions VEGF-R1 VEGF-R2 VEGF-R3 (Flt-1) (KDR/Flk-1) (Flt-4) Migration Proliferation Lymphangiogenesis Invasion, Survival Survival, Permeability The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Aflibercept • Soluble fusion protein Aflibercept • Consists of portion of extracellularVEGFR-1 domains of human VEGF receptors 1 and 2 fused to human IgG1 Fc portion • Binds all VEGF-A isoforms, VEGF-B and PlGF • High affinity: binds VEGF-A and PlGF IgG more tightly than native receptors VEGFR-2 Fc • Half-life in humans ~17 days The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • 17 VELOUR Phase III Trial 2nd Line VEGF1 &2 and PDGF Decoy30% of patients had prior BEV Aflibercept 600 pts 4 mg/kg IV + FOLFIRI mCRC after failure of an oxaliplatin R based regimen Placebo + FOLFIRIStratification factors: 600 ptsPrior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2) PI: Allegra The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Overall Survival - ITT Population The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. SoloveCut-off date = February 7, 2011; Median follow-up = 22.28 months Research Institute
  • Progression Free Survival The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. SoloveCut-off date = May 6, 2011 Research Institute
  • Response Rate Placebo AfliberceptEvaluable population*, % N = 530 N = 531Best Overall Response Complete response 0.4 0 Partial response 10.8 19.8 Stable disease 64.9 65.9 Progressive disease 21.5 10.4 Not evaluable 2.5 4.0Overall Response Rate (CR or PR) 11.1 19.8 95% CI 8.5 to 13.8 16.4 to 23.2 p= 0.0001** The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Safety – Most frequent Adverse EventsSafety Population, % of patients Placebo, N = 605 Aflibercept N = 611 All All Grade 3-4 Grade 3-4 Grades GradesDiarrhea 56.5 7.8 69.2 19.3Neutropenia** 56.3 29.5 67.8 36.7 Complicated neutropenia 2.8 5.7Asthenic conditions (HLT) 50.2 10.6 60.4 16.9Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7Thrombocytopenia** 33.8 1.7 47.4 3.3Infections (SOC) 32.7 6.9 46.2 12.3Decrease appetite 23.8 1.8 31.9 3.4Weight decreased 14.4 0.8 31.9 2.6Palmar plantar 4.3 0.5 11.0 2.8erythrodysaesthesiaSkin hyperpigmentation 2.8 0 8.2 0Dehydration 3.0 1.3 9.0 4.3 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove ** From lab Research Institute
  • Safety – Anti-VEGF Associated EventsSafety population, % of Placebo N = 605 Aflibercept N = 611patientsGrouped Term, PT All Grade Grade 3/4 All Grade Grade 3/4Proteinuria* 40.7 1.2 62.2 7.9Hypertension 10.7 1.5 41.4 19.3Haemorrhage 19.0 1.7 37.8 2.9 Epistaxis 7.4 0 27.7 0.2 GI origin 5.1 1.0 10.0 2.0Dysphonia (PT) 3.3 0 25.4 0.5Headache (PT) 8.8 0.3 22.3 1.6Venous thromboembolic event 7.3 6.3 9.3 7.9 Pulmonary embolism 3.5 3.5 4.7 4.7Arterial thromboembolic event 1.5 0.5 2.6 1.8Fistula (GI origin) 0.3 0.2 1.1 0.3Wound healing 0.8 0 0.5 0.3GI perforation 0.5 0.3 0.5 0.5 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Deaths During Study Treatment Placebo Aflibercept% – Safety Population N = 605 N = 611Number of deaths within 30d from last dose 3.1 4.9 Disease progression 2.1 2.3 Adverse events: 1.0 2.6 Infections (sepsis and neutropenic sepsis) 0.5 0.7 Death/sudden death 0.3 0.3 Pulmonary embolism 0 0.2 GI hemorrhage (duodenal ulcer) 0 0.2 GI disorders (inflammation/obstruction) 0 0.3 Respiratory disorders 0.2 0.3 Other** 0 0.7**Other: dehydration (2pts), metabolic encephalopathy (1pt), hypovolemic shock (1pt) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Discontinuation of Study TreatmentITT Population Placebo Aflibercept% N = 614 N = 612Discontinued study treatment 97.4 96.9 Disease progression 71.2 49.8 Adverse event 12.1 26.6 Patient request 7.0 12.6 Investigator decision 3.4 3.3 Metastatic surgery 1.6 2.0 Other causes* 2.1 2.6Study treatment ongoing 1.8 2.3 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • A drug that hitsA cell surface receptor RAMUCIRUMAB The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • 26 Phase III Trial 2nd Line Targets VEGFR-2 Projected completion date 8/2014Primary EP: OS 525 pts Ramucirumab IV + FOLFIRI q 2 weeks mCRC after failure FP/oxaliplatin R + BEV regimen 525 pts Placebo + FOLFIRI q 2 weeksPIs: Tabernero, Grothey The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • A drug being compared To bevacizumab with chemotherapy BIBF 1120 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • 28 Phase II Trial First Line Targets , VEGF, PDGF, FDGF Presented at ESMO 9/11Primary EP: OS 63 pts BIBF1120 + mFOLFOX6 mCRC R Bevacizumab 63 pts + mFOLFOX6Van Cutsem The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Efficacy/Toxicity FOLFOX + FOLFOX + Bevacizumab BIBF1120No. of patients 63 63ORR 53.7% 61.2%PFS at 9 mos 69% 63%Median OS N.A. N.AGI toxicity, G>3 29.3 % 11.8% The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • A drug that hitsmultiple internal targets REGORAFINIB The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Mode of action of regorafenib Regorafenib inhibits multiple cell-signaling kinases:  Angiogenic  VEGFR1–3, TIE2  Stromal  PDGFR-β, FGFR  Oncogenic  KIT, PDGFR, RET The Ohio State University Comprehensive Cancer Center – Wilhelm SM et al. Int J Cancer 2011 Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • 32 CORRECT Trial Targets VEGF, TIE2, RAF, Ret, c-KitPrimary EP: OS 505 pts Regorafinib po + BSC mCRC after failure of all R standard Rx Placebo 255 pts + BSCPI: Grothey The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis(1-sided p<0.009279 at approximately 74% of events required for final analysis) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Progression-free survival The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Overall response and disease control rates Regorafenib PlaceboBest response, % N=505 N=255Complete response 0 0Partial response 1.0 0.4Stable disease 43.8 14.9Progressive disease 49.5 80.0Disease control rate, %* 44.8 15.3*DCR = PR + SD; p<0.000001 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade Regorafenib PlaceboAdverse event, % N=500 N=253 All Grade Grade Grade All Grade Grade Grade grades 3 4 5 grades 3 4 5Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0Hypertension 27.8 7.2 0 0 5.9 0.8 0 0Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0Anorexia 30.4 3.2 0 0 15.4 2.8 0 0Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0Fever 10.4 0.8 0 0 2.8 0 0 0Nausea 14.4 0.4 0 0 11.1 0 0 0Bleeding 11.4 0.4 0 0.4 2.8 0 0 0Voice changes 29.4 0.2 0 0 5.5 0 0 0Weight loss 13.8 0 0 0 2.4 0 0 0 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Summary of CORRECT Overall survival:  6.4 vs 5.0 months, HR=0.77, p=0.0052 Progression-free survival:  1.9 vs 1.7 months, HR=0.49, p<0.000001 Disease control rate (PR + SD):  44.8% vs 15.3%, p<0.000001 Main treatment-related adverse events:  fatigue, hand–foot skin reaction, diarrhea, poor appetite, voice changes, hypertension, oral mucositis, and rash/peeling skin The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • A drug that apparently didn’t make it PERIFOSINE The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Perifosine Oral alkylphospholipid Inhibition of multiple signal transduction pathways  AKT inhibition  NF- B inhibition  Activation of apoptotic pathway via JNK Selective tumor cell accumulation and potential disruption of membrane asymmetry The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Perifosine: Mechanism of Action Selective tumor cell accumulation and potential disruption of membrane asymmetry Activates Prevents apoptotic JNK AKT recruitment pathway of AKT to the Apoptosis Cell growth cell and Survival membraneInhibition of Modulates the NF- CDK 2chemoresistance cell cycle via Cellular Stress Cell Cyclep21 and Survival The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • 41 Perifosine Targets PI3K & akt Pathway and NF-kBPrimary EP: OS 20 pts Perifosine po + capecitabine after failure of all R standard Rx 18 pts Capecitabine Bendell, J Clin Oncol, 33:3394-4400, 2011 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Results: Response 35 / 38 Patients evaluable for efficacy 3 placebo patients not evaluable: 2 off for toxicity at d 14, 46; 1 off at d 4 for other disease All Evaluable: n = 35 CR PR Duration of Response SD > 12 Weeks SD or >* Group n N (%) N (%) (months) N (%) N (%) CR: 34 P-CAP 20 1 (5%) 3 (15%) 11 (55%) 15 (75%) PR: 21, 19, 11 CAP 15 0 1 (7%) PR: 7 5 (33%) 6 (40%) *p = 0.036 5-FU Refractory: n = 25 PR Duration of Response SD > 12 Weeks SD or >* Group n N (%) (months) N (%) N (%) P-CAP 14 1 (7%) 19 months 8 (57%) 9 (64%) CAP 11 0 - 3 (27%) 3 (27%) *p = 0.066 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Kaplan-Meier plot of time to progression (TTP) in (A) all evaluable patients and (B) evaluable fluorouracil-refractory patients. Bendell J C et al. JCO 2011;29:4394-4400 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove©2011 by American Society of Clinical Oncology Research Institute
  • Kaplan-Meier plot of overall survival (OS) in (A) all evaluable patients and (B) evaluable fluorouracil-refractory patients. Bendell J C et al. JCO 2011;29:4394-4400 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove©2011 by American Society of Clinical Oncology Research Institute
  • Efficacy perifosine+ Capecitabine capecitabine P-valueNo. of patients 18 20ORR (%) 7% 20% n.s.TTP (wks) 10.1 27.5 p< 0.001Median OS (mo) 6.5 15.1 p< 0.006 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • 46 X-Pect Phase III Study: Completed Enrollment 7/11Primary EP: OS 215 pts Perifosine po + capecitabine mCRC after failure of all R standard Rx 215 pts Capecitabine The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Press release 4/12:Did not meet survival endpoint Details pending The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Conclusions Patients with resectable disease at presentation are potentially curable Some with unresectable disease are too Combination chemotherapy +/- biologics are standard in fit patients We are still learning how to best exploit out tools We have a number of new drugs coming The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Another drug that apparently didn’t make it BRIVINIB The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • PHASE III RANDOMIZED TRIAL OF CETUXIMAB + EITHER BRIVANIB OR PLACEBO IN PATIENTS WITH METASTATIC, CHEMOTHERAPY REFRACTORY, K-RAS WILD-TYPE COLORECTAL CARCINOMA: THE NCIC CLINICAL TRIALS GROUP AND AGITG CO.20 TRIALLL Siu, JD Shapiro, DJ Jonker, CS Karapetis, JR Zalcberg, J Simes,F Couture, MJ Moore, TJ Price, J Siddiqui, LM Nott, D Charpentier, WLiauw, M Sawyer, M Jefford, NM Magoski, A Haydon, I Walters, D Tu, CJO’Callaghan GI ASCO 2012, Abstract 386 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Schema Targets VEGF and FGF BrivanibR + 1° endpoint:A Cetuximab Overall SurvivalN n = 376D Last pt randomized:O February 10, 2011M PlaceboI Median follow-up:Z + 19 monthsE Cetuximab n = 374 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Combining targeted agents The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • A RANDOMIZED, PHASE IB/II TRIAL OF RILOTUMUMAB OR GANITUMAB WITH PANITUMUMAB VS PMAB ALONE IN PATIENTS WITH WILD-TYPE KRAS METASTATIC COLORECTAL CANCERC Eng, E Van Cutsem, E Nowara, A Świeboda-Sadlej, NC. Tebbutt, Mitchell, I Davidenko, KS Oliner, L Chen, J Huang, I McCaffery, E Loh, D Smethurst, J Tabernero The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Primary Endpoint:Objective Response Rate Panitumumab Panitumumab Panitumumab + Rilotumumab + Ganitumab + Placebo (AMG 102) (AMG 479) (n = 48) (n = 48) (n = 46)Objective Response - n (%) 10 (21) 15 (31) 10 (22) Complete Response (CR) 0 (0) 0 (0) 0 (0) Partial Response (PR) 10 (21) 15 (31) 10 (22) Stable Disease (SD) 17 (35) 19 (40) 18 (39) Progressive Disease (PD) 16 (33) 11 (23) 15 (33) Unevaluable/Not done 5 (10) 3 (6) 3 (6)Disease control rate - % (95% CI) 56 (41-71) 71 (56-83) 61 (45-75)Duration of response - median months 3.7 (3.6-NE) 5.1 (3.7-5.6) 3.7 (3.6-5.8)(95% CI)Posterior probability of Odds Ratio > 1 0.93 0.63 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Progression-Free SurvivalPanitumumab ± Rilotumumab (AMG 102) (AMG 102)Panitumumab ± Ganitumab (AMG 479) (AMG 479) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Adverse Events (Any Grade in 20% or Grade 3/4 in 2 Patients) Panitumumab Panitumumab Panitumumab + Rilotumumab + Ganitumab + Placebo (AMG 102) (AMG 479) (n = 48) (n = 48) (n = 46)AE (Preferred term) - % Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4Any AE 94 52 98 71 100 63Rash 52 8 58 29 48 13Acneiform dermatitis 33 10 35 15 26 11Pruritus 25 0 21 0 28 2Skin fissures 17 0 15 2 26 0Paronychia 15 2 31 4 20 2Dry skin 15 0 23 2 22 0Acne 0 0 8 4 11 0Skin toxicity 0 0 2 2 4 4Constipation 25 6 10 0 13 0Decreased appetite 17 2 21 2 20 2Abdominal pain 15 6 10 4 9 7Diarrhea 10 0 15 4 26 2Hypomagnesemia 21 2 29 4 41 15Fatigue 21 2 10 4 17 2Anemia 17 8 4 0 2 0Asthenia 15 0 8 0 13 4AE, adverse event The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Combinations Also on the Radar Screen Agent(s) Target(s) Bortezomib + cetuximab NFk-B, EGFR Pertuzumab + cetuximab closed, toxicity Rilotumumab + panitumumab HGF, EGFR Ganitumab + panitumumab IGFR, EGFR IMC-A12 + cetuximab IGFR, EGFR Sorafenib + bevacizumab raf, VEGF Erlotinib + panitumumab EGFR Everolimus + cetuximab mTOR + EGFR The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Cominations Also on the Radar Screen Agent(s) Target(s) AZD6244 + cetuxumab MEK, EGFR BEZ235 + MEK 162 PI3-k, MEK BKM120 + MEK162 PI3-k, MEK Decitabine + panitumumab DNA methyltransferase Simvistatin + panitumumab Turpenes + EGFR Imprime PGG + cetuximab Immunity + EGFR EMD 525797 + cetuximab Integrin + EGFR Dasatinib + cetuximab BCR/ABL + EGFR Lenalidomide + cetuximab Apoptotic + EGFR The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Modulating BRAF Downstream of RAS A potential target for patients with k-RAS mt tumors The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • The Ohio State University Comprehensive CancerCenter –Arthur G. James Cancer Hospital and Richard J. SoloveResearch Institute
  • BRAF Inhibitors: In early testing Vemurafenib (PLX-4032) Dabrafenib (GSK2118436) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Conclusions Multiple targeted agents are in development It is likely that combinations will be more effective than single agents Agents may work in specific subsets of CRC patients who can be identified by genetic profiling It appears the lean years in CRC drug development may be over The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • Thanks for yourattention!Questions?
  • UPCOMING WEBINARSMANAGING YOUR SYMPTOMS AND TREATMENT SIDE EFFECTS MAY 16, 2012 8-9:30 PM EASTERN TIMEWHATS NEW IN COLORECTAL CANCER RESEARCH? JUNE 20, 2012 8 - 9:30 PM EASTERN TIME WHEN YOURE OUT OF OPTIONS JULY 18, 2012 8 - 9:30 PM EASTERN TIME