1. Nexavar™ Sorafenib A Multikinase inhibitor January 2009 Chloé DINGREVILLE Diane-Laurène SMALAurélie TELLIER

2. 2 2 major isoforms: B-Raf C-Raf or Raf1 EGFR VEGFR Ras Raf MEK ERK Voie MAPK VEGF Ser/Thr Kinase PDGFR PDGF Initial target: Raf EGF

3. Raf: Often hyper activated in human solid tumour: 1.caused by activation oncogenic mutations: as b-raf V600E mutation Prevalent in melanomas 63% Papillary thyroid carcinoma 50%

4. 2. Activation upstream of oncogenic ras mutants (K- ras ) 90% of pancreatic cancers 30% of Hepatocellular carcinoma HCC 35% of Non-Squamous-cell lung cancers NSCLC 15% of melanoma 10% of kidney RCC

5. 3.expression of upstream growth factor or/ and their RTKs renal cell carcinoma (RCC) 50% hepatocellular carcinoma (HCC) 100%

6. Discovery and development of Sorafenib Sorafenib is a bi-aryl urea First oral kinase inhibitor, that targets RAF

7. Three Levels of Preclinical Evaluation Kinase Inhibition Biochemical First level: In vitro inhibitory profile of Sorafenib

8. 8 Interaction between Sorafenib and kinases Nexavar® Raf kinase, PDGFR, VEGFR, c- Kit, RET, etc…

9. In vitro inhibitory profile of Sorafenib

10. Sorafenib: Target cell proliferation By inhibiting Raf which is: Central downstream of Ras  Inhibit tumor growth

11. In vitro inhibitory profile of Sorafenib

12. Solid Tumors

13. Sorafenib: Target cell proliferation and angiogenesis Sorafenib is a multi-kinase inhibitor

14. Which cancers should be targeted ? « Because they attack multiple targets, it is hard to predict how drugs like Nexavar sorafenib will perform against a specific tumour type. »

15. Three Levels of Preclinical Evaluation Kinase Inhibition Biochemical In vitro Inhibition of cell proliferation Tumor Xenograft Determine the enter in Clinical Evaluation

16. A balanced portfolio strategy involves testing the drug both in: low-risk indications: highly likely to work given past successes EX: Broad already approved indication in HCC and RCC and geographical extension high-risk indications: less likely to work but the market would be worthwhile EX: Find new indications in other cancers

17. Cancer typeNexavar treatmentStatus Liver cancer HCCPost-transarterial chemoembolization (TACE) (Japan) 1st line, docorubicin TACE Adjuvant Combinations Ph III Ph II Planned Ph III Kidney cancer RCCAdjuvant Dose escalation Combinations Ph III Ph II Non-small cell lung cancer (NSCLC) 1st line, carboplatin/paclitaxel 1st line, gemcitabine/cisplatin 2 nd /3rd line, single-agent 2nd line, Alimta pemetrexed 1st line, carboplatin/Alimta 2nd line, Tarceva erlotinib Ph III * Ph II Ph I Planned Ph II Melanoma1st line, carboplatin/paclitaxel Multiple lines, temozolomide Ph III Ph II Nexavar clinical program

18. Two already approved indications: I.RCC: Renal Cell Carcinoma II. HCC: Hepatocellular Carcinoma

19. Renal Cell Carcinoma 19

20. Nearly 3% of all cancers The most common kidney cancer Each year:  32,000 new cases diagnosed in the United States  40,000 diagnosed in the European Union  11,000 cases in Japan Maximum incidence on 6th decade Poor prognosis with a median survival of 10 to 12 months 5-year-survival rate is less than 10% 20

21. Approved therapies before Nexavar® Role of surgery: -Nephrectomy -Surgical metastasectomy First line treatment: First line systemic treatment Good or intermediate prognosisBevacizumab + IFNαAge<60, good performance status High dose IL-2 high unmet medical need 21

22. 75% RCC tumor possessed alterations in the Von Hippel Lindau (VHL) gene responsible for dysregulation of growth factor signaling: - TGF-α - VEGF, PDGF-β, that play key roles in angiogenesis 22

23. Sorafenib inhibits the growth of s.c. implanted human 786-O 23

24. significant reduction in tumor vasculature within 3 days of sorafenib treatment angiogenesis was assessed by measuring the level of CD31 endothelial marker 24

25. The TARGET study Treatment Approches in Renal cancer Global Evaluation Trial A randomized double-blind international phase III trial of the effects of sorafenib on overall survival (OS) in people with RCC Objective: Primary endpoint: Overall survival (OS) Secondary endpoint: Progression-free-survival (PFS) Tumor response Clinical benefit rate Toxic effects Time to self-reported health status deterioration 25

26. Patients eligibility: Disease progression after they received at least one systemic treatment for mRCC Low/intermediate risk as prognostic score Method: 451 452 Sorafenib Placebo 26 903 patients randomized

27. Results: Progression free survival Kaplan-Meier analysis in phase III RCC trial Twofold increased median PFS compared with placebo (24 vs 12 weeks; p <0.000001) This PFS benefit was independent of gender, age and prior therapy 27

28. Overall survival Kaplan-Meier analysis in phase III RCC trial Median OS was 19, 3 months for patients in the sorafenib group and 15,9 months for patients in the placebo group (hazard ratio, 0,77; 95% CI, 0,63 to 0,95; P=0,02) No statistical significance

29. Second line treatment: Second line systemic treatmentPrior cytokine therapySunitinib Sorafenib Prior tyrosine kinase inhibitor Other anti- VEGF Temsirolimus Bevacizumab + IFN α Approved by the FDA in December 2005 Approved by the EMEA in July 2006 Indication and usage: Treatment of patients with advanced renal cell carcinoma (RCC), a type of kidney cancer 29

30. Low-risk extension of indication

31. Sorafenib Dose Escalation in RCC A non-randomized, open-label and multi-centre phase II trial to study the impact of dose escalation of sorafenib as first line treatment in mRCC Objective: recording Tumor Response Rates And then: -Safety and tolerability -Pharmacokinetics -Progression free survival -Time to progression Method : One arm Treatment cycle of 28 days Initial dose of sorafenib will be 400mg bid administered orally Day 29-56 600mg bid Day 57 onwards 800mg bid Results due 31

32. H epatoCellular Carcinoma 32

33. HCC: Unresectable hepatocellular carcinoma Primary malignant cancer of the liver (80 to 90%) 5th most frequent form of cancer worldwide 1 million news cases each year Third leading cause of cancer related mortality More than 600 000 deaths per year Fatal disease: Die within 1 year after the diagnosis Poor prognosis: fast spreading! and hard to treat Etiology: viral hepatitis B and C, alcohol, cirrhosis Urgent need of new therapy for this aggressive disease !!! 33

34. Important role in the development of HCC : - Frequent mutation of k-ras - overexpression of Raf-1kinase in a high number of HCC - Angiogenesis 34 Preclinical Overview of Sorafenib,p 3130

35.  Sorafenib strongly inhibits the growth of PLC/PRF/5 HCC tumors in a xenograft mouse model 35 Preclinical Overview of Sorafenib,p 3135

36. Sorafenib significantly inhibits CD34 in PLC/PRF/5 HCC tumors in mice. CD34 and microvessel density were plotted 36 Preclinical Overview of Sorafenib,p 3135

37. The unresectable HepatoCellular Carcinoma HCC The SHARP study Sorafenib HCC Assessement Randomized Protocol Pivotal study in Phase III International, multicenter (America, Australia, New-Zealand, Europe), double-blind, placebo-controlled trial, randomized 602 patients with advanced HCC Outcomes: Firstly : - Overall survival (OS) - Time to progression (TTP) Secondly : - Time to radiologic progression -Safety 37

38. Patients eligibility: for inclusion in the SHARP trial : – Histologically proven HCC – Advanced HCC – Measurable untreated lesions – Child pugh class A – No prior systemic treatment Methods: 303 299 Placebo Sorafenib 602 patients randomized 38

39. Results: OS =10,7 months Sorafenib / 7,9 months Placebo  44% of the overall survival ! Statistically signifiant advantage for Sorafenib 39

40. TTP =5,5 months Sorafenib / 2,8 months Placebo  So convincing  stop of trial (interim analysis) : significant survival advantage 40

41. NEXAVAR ® Considered as new, first, and only standard of care in patients with advanced HCC constitutively active upstream oncogenic ras mutants (K-ras ) : 30% of HCC overexpression of upstream growth factor or/ and their RTKs : 100% of HCC Treatment of patients with Unresectable Hepatocellular Carcinoma (HCC), a type of liver cancer No other substance with this label Approved by the FDA in November 2007 Approved by EMEA in autumn 2007

42. Geographical extension of Nexavar indication in HCC 42

43. Geographical extension of Nexavar indication in HCC 43

44. Extend of SHARP study SHARP trial is not able to address the relevance of Sorafenib for the Asian population:  Parallel trial in an Asia-Pacific population  Efficacy and safety of Sorafenib Multinational phase II, randomised, doubled-blind, placebo controlled-trial Method: 76 150 placebo Sorafenib 226 patients randomized 44

45. Outcomes: - Overall Survival : 6,5 vs 4,2 months 45 www.thelancet.com/oncology Vol 10, January 2009

46. - TTP :2,8 vs 1,4 months 46 www.thelancet.com/oncology Vol 10, January 2009

47. High-risk indication: NSCLC: No Squamous Cell Lung Carcinoma

48. 1.Sorafenib and NSCLC:  proliferation signalling of the Ras/Raf/MEK/ ERK pathway is increased in NSCLC due to K-Ras mutations  sorafenib inhibited the growth of two NSCLC xenograft models (A549 and NCI-H460)

49. 2.Epidemiology: 1,2 million new cases worldwide every year the third most common cancer after prostate and breast cancer the incidence of lung cancer had been rising in women, and still high in men Age: median age is 70 years Geography: North America and Eastern Europe population Survival: The overall 5-year survival rate for lung cancer is 15% median survival is 4 months for untreated patient A commercial opportunity and a great patient need!

50. 3.Standard treatment:  Surgery for patients with early- stage NSCLS  Adjuvant treatment: Radiation and Chemotherapy: chemotherapy-naïve: bevacizumab (Avastin®)- chemotherapy chemotherapy-refractory: erlotinib (Tarceva®)  tumour control and symptom palliation

51. Promising signals in two non-randomized Phase II NSCLC combination trials with Nexavar + Commercial Opportunity + great patient need =international, randomized, 900 patients ESCAPE study: Ph III trial without a randomized Ph II study No possibility to predict how a multi-target agent such as Nexavar will perform against a given tumor type

52. ESCAPE: Phase III Trial Comparing Carboplatin- Paclitaxel +/- Sorafenib in NSCLC Stratification: geographical region ECOG PS 0 vs1 Squamous cell vs Non- Squamous Cell Stage IIIb vs Stage IV Stratification: geographical region ECOG PS 0 vs1 Squamous cell vs Non- Squamous Cell Stage IIIb vs Stage IV RANDOMiSATIONRANDOMiSATION RANDOMiSATIONRANDOMiSATION Carboplatin+ Paclitaxel+ Sorafenib (CPS) Carboplatin+ Paclitaxel+ Sorafenib (CPS) Carboplatin+ Paclitaxel+ Placebo (CPP) Carboplatin+ Paclitaxel+ Placebo (CPP) Sorafenib 400mg bid Sorafenib 400mg bid Placebo n=900

54. Phase III ESCAPE study of Nexavar in combination with carboplatin/paclitaxel The trial would not meet its Primary endpoint:  improved Overall survival In the subset of patients with squamous cell carcinoma of the lung, higher mortality was seen when Nexavar was given in combination with carboplatin/paclitaxel than chemotherapy only

55. Why did it fail? Main reasons: Limits of the xenograft: only 1 cell type tumor implanted Heterogeneous with multiple mutations

56. Melanoma 56

57. PREVALENCE Less than 10% of skin cancer cases Large majority of skin cancer deaths: responsible for nearly three times the number of deaths by nonmelanoma skin cancers (approximately 7,910 vs 2,800) The incidence of melanoma has increased steadily since 1930 and continues to rise at a rate that has exceeded all other cancer types AGE Average age of development: 55 years LIFE EXPECTANCY Patients with advanced metastatic melanoma (stage IV) have a 5-year survival rate of only 2%  Failure of chemotherapy (dacarbazine) or immunotherapy regimens (IL-2, TNF- α )

58. The MAPK signaling pathway is activated in majority of melanomas Activating mutations of the B-RAF gene for 60% (B-raf V 600 E) Constitutively active RAS oncogenes for 15% 58

59. Sorafenib inhibits growth 59

60. 60

61. The 11715 Study A double-blind randomized and multicenter phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma 2 arms: placebo plus dacarbazine sorafenib plus dacarbazine evaluate the efficacy and safety of sorafenib plus dacarbazine Patients eligibility: chemotherapy-naïve patients unresectable stage III or stage IV melanoma Method: 101 patients randomized: 50 with placebo and 51 with sorafenib 61

62. Median PFS in the sorafenib arm was 21.1 weeks vs 11.7 weeks in the placebo arm (hazard ratio [HR], 0.665; P.068) Results were statistically significant 62 Results:

63. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo and sorafenib arms, respectively; HR, 1.022) 63

64. CONCLUSION

65. 65

66. 66

67. Thank you for your attention 67 Chloé DINGREVILLE Diane-Laurène SMALAurélie TELLIER