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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.

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Targetted agents in head and neck cancers

  1. 1. Dr Sanudev Sadanandan.V.P Junior Resident Div of Radiation Oncology RCC Trivandrum Kerala
  2. 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. 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. 4. Targeted agents in HNSCC  1.EGFR inhibitor  2. IGF inhibitors  3.VEGF Receptor inhibitor  4.Non receptor targets
  5. 5. Erb B family of receptor
  6. 6. EGFR Receptor
  7. 7. EGFR pathway
  8. 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. 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. 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. 11. CETUXIMAB Recombinant human/mouse chimeric IG G1 monoclonal antibody
  12. 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. 13. Side effects  Infusion reaction 40-50%  acniform skin rash  Constitutional symptoms 50%  pulmonary-ILD( rare)  hypomagnesemia
  14. 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. 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. 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. 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. 18. Patient Characteristics
  19. 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. 20. Results-efficacy
  21. 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. 22. Overall Survival Median os 49 mon Vs 29.3 mon hazard ratio for death, 0.74; P = 0.03
  23. 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. 24. Results-safety
  25. 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. 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. 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. 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. 29.  Following the land mark study by “Bonner etal” Cetuximab was approved by FDA in LA HNSCC concurrent with RT.
  30. 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. 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. 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. 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. 34. RESULTS overall pop-NS ITT 12.8mon vs 14.4mon
  35. 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. 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. 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. 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. 39.  RCT do not show any advantage with Gefitinib  Afatinib –some promising response  Other molecules –under study
  40. 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. 41. Vascular Endothelial Growth Factor (VEGF) Pathway Angiogenesis Vasculogenesis Lymphangiogenesis
  42. 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. 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. 44.  Bevacizumab is well tolerated,with response rate of 30% but need more RCT s to confirm its role.
  45. 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. 46.  Cediranib is the only molecule showing significant activity and tolerability comparing other multikinase inhibitors.
  47. 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. 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. 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. 50.  Conclusion:We need more number of well conducted RCT s to ascertain role of Targeted agents against non receptor targets.
  51. 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. 52. Molecular Changes in Thyroid Cancer
  53. 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. 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. 55. Thank you

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