Epidermal Growth Factor Receptor (EGFR) Inhibitors

1. Epidermal Growth Factor Receptor (EGFR) Inhibitors Dr.M.Jayanthi

2. Introduction

3. Cellular Signalling Pathways • Vital for cell cycle progression, growth, differentiation & death. • Growth Factors – The key stone • A delicate balance between activating and inhibitory signals needs to be maintained normally • Alteration in this balance - Dysregulated cellular proliferation & survival of abnormal cells.

4. GeneTranscription S Growth Factors + Priming G1 G0 G2 Cell Cycle M Growth Factors & Cell Cycle Receptors

5. Epidermal Growth Factor Receptor (EGFR)

6. Tumour EGFR Expression Rate Breast 14 % - 91 % Colon 25 % - 77 % Lung Cancer 40 % - 80 % (Non small cell) Head & Neck 80 % - 95 % Ovarian 35 % - 70 % Pancreatic 30 % - 50 %

7. Some Landmarks in EGFR Signalling Stanley Cohen EGF in mice (1960’s) Human EGF (1970’s) Isolation and cloning of EGFR (1980’s). Link between EGFR and malignant transformation of cells demonstrated 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

8. Human Epidermal Growth Factor Receptor Family TK TK TK No specific ligands - often acts as dimer partner NRG2 NRG3 Heregulins β-cellulin EGF, TGFa ,b Cellulin Amphiregulin, HB-EGF Heregulins erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4

9. EGFR Structure TK Extracellular Domain Transmembrane Domain Intracellular Domain

10. TK TK TK TK EGFR Stimulation & dimerisation EGFR Homo Dimerisation erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4

11. TK TK Risk for cancer TK EGFR stimulation cont… Hetero Dimerisation erbB4 HER4 erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3

12. ATP ATP TK TK + EGFR Function in Normal Cell Gene Transcription Cell Cycle Progression Antiapoptosis Cell Proliferation Angiogenesis

13. TK TK PTEN EGFR signal transduction in tumour cells PI3-K GRB2 pY pY SOS pY RAS RAF STAT3 AKT MEK Gene transcription MAPK G1 M S Survival(anti-apoptosis) Proliferation/maturation G2 Chemotherapy /radiotherapyresistance Metastasis Angiogenesis

14. Other mechanisms of EGFR stimulation MMP α + + + γ β P P Pyk2 Src Ras MAPK Transcription erbB Ligand Gene Steroid hormone HB-EGF G protein Ca++ Steroid hormone receptor

15. How EGFR variant differs from the wild type 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

16. ATP TK Gene transcription Cell Cycle Progression Cancer EGFR variant Cell Proliferation Metastasis Anti Apoptosis

17. Mutation Consequence of proliferation of EGFR receptors Normal Cell Cancerous Cell Up Regulation

18. 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.

19. 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.

20. ATP TK TK TK TK - - - - Strategies to inhibit EGFR signaling Anti-ligand mAbs Immune effector cell EGFR tyrosine kinase inhibitors BispecificAbs Anti-EGFR mAbs

21. Highly selective, potent & reversible EGFR Tyrosine Kinase Inhibitor Gefitinib Erlotinib Bispecific Anti EGFR antibody linked to Anti CD 64 H 447 MDX 210 Drugs Available Cetuximab – Monoclonal Anti EGFR antibody

22. Indications Gefitinib & Erlotinib: Monotherapy in advanced stage of NSCLC Cetuximab Metastatic colorectal cancer with/without Irinotecan Dose Gefitinib 250 mg O.D. oral Erlotinib 150 mg O.D. oral Cetuximab 400 mg/ m2 i.v.→ 200 mg / m2 i.v. wkly

23. 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.

24. 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.

25. 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

26. 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

27. Clinical Trials

28. Randomized double blind Parallel Group, multicenter Randomized double blind parallel group, multicenter Design Protocol Monotherapy Monotherapy 209 216 N of patients 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 GI, Rash Adverse effects GI, Rash Activity CR/PR 12% & 9%,CR/PR/SD 42 % & 36%; OS 6.5 & 5.9 mnths at 250 & 500 mg/d CR/PR 18% & 19%,CR/PR/SD 54 % & 51 OS 7.6 & 7.9 mnths at 250 & 500 mg/d Gefitinib Phase II Trials Parameter IDEAL I IDEAL II

29. Randomized double blind Placebo cont., multicenter Randomized double blind placebo cont.,multicenter Design Combination – gemcitabine & cisplatin Combination- Carboplatin & Paclitaxel Protocol 1093 1037 N of patients Adv.NSCLC Chemotherapy naïve stage III/IV Adv. NSCLC; Chemotherapy naïve stage III/IV Cancer Std. chemo plus 250 or 500 mg/day Std. chemo plus 250 or 500 mg/day Dose / regimen Adverse effects Diarrhoea, Rash Diarrhoea, Rash 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 Activity Gefitinib Phase III Trials Parameter INTACT I INTACT II

30. Design Open label Open label Protocol Monotherapy Monotherapy 124 57 N of patients Head & neck Ca refractory to chemo-/radiotherapy Advanced NSCL refractory to platinum based therapy Cancer Dose / regimen 150 mg/day 150 mg/day Diarrhoea, Rash Adverse effects Diarrhoea, Rash CR/PR 12%, CR/PR/SD 51 %; OS 8.4 mnths Activity PR 6%; PR/SD 46 % Erlotinib – Phase II Trials Parameter I II

31. Outcomes with Targeted Therapy Progression-free survival Quality of life Response to treatment Safety Overall Survival

32. 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

33. 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

34. Conclusion

35. Conclusion… • EGFR inhibitors- a definite role in treatment of cancer • Combination chemotherapy – Further studies needed • Improves QOL with minimal adverse effects • Can be administered at optimal biological dose • Potential for use in multiple tumors

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

37. Reference

38. 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.

39. 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.

40. 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.