Targetted agents in head and neck cancers
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Targetted agents in head and neck cancers

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This is a small presentation about various targeted agents used in head and neck cancer.

This is a small presentation about various targeted agents used in head and neck cancer.

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  • - 4 closely related receptor tyrosinekinases (Cell surface receptors)
  • Extracellular domain-ligand attaches-Epidermal growth factor

Targetted agents in head and neck cancers Presentation Transcript

  • 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 cells by 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 normal cells Definition of targeted therapy-NCI Dictionary of cancer terms
  • 3. Genetic alteration in HNSCC ALTERATION FREQUENCY P16 inactivation 70% Homologous deletion P53 mutation 50% Mutation High risk HPV integration (16,18) 25% Oropharyngeal sites EGFR aleration 80-90% Amplification,overexpression,downst ream target activation Pi3k/akt/mtor >40% ATM,P15,TIMP3,MGMT,RARB-2,DAP-E,E Cadherin,Cycline A1,dcc Variable Upto 60% (DCC) Inactivated by promoter hypermethilation HIF-1 Aalfa 60% Proliferation,angiogenesis VEGF Variable TKTL1,Cancer testes antigen 50% 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 in Colo-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. CETUXIMAB Recombinant 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 effects  Infusion reaction 40-50%  acniform skin rash  Constitutional 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 -Cetuximab Response 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+5FU RR 35% VS 20% Burtress, et al Phase III,RCT -123 patients -Rec/Met HNSCC RR 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 mon OS ,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, Multicenter 424 Patients HNSCC ,Stage III/IV(OPx.Lx.HPx) Measurable disease KPS>60 randomized N=213 High dose radiotherapy High dose Radiotherapy + Cetuximab Primary Duration of locoregional control Secondary -Os -PFS -ORR -Safety N=211 Bonner etal NEJM 2006
  • 18. Patient Characteristics
  • 19. Results- Patients  Balanced between both treatment groups with respect to Compliance  Type of RT chosen  Subsequent neck dissections  Subsequent salvage surgery  Subsequent chemotherapy
  • 20. Results-efficacy
  • 21. Locoregional Control Median duration of LRC 24 mon VS 14.9 mon (hazard ratio for locoregional progression or death, 0.68; P = 0.005)
  • 22. Overall Survival Median os 49 mon Vs 29.3 mon hazard 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 including mucositis, 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 UPDATE RT +CET RT Median OS 49·0 months 29·3 months (95% CI (20·6–41·4) 32·8–69·5) 5-year OS 45·6% 36·4% OS (cet with rash >gr2) (HR 0·49, 0·34–0·72; p=0·002). --------
  • 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 deaths cetuximab + chemoradiation with cisplatin in LAHNSCC high rates of grade 3 toxicity NS-DFS,OS
  • 28. ONGOING TRIALS RTOG 1016 accelerated-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 etal” Cetuximab was approved by FDA in LA HNSCC concurrent with RT.
  • 30. Humanised monoclonal antibodies Drug Panitumuma -human IgG2 b (Vectibix) mAB -bind extracellular domain of the EGFR Trial SPECTRUM 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+Panitumumab Result Local PFS-Improved OS-NS Benefit-HPV neg Ongoing
  • 31. Drug Trial Zalutumumab -human IgG1 mAB (HUMax-extracellular EGFR) domain of EGFR Nimotuzuma b (BIOMAb EGFR) -human mab Result Hx-EGFr-202 trial -Phase III,RCT -Incurable HNSCC -Failed on std platinum based regime -273 patients -Humax EGFR Vs BSC •PFS (2yrs)26% vs 7.3%.-SS -4 arm study -BEST study IND OO1 -improved overall survival •overall survival-NS -intermediate affinity to EGFR -reduce toxicity 1.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 SCCHN Nimo 200mg + RT (60 – 66Gy) + CDDP 50mg/w RT (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 patients 1.RT 66gY/33# Evaluable for Efficacy Patients that received at least one dose of nimotuzumab Protocol compliant with second image evaluation 2.Nimo- 200mg given 3 days before RT and then weekly 3.CDDP 50mg/week R R RT RT + h-R3 CT + RT CT + RT + h-R3 18 patients 18 patients 20 patients 20 patients
  • 34. RESULTS overall pop-NS ITT 12.8mon vs 14.4mon
  • 35. Survival Data of ITT Population After End of RT CT+RT CT+RT+h-R3 n =23 (%) N=23 (%) 1 year 12 (52.17) 18 (78.26) 0.0633 2 years 9 (39.13) 18 (78.26) 0.0070 30 mths 5 (21.74) 16 (69.57) 0.0011 48 mths 5 (21) 11 (47) 0.0149 After End of RT RT RT+h-R3 n=23 (%) n=23 (%) 1 year 12 (52.17) 11 (47.83) 0.7681 2 years 5 (21.74) 9 (39.13) 0.1999 30 mths 5 (21.74) 9 (39.13) 0.1999 48 mths 3 (13) 8 (34.7) 0.4278 p-Value p-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 Gefitinib Phase II trial Cohen etal, JCO 2003 Met/rec HNSCC Dose-500mg Response rate 10.6% phase III study Stewart JS,JCO 2009 486 patients ,met/rec HNSCC Geftinib 250mg Geftinib 500 mg Mtx 40mg iv weekly RR-NS OS-NS tumor hge-more common with gefitinib Argiris A asco 2009 phase III ,RCT met/rec HNSCC Docetaxel+/-gef No benefit Gregoire V,Green journal,2011 ChemoRT +/- Gef No benefit
  • 38. Erlotinib intracellular domain of Met/rec HNSCC the EGFR Response rate= 4.3% Lapatinib reversible inhibitor of EFGR &HER2. ongoing trials-increased CR in preliminary analysis. -Monotherapy-no significant activity . Afatinib irreversible inhibitor of EGFR and HER2 RCT,phase II Rec/met HNSCC Plat refractory ,n=74 Afatinib vs Cet RR 18 VS 8% Dacomitinib irreversible 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 with activation of the Ras/MAP kinase pathway.  Growth and survival are mediated primarily through downstream 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) Pathway Angiogenesis Vasculogenesis Lymphangiogenesis
  • 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 trial Rec/met HNSCC N=60 BV +Pemetrxed RR 30% Higher gr 3 hemorrages PhaseI/II Cohen etal Lancet 2009 Rec/met HNSCC -well tolerated BV+Erlotinib Phase II DG P Etal JCO 2009 Phase II, RTOG trial 0615 Lee N,ASCO,JCO-2011 LAHNSCC BV+CDDP+IMRT LA-Ca NPX N=44 BV+CDDP+RT BV+CDDP *3cycle Prelim-well tolerated,good efficasy Final-awaiting -Fewer distant mets (prelim)
  • 44.  Bevacizumab is well tolerated,with response rate of 30% but need more RCT s to confirm its role.
  • 45. Cediranib (AZD2171, Recentin) TKI -VEGFR1, met/rec VEGFR2, and VEGFR3. HNSCC , rec NSCLC -monotherapy mean 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 bleeding Sorafenib (Nexavar multikinase 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 2010 Pazopani b (Votrient) multityrosine kinase inhibitor -VEGFR1, VEGFR2, VEGFR3, ckit, and PDGFR RR-6.1% Phase –II Lim W Etal JCO 2010 Ongoing Phase II -Monotherapy 800 mg daily -rec/met NPC -33 patients Vandeteni TKI targeting VEGFRs -LAHNSCC b and EGFR -Van+cisplatin PR- 18% Phase II Saura C etal JCO 2009 Phase II Machiels JP JCO 2010
  • 46.  Cediranib is the only molecule showing significant activity and tolerability comparing other multikinase inhibitors.
  • 47.  Downstream pathways are also explored for treatment  The PI3K/Akt/mTOR pathway plays a central role in apoptosis, cell survival, transformation, angiogenesis,and invasion and metastasis  Mtor activation may occur without EGFR activation in many head and neck cancers.
  • 48. Src  encodes for a nonreceptor tyrosine kinase  Src family proteins can associate with cellular membranes and transduce receptor signals (eg, EGFR) to internal signaling pathways, including PI3K and STAT.  STATs :transcription factors that on phosphorylation migrate to the nucleus to mediate expression of genes involved in proliferation, differentiation, and apoptosis
  • 49. DRUG MOA TRIAL RESULTS XL147 Oral PI3K inh (SARs 245,408) XL147, carboplatin and paclitaxel in 19 patients with advanced solid tumors Phase-I favorable responses were described in 2 patients with HNSCC perifosine (KRX-040) oral ,inhibits AKT activation. monotherapy in rec/met HNSCC no objective response Everolimus Mtor inhibitor oral Trials ongoing Temsirolimus Mtor inhibitor iv Trials ongoing Saracatinib AZD0530 Oral-src TKI -Dose- 175 mg/d -no response -Monotherapy rec/met (Fury MG,Anticancer res 2011) HNSCC Dasatinib (Sprycel) Oral TKI-src & BCRABL -monotherapy -Rec/met HNSCC No activity (Brooks,Cancer 2011)
  • 50.  Conclusion:We need more number of well conducted RCT s to ascertain role of Targeted agents against non receptor targets.
  • 51. Summary  At present Cetuximab is the only targeted agent that is approved in Head and neck squamous cell ca  Initial studies targeting other pathways have not yet yielded 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 a unavoidable 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 months Ind-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