1.Dr Sanudev Sadanandan.V.P Junior Resident Div of Radiation Oncology RCC Trivandrum Kerala

2. Targeted therapy ??? It is type of medication that blocks growth of cancer cellsby interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than simply interfering with all rapidly dividing cells. Expected to be more effective and less harmful to normalcellsDefinition of targeted therapy-NCI Dictionary of cancer terms 3. Genetic alteration in HNSCC ALTERATIONFREQUENCYP16 inactivation70%Homologous deletionP53 mutation50%MutationHigh risk HPV integration (16,18)25%Oropharyngeal sitesEGFR aleration80-90%Amplification,overexpression,downst ream target activationPi3k/akt/mtor>40%ATM,P15,TIMP3,MGMT,RARB-2,DAP-E,E Cadherin,Cycline A1,dccVariable Upto 60% (DCC)Inactivated by promoter hypermethilationHIF-1 Aalfa60%Proliferation,angiogenesisVEGFVariableTKTL1,Cancer testes antigen50%Proto oncogene-promoter hypermethylation 4. Targeted agents in HNSCC 1.EGFR inhibitor 2. IGF inhibitors 3.VEGF Receptor inhibitor 4.Non receptor targets 5. Erb B family of receptor 6. EGFR Receptor 7. EGFR pathway 8. EGFR in HNSCC EGFR is detectable by IHC in 90% of HNSCCs 40%-90% of HNSCCs -EGFR over expression. High levels of EGFR protein expression-worse prognosis Activating mutations in the EGFR gene (chromosome 7) -uncommon in HNSCC cases 9. High EGFR gene copy number-FISH 10%-60% of HNSCC -prognostic significance-debated EGFR pathway deregulated also inColo-rectal cancer, Lung, Breast and brain 10. EGFR- targeted therapies EGFR Inhibitors: Cetuximab, Panitumumab,ZalutumumabGefitinib, Erlotinib etc Show enhanced radiosensitivity supra addictive Mechanism: inhibit cell proliferation: impair DNA damage repair : alternate tumor angiogenesis :promote apoptosis : inhibit radiation induced EGFR nuclear import 11. CETUXIMABRecombinant human/mouse chimeric IG G1 monoclonal antibody 12. Indications FDA approved-metastatic colorectal ca , KRAS wild type -concurrent with RT for LAHNSCC -Met/rec HNSCC Under inv-Ca pancreas,Breast,NSCLC Dose-loading 400mg/m2 over 2hrs-maintainance-250mg/m2 iv weekly 13. Side effectsInfusion reaction 40-50%acniform skin rashConstitutional symptoms 50%pulmonary-ILD( rare)hypomagnesemia 14. Pregnancy category-D Level of EGFR expression No Rx benefit-KRAS mutation codon 12/13 Skin toxicity-surrogate marker of activity Hypersensitivity Cardiopulmonary arrest/sudden death 15. Cetuximab as a single agent RESULTS -rec/metastatic platinum refractory HNSCC -103 patients -CetuximabResponse 17% CR-5% Median TTP-85 day, survival -175 days Cetuximab was well tolerated rash (80%), fatigue (24%), fevers/chills (19%), and nail changes (15%).Trigo, et alia,phase II trial,asco 2004 abstract 16. Cetuximab combined with cytotoxic chemotherapy EXTREME trial N=424 Rec/met HNSCC Vermorkan etal Phase III,RCT Cis/carbo+5FU+ Cet NEJM 2008 vs Cis/carbo+5FURR 35% VS 20%Burtress, et al Phase III,RCT-123 patients -Rec/Met HNSCCRR 9% vs 26.1%JCO 2005-CDDP 100 mg/m2 Q4weeks+Placebo vs CDDP 100 mg/m2 Q4weeks + cetuximab.mPFS 5.6 vs 3.3 mon Mos 10.1 vs 7.4 monOS ,PFS-ns-adverse eventslargely similar. -grade 3 / 4 sepsis in the cetuximab plus PF group (4%), versus PF alone (1%). CDDP+CET -90% grade3 -4 toxicity -Hypomagnesmia -Hematological 17. Radiotherapy with Cetuximab in LAHNSCC Phase III, Randomized, Multicenter424 Patients HNSCC ,Stage III/IV(OPx.Lx.HPx) Measurable disease KPS>60randomizedN=213High dose radiotherapyHigh dose Radiotherapy + CetuximabPrimary Duration of locoregional control Secondary -Os -PFS -ORR -SafetyN=211Bonner etal NEJM 2006 18. Patient Characteristics 19. Results- Patients Balanced between both treatment groups with respectto Compliance Type of RT chosen Subsequent neck dissections Subsequent salvage surgery Subsequent chemotherapy 20. Results-efficacy 21. Locoregional ControlMedian duration of LRC 24 mon VS 14.9 mon(hazard ratio for locoregional progression or death, 0.68; P = 0.005) 22. Overall SurvivalMedian os 49 mon Vs 29.3 monhazard ratio for death, 0.74; P = 0.03 23. Results-safety 13 patients discontinued cetuximab 4 due to hypersensitivity post 1st dose 8 due to grade 3 rash Cetuximab did NOT add to radiation toxicities includingmucositis, xerostomia, dyphagia, pain, (weight loss), decreased performance status 24. Results-safety 25. Study Limitations Lacked standard of care arm Different RT regimens Not site specific Results for hypopharyngeal subgroup Quality of Life Data Concomitant boost vs other RT Late complications 26. 5YEAR UPDATERT +CETRTMedian OS490 months 293 months (95% CI (206414) 328695)5-year OS456%364%OS (cet with rash >gr2)(HR 049, 034072; p=0002).-------- 27. phase II ,RCT, RTOG 0234-possibly improved efficacy on the docetaxel-concomitant boost radiotherapy (70 Gy total)3-year overall survival was 76%.-with 2 cycles of conc CDDP and weekly cetuximab ECOG 3303, phase II trial-toxicity to be Comparable.-cetuximab +cisplatin /docetaxel Conc with PORT phase II trial Pfister DG Jco 2010-resected, advanced HNSCC-stopped early due to 2 deathscetuximab + chemoradiation with cisplatin in LAHNSCChigh rates of grade 3 toxicity NS-DFS,OS 28. ONGOING TRIALS RTOG 1016accelerated-fraction RT +CDDP Vs accelerated RT + cetuximab -HPV-associated oropharynx cancer.RTOG 0920-intermediate-risk HNSCC following surgery -compares postoperative radiation +/- cetuximab (conc &maintanance) -stratification based on EGFR overexpression (IHC) 29. Following the land mark study by Bonner etalCetuximab was approved by FDA in LA HNSCC concurrent with RT. 30. Humanised monoclonal antibodies DrugPanitumuma -human IgG2 b (Vectibix) mAB -bind extracellular domain of the EGFRTrialSPECTRUM trial -Phase-III -met/rec HNSCC -CDDP+5FU+/Panitumumab -n=657 NCIC Canada -Phase III trial LAHNSCC III/IV RT+ Conc CDDP Vs Acc fraction RT+PanitumumabResultLocal PFS-Improved OS-NS Benefit-HPV negOngoing 31. DrugTrialZalutumumab -human IgG1 mAB (HUMax-extracellular EGFR) domain of EGFRNimotuzuma b (BIOMAb EGFR)-human mabResultHx-EGFr-202 trial -Phase III,RCT -Incurable HNSCC -Failed on std platinum based regime -273 patients -Humax EGFR Vs BSCPFS (2yrs)26% vs 7.3%.-SS-4 arm study -BEST study IND OO1-improved overall survivaloverall survival-NS-intermediate affinity to EGFR -reduce toxicity1.Michael j etal,ASCO 2010 2. Babu K, . ASCO annual meeting. J Clin Oncol 28:5530 32. Study Design-Phase II Trial - BEST Study Nimo 200mg + RT (60 66Gy) Group A RT (60 66Gy) First Line, Unresectable, Stage III/IV SCCHNNimo 200mg + RT (60 66Gy) + CDDP 50mg/wRT (60 66Gy)Group B+ CDDP 50mg/w Patients were allocated at the discretion of the physician to RT alone or Chemoradiotherapy and then randomized to +/- nimotuzumab Groups were not stratified 48 months follow up (as of August 2009) 33. Study Design-BEST Study 92 patients Enrolled (safety pop) 76 patients1.RT 66gY/33#Evaluable for EfficacyPatients that received at least one dose of nimotuzumabProtocol compliant with second image evaluation2.Nimo- 200mg given 3 days before RT and then weekly 3.CDDP 50mg/weekRRRTRT + h-R3CT + RTCT + RT + h-R318 patients18 patients20 patients20 patients 34. RESULTSoverall pop-NSITT 12.8mon vs 14.4mon 35. Survival Data of ITT Population After End of RTCT+RTCT+RT+h-R3n =23 (%)N=23 (%)1 year12 (52.17)18 (78.26)0.06332 years9 (39.13)18 (78.26)0.007030 mths5 (21.74)16 (69.57)0.001148 mths5 (21)11 (47)0.0149After End of RTRTRT+h-R3n=23 (%)n=23 (%)1 year12 (52.17)11 (47.83)0.76812 years5 (21.74)9 (39.13)0.199930 mths5 (21.74)9 (39.13)0.199948 mths3 (13)8 (34.7)0.4278p-Valuep-Value 36. Panitumumab,Zalutumumab improve PFS,No OS Nimotuzumab-?Overall survival improvement-approved in HNSCC in some countries(not US FDA) -Need Phase 3 RCT for confirmation 37. Small Molecule Inhibitors of EGFR/HER GefitinibPhase II trial Cohen etal, JCO 2003Met/rec HNSCC Dose-500mgResponse rate 10.6%phase III study Stewart JS,JCO 2009486 patients ,met/rec HNSCC Geftinib 250mg Geftinib 500 mg Mtx 40mg iv weeklyRR-NS OS-NS tumor hge-more common with gefitinibArgiris A asco 2009 phase III ,RCTmet/rec HNSCC Docetaxel+/-gefNo benefitGregoire V,Green journal,2011ChemoRT +/- GefNo benefit 38. Erlotinibintracellular domain of Met/rec HNSCC the EGFR Response rate= 4.3%Lapatinibreversible inhibitor of EFGR &HER2.ongoing trials-increased CR in preliminary analysis. -Monotherapy-no significant activity .Afatinibirreversible inhibitor of EGFR and HER2RCT,phase II Rec/met HNSCC Plat refractory ,n=74 Afatinib vs Cet RR 18 VS 8%Dacomitinibirreversible inhibitor of Phase I well tolerated EGFR (HER1), HER2, Phase II ongoing HER3, and HER4 39. RCT do not show any advantage with Gefitinib Afatinib some promising response Other molecules under study 40. Insulin-like Growth Factor (IGF) Pathway IGF-1R stimulation induces autophosphorylation withactivation of the Ras/MAP kinase pathway. Growth and survival are mediated primarily throughdownstream activation of PI3K/AKT/mTOR signaling. Figitumumab (CP-75187)-human IgG2 monoclonal antibody that binds IGF-1-R. -dose- 20 mg/kg every 3 weeks -monotherapy in rec/met HNSCC - no significant activity 41. Vascular Endothelial Growth Factor (VEGF) PathwayAngiogenesis VasculogenesisLymphangiogenesis 42. Bevacizumab humanized monoclonal IgG1 antibody Bind to VEGF-A to inhibit signaling Reduce new blood vessel formation in primary and mets. Inhibit blood vessel permeability-incr blood flow to tumor-Incr drug delivery 43. Bevacizumab trials Phase II trialRec/met HNSCC N=60 BV +PemetrxedRR 30% Higher gr 3 hemorragesPhaseI/II Cohen etal Lancet 2009Rec/met HNSCC-well toleratedBV+ErlotinibPhase II DG P Etal JCO 2009 Phase II, RTOG trial 0615 Lee N,ASCO,JCO-2011LAHNSCC BV+CDDP+IMRT LA-Ca NPX N=44 BV+CDDP+RT BV+CDDP *3cyclePrelim-well tolerated,good efficasy Final-awaiting -Fewer distant mets (prelim) 44. Bevacizumab is well tolerated,with response rate of30% but need more RCT s to confirm its role. 45. Cediranib (AZD2171, Recentin)TKI -VEGFR1, met/rec VEGFR2, and VEGFR3. HNSCC , rec NSCLC -monotherapymean decr in tumor size - 25.9%Sunitinib (Sutent)multitargeted receptor Rec/met TKI-VEGFRs,PDGFR, HNSCC c-kit, RET, CSF- 1 -monotherapy receptor, flt3-minimal activity significant toxicity - Tumor ulceration, fistula bleedingSorafenib (Nexavarmultikinase inhibitor - Monotherapy VEGF-R, PDGF-R, Raf, 400 mg bid and c-kit kinase Met/rec HNSCC-minimal activity was Phase II seen Williamson -well tolerated SK,JCO 2010Pazopani b (Votrient)multityrosine kinase inhibitor -VEGFR1, VEGFR2, VEGFR3, ckit, and PDGFRRR-6.1%Phase II Lim W Etal JCO 2010OngoingPhase II-Monotherapy 800 mg daily -rec/met NPC -33 patientsVandeteni TKI targeting VEGFRs -LAHNSCC b and EGFR -Van+cisplatinPR- 18%Phase II Saura C etal JCO 2009 Phase II Machiels JP JCO 2010 46. Cediranib is the only molecule showing significantactivity and tolerability comparing other multikinase inhibitors. 47. Downstream pathways are also explored for treatment The PI3K/Akt/mTOR pathway plays a centralrole in apoptosis, cell survival, transformation, angiogenesis,and invasion and metastasis Mtor activation may occur without EGFR activation inmany head and neck cancers. 48. Src encodes for a nonreceptor tyrosine kinase Src family proteins can associate with cellular membranes andtransduce receptor signals (eg, EGFR) to internal signaling pathways, including PI3K and STAT. STATs :transcription factors that on phosphorylation migrateto the nucleus to mediate expression of genes involved in proliferation, differentiation, and apoptosis 49. DRUGMOATRIALRESULTSXL147 Oral PI3K inh (SARs 245,408)XL147, carboplatin and paclitaxel in 19 patients with advanced solid tumorsPhase-I favorable responses were described in 2 patients with HNSCCperifosine (KRX-040)oral ,inhibits AKT activation.monotherapy in rec/met HNSCCno objective responseEverolimusMtor inhibitororalTrials ongoingTemsirolimus Mtor inhibitorivTrials ongoingSaracatinib AZD0530Oral-src TKI-Dose- 175 mg/d -no response -Monotherapy rec/met (Fury MG,Anticancer res 2011) HNSCCDasatinib (Sprycel)Oral TKI-src & BCRABL-monotherapy -Rec/met HNSCCNo activity (Brooks,Cancer 2011) 50. Conclusion:We need more number of well conductedRCT s to ascertain role of Targeted agents against non receptor targets. 51. Summary At present Cetuximab is the only targeted agent that isapproved in Head and neck squamous cell ca Initial studies targeting other pathways have not yetyielded clinical applications, they have improved our understanding of the biology of HNSCC. There remains much to be discovered It is clear that molecular-targeted therapies will be aunavoidable part of the management of HNSCC in future. 52. Molecular Changes in Thyroid Cancer 53. Multikinase inhibitor -Sorafenib,sunitinib cat 1 -Pazopanib-Cat 2b -PR+SD 50-60% for 12-24 monthsInd-Not amenable to surgical resection and EBRT -RI negative papillary/follicular ca -Clinically significant structural progression in 6-24mon 54. Medullary ca (FDA approved drugs)Vandetanib LA/met MTC not amenable for surgery and disease causing symptoms. -Cardiotoxicity Cabozantinib (vegfr-2,MET,RET) -progressive metastatic MTC -bleeding,GI perfo 55. Thank you