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Manejo oncológico del cáncer de pulmón

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  • 1. MANEJO ONCOLOGICO DEL CANCER DE PULMON DR. JOSE ALFREDO ALMENAREZ GOMEZ ONCOLOGIA CLINICA CENTRO ONCOLOGICO DE ANTIOQUIA I.P.S. UNIVERSITARIA – UNIVERSIDAD DE ANTIOQUIA / MEDELLIN CATEDRA DE ONCOLOGIA CLINICA – UNIVERSIDAD DEL MAGDALENA / SANTA MARTA
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  • 13. Epidermal Growth Factor Receptor (EGFR) Inhibitors
  • 14. Growth Factors & Cell Cycle Receptors Gene Transcription G 0 G 1 Priming S G 2 M Cell Cycle Growth Factors +
  • 15. Epidermal Growth Factor Receptor (EGFR)
  • 16. Breast 14 % - 91 % Colon 25 % - 77 % Lung Cancer 40 % - 80 % (Non small cell) Ovarian 35 % - 70 % Pancreatic 30 % - 50 % Head & Neck 80 % - 95 % EGFR Expression Rate Tumour
  • 17. Some Landmarks in EGFR Signalling Stanley Cohen
    • Human EGF (1970’s)
    • Isolation and cloning of EGFR (1980’s). Link between EGFR and malignant transformation of cells demonstrated
    • EGF in mice (1960’s)
    Mendelsohn et al.,
    • Blocking EGFR signalling to treat cancer
    • Murine monoclonal antibodies targeting EGFR-TK -> Human:murine chimeric version
    More than 20 anti-EGFR agents in development
  • 18. erbB1 HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 No specific ligands - often acts as dimer partner Heregulins NRG2 NRG3 Heregulins β -cellulin EGF, TGF    Cellulin Amphiregulin, HB-EGF Human Epidermal Growth Factor Receptor Family TK TK TK
  • 19. Intracellular Domain Transmembrane Domain Extracellular Domain EGFR Structure TK
  • 20. erbB1 HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 EGFR Homo Dimerisation EGFR Stimulation & dimerisation TK TK TK TK
  • 21. erbB1 HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 Hetero Dimerisation EGFR stimulation cont… TK TK TK Risk for cancer
  • 22. EGFR Function in Normal Cell Cell Proliferation Antiapoptosis Angiogenesis Gene Transcription Cell Cycle Progression TK TK ATP ATP +
  • 23. EGFR signal transduction in tumour cells Survival (anti-apoptosis) PI3-K STAT 3 AKT MEK Gene transcription MAPK Proliferation/ maturation Chemotherapy / radiotherapy resistance Angiogenesis Metastasis pY pY RAS RAF SOS GRB2 pY G 1 S M G 2 TK TK PTEN
  • 24. Ca ++ HB-EGF Steroid hormone Steroid hormone receptor G protein Other mechanisms of EGFR stimulation MMP α β γ Pyk2 Src Ras MAPK P P erbB Ligand Gene Transcription + + +
  • 25. EGFR - Variant III EGFR – Wild Type No extracellular domain Present Ligand cannot bind Can bind TK constitutively active TK activated by ligand binding Cannot dimerise Can dimerise Not found in normal cells Found normally More propensity for cancer Up regulation leads to cancer How EGFR variant differs from the wild type
  • 26. Cell Proliferation Metastasis Anti Apoptosis EGFR variant TK Gene transcription Cell Cycle Progression Cancer ATP
  • 27. Normal Cell Cancerous Cell Up Regulation Consequence of proliferation of EGFR receptors Mutation
  • 28. EGFR – A good target for lung cancer ( non small cell )
    • High level of receptor expression compared with healthy tissue.
    • EGFR - Key role in tumour cell growth & function.
    • EGFR inhibition can inhibit downstream activity.
    • EGFR inhibitors have no severe toxicity.
  • 29. Rationale for EGFR Inhibitors in Head & Neck cancer
    • EGFR expressed in > 90% of head & neck cancers.
    • EGFR over expression associated with decreased survival.
    • Increased EGFR expression is an early event in carcinogenesis & even present in premalignant lesions.
    • Inhibition of EGFR – TK slows the growth of xenograft tumour models of head & neck.
  • 30. Strategies to inhibit EGFR signaling EGFR tyrosine kinase inhibitors Anti-EGFR mAbs Anti-ligand mAbs Bispecific Abs Immune effector cell TK TK TK TK - - - - ATP
  • 31. Drugs Available
    • Cetuximab – Monoclonal Anti EGFR antibody
    • Gefitinib
    • Erlotinib
    Highly selective, potent & reversible EGFR Tyrosine Kinase Inhibitor
    • H 447
    • MDX 210
    Bispecific Anti EGFR antibody linked to Anti CD 64
  • 32. Indications Monotherapy in advanced stage of NSCLC Gefitinib & Erlotinib : Gefitinib 250 mg O.D. oral Erlotinib 150 mg O.D. oral Cetuximab 400 mg/ m 2 i.v. -> 200 mg / m 2 i.v. wkly Cetuximab Metastatic colorectal cancer with/without Irinotecan Dose
  • 33. Side Effects
    • Skin rash
    • Diarrhoea ( EGFR – TKI s )
    • Fever ( EGFR – mAb )
    • Interstitial lung disease – 1% (only for Gefitinib)
    Discontinuation rates due to adverse effects are very low unlike chemotherapy.
  • 34. Drug Interactions
    • EGFR – TK Inhibitors metabolised by CYP3A4.
    • Inhibitors / inducers of CYP3A4 can alter drug levels.
    • Warfarin interactions have occurred in clinical trials of Gefitinib.
    • Concomitant administration with warfarin requires monitoring of PT, INR.
  • 35. Advantages of EGFR Inhibitors
    • Orally effective
    • Better quality of life.
    • Can be used as monotherapy.
    • No need for premedication or dose monitoring.
    • No hematological toxicity.
    • Potential for long term treatment.
    • Reduced resistance to radiation or hormone therapy
  • 36. Current Status Gefitinib
    • FDA Approved on May ,2003 for Lung cancer-NSC (Accelerated Approval Programme)
    Erlotinib
    • FDA Approved on Nov, 2004 for Lung cancer – Non Small Cell (AAP)
    Cetuximab
    • FDA Approved on Feb, 2004 for advanced colorectal cancer
  • 37. Clinical Trials
  • 38. Parameter IDEAL I IDEAL II Gefitinib Phase II Trials Design Randomized double blind Parallel Group, multicenter Randomized double blind parallel group, multicenter Protocol Monotherapy Monotherapy N of patients 209 216 Cancer Advanced NSCLC; 1-2 prior Chemotherapy cycles Advanced NSCLC; >2 prior Chemotherapy cycles Dose / regimen 250 or 500 mg/day 250 or 500 mg/day Adverse effects GI, Rash GI, Rash Activity CR/PR 18% & 19%,CR/PR/SD 54 % & 51 OS 7.6 & 7.9 mnths at 250 & 500 mg/d CR/PR 12% & 9%,CR/PR/SD 42 % & 36%; OS 6.5 & 5.9 mnths at 250 & 500 mg/d
  • 39. Parameter INTACT I INTACT II Gefitinib Phase III Trials Design Randomized double blind Placebo cont., multicenter Randomized double blind placebo cont.,multicenter Protocol Combination – gemcitabine & cisplatin Combination- Carboplatin & Paclitaxel N of patients 1093 1037 Cancer Adv.NSCLC Chemotherapy naïve stage III/IV Adv. NSCLC; Chemotherapy naïve stage III/IV Dose / regimen Std. chemo plus 250 or 500 mg/day Std. chemo plus 250 or 500 mg/day Adverse effects Diarrhoea, Rash Diarrhoea, Rash Activity No difference in overall surv., Prog. Free surv., or time to worsening symptoms No difference in overall surv., Prog. Free surv., or time to worsening symptoms
  • 40. Parameter I II Erlotinib – Phase II Trials Protocol Monotherapy Monotherapy N of patients 124 57 Cancer Head & neck Ca refractory to chemo-/radiotherapy Advanced NSCL refractory to platinum based therapy Dose / regimen 150 mg/day 150 mg/day Adverse effects Diarrhoea, Rash Diarrhoea, Rash Activity PR 6%; PR/SD 46 % CR/PR 12%, CR/PR/SD 51 %; OS 8.4 mnths Design Open label Open label
  • 41. Outcomes with Targeted Therapy
    • Progression-free survival
    • Quality of life
    • Response to treatment
    • Safety
    • Overall Survival
  • 42. Unanswered Questions
    • Patient selection
    • How long patients should be treated
    • Timing and sequencing of combination therapy
    • Use in various stages of disease
    • Appropriate markers for response
    • Managing unique adverse events
    • -> ILD
    • -> Liver toxicity
    • Best use in other solid tumours
  • 43. Ongoing Trials…
    • Different treatment schedules for use in combination chemotherapy
    • In other malignancies – Breast, Prostate, Head & Neck, Colon as single / combination therapy
    Strategies
    • Combining EGFRI with Radiotherapy / Surgery or other novel targeted agents like trastuzumab
    • Identify subset of people who will benefit from TKI
    • Skin rashes, Mutation in TK, KRAS
  • 44. Conclusion
  • 45. Conclusion…
    • EGFR inhibitors- a definite role in treatment of cancer
    • Combination chemotherapy – Further studies needed
    • at optimal biological dose
    • Potential for use in multiple tumors Improves QOL with minimal adverse effects
    • Can be administered
  • 46.  Role in early stage of cancer needs to be assertained  Survival not significantly prolonged  Costly Conclusion…
  • 47. Reference
  • 48. Review Articles 1. Soler R.P. HER1/ EGFR Targeting :Refining the strategy. Oncologist 2004 ; 9 : 58 – 67. 2. Herbst R.S, Fukuoka M, Baselga J. Gefitinib – a novel targeted approach to treating canver. Nature rev cancer 2004 ; 4 : 956 – 65. 3. Strausberg R.L, Simpson A.J.G, Old L.J, Riggins G.J. Oncogenomics and the development of new cancer therapies. Nature 2004 ; 429 : 469 – 74. 4. Noble M.E.M, Endicott J.A, Johnson L.N. Protein kinase inhibitors : Insights into drug design from structure. Science 2004 ; 303 : 1800 – 05. 5.Glover K.Y, Soler R.P, Papadimitradopoulou V.A. A review of small molecule Epidermal Growth Factor Receptor specific tyrosine kinase inhibitors in development for non small cell lung cancer. Sem. Oncol. 2004 ; 31 suppl : 83 – 92. 6. Janmaat M.L, Giaccone G. Small molecule Epidermal Growth Factor Receptor tyrosine kinase inhibitors. Oncologist 2003 ; 8 : 576 – 86.
  • 49. Review Articles – cont … 7. Yano S, Nishioka Y, Goto H, Sone S. Molecular mechanism of angiogenesis in non small cell lung cancer and therapeutics trageting related molecules. Cancer sci. 2003 ; 94 : 479 – 85. 8. Vlahovic G, Crawford J. Activation of tyrosine kinases in cancer. Oncologist 2003 ; 8 : 531 – 8. 9. Spiro S.G, Porter J.C. Lung cancer – where are we today ? Current advances in staging and non surgical treatment. Am J Respir Crit Care Med 2002 ; 166 : 1166 – 96. 10. Arteaga C.L, Epidermal Growth Factor Receptor dependence in human tumors : more than just expression ? Oncologist 2002 ; 7 suppl 4 : 31 – 9. 11. Raymond E, Faivre S, Armand J.P. Epidermal growth factor receptor tyrosine kinaase as a target for anticancer therapy. Drugs 2000 ; 60 suppl 1 : 15 – 23.
  • 50. Mini Review 1. Levin E.R. Bidirectional signalling between the estrogen receptor and the epidermal growth factor receptor. Mol. Endocrinol. 2003 ; 17 : 309 – 17. Original Articles
    • Kelly K, Averbuch S. Gefitinib : Phase II and III results in advanced non small cell lung cancer. Sem. Oncol. 2004 ; 31 suppl1 : 93 – 9.
    • Pao W, Wang T, Riley G.J, Miller V.A, Pan Q, Varmus H.E et al . KRAS mutations and primary resistance of lung adenocarcinoma to Gefitinib or Erlotinib. PLOS Medicine 2005 ; 2 : e17.
  • 51.