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

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

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

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

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

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

44. Conclusion

46.  Role in early stage of cancer needs to be assertained  Survival not significantly prolonged  Costly Conclusion…

47. Reference

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