Nierkanker. Sylvie Rottey Department of Medical Oncology UZ Gent 23 Jan 2015

Transcription

1 Nierkanker Sylvie Rottey Department of Medical Oncology UZ Gent 23 Jan 2015

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3 Nierkanker 2012, Belgie Absolute aantallen per leeftijdsgroep Belgian Cancer Register

4 Nierkanker 2012, Belgie Leeftijdsspecifieke incidentie Belgian Cancer Register

5 Histologic classification Clear Cell Non Clear Cell Type Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma Approximate Incidence 75% 12% 4% 4% Associated VHL c-met FH BHD BHD mutations VHL = von Hippel-Lindau, FH = fumarate hydratase, BHD = Birt-Hogg-Dube Modified from Cohen HT et al. N Engl. J Med. 2005;353:

6 Prevalence of RCC Histologic Subtypes Chromophobe (5%) Papillary Type 1 (5%) BHD Other Clear cell (75%) Papillary Type 2 (10%) Gene: BHD = Birt Hogg Dubé FH = Fumarate hydratase VHL = von Hippel Lindau Linehan WM, et al. In: Cancer: Principles and Practice of Oncology. 2006:

7 Staging renal cell cancer TNM 7th edition T2 T3 T3a T3b T3c Tumour more then 7cm in greatest dimension, limited to the kidney T2a Tumour more than 7cm but no more than 10 cm T2b Tumour more than 10cm, limited to the kidney Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia Tumour grossly extends into the renal vein or its segmental (muscle containing) branches, or tumour invades perirenal and/or renal sinus fat (peripelvic) fat but not beyond Gerota fascia Tumour grossly extends into vena cava below diaphragm Tumour grossly extends into vena cava above the diaphragm or invades the wall of the vena cava T4 Tumour invades Gerota fascia (including contiguous extension into the ipsilateral adrenal gland) 7th edition Stage IV T4 / any N / M0 Any T/ N2/ M0 Any T/ any N/ M1

8 Staging renal cell cancer 5 year survival Aorta Gerota s fascia Adrenal gland Kidney Stage I (5 year survival: 96%) 1 Tumor <7 cm in greatest dimension and limited to kidney. 2,3 Inferior vena cava Stage II (5 year survival: 82%) 1 Tumor >7 cm in greatest dimension and limited to kidney. 2,3 Lymphn odes Adapted from Cohen et al. 2 Stage III (5 year survival: 64%) 1 Tumor in major veins, adrenal gland, or perinephric tissue (not beyond Gerota s fascia), and/or 1 regional lymph node involved. 2,3 Stage IV (5 year survival: 23%) 1 Tumor beyond Gerota s fascia, >1 regional lymph node involved, and/or >1 distant metastasis. 2,3 1 Linehan WM, et al. In: Cancer: Principles and Practice of Oncology. 2005: Cohen HT, et al. N Engl J Med. 2005;353: Kidney. In: AJCC Cancer Staging Manual. 2002:

9 Motzer criteria for Advanced RCC Percentage of population (%) 4,9 months 20 % 13,8 months 62 % 29,6 months 18 % Prognostic Factor 1. Karnofsky performance status < Time from diagnosis to treatment with IFN-α < 12 months 3. Hemoglobin < Lower limit of laboratory s reference range 4. Lactate dehydrogenase > 1.5 x the upper limit of laboratory s range 5. Corrected serum calcium > 10.0 mg/dl MSKCC Risk groups Median Overall Survival (Months) Motzer RJ, et al. J Clin Oncol. 2002;20: /5 Good prognosis 1-2/5 Intermediate prognosis 3-5/5 Poor prognosis

10 Renal cell cancer treatment Surgery Radiotherapy Chemotherapy : response rate of 2 6% Immunotherapy : % RR, toxicity!! CAVE LONG TERM REMISSIONS Hormonotherapy : 2 % RR

11 Consequences of VHL gene mutation VHL complex disrupted Mutant α domain Multiprotein complex VHL protein domain HIF HIF HIF HIF1, HIF2 accumulation CXCR4 VEGF PDGF TGF α Organ specific metastasis Angiogenesis Endothelial stabilisation Autocrine growth stimulation VHL = von Hippel Lindau; HIF = hypoxia inducible factor CXCR4 = chemokine receptor 4; VEGF = vascular endothelial growth factor; PDGF = platelet derived growth factor TGF = transforming growth factor Bernards R. Nature 2003;425:247 8 Lineham WM, et al. J Urol 2003;170:

12 Renal cell cancer

13 Molecular pathways

14 Renal cancer

15 Treatments for metastatic renal cell cancer Cytokines Immunotherapy IL 2 and IFN α first to report activity VHL tumour suppressor gene isolated First gene identified to cause a proportion of hereditary RCC and other tumours Bevacizumab + IFN FDA (2009) and EMA (2007) approval Temsirolimus FDA and EMA approval Everolimus FDA and EMA approval 1990s 1990s 2000s High dose IL 2 FDA approval based on phase II data Bevacizumab Data established activity of anti angiogenic agents in RCC Sorafenib and sunitinib FDA and EMA approval + Jan 2012 : FDA approval axitinib Pazopanib FDA approval EMA = European Medicines Agency. FDA = US Food Drug Administration; Quesada, et al. Cancer Res. 1983;43: ; dekernion, et al. J Urol. 1983;130: ; Rosenberg, et al. N Engl J Med. 1985;313: ; Latif, et al. Science. 1993;260: ; Yang, et al. N Engl J Med. 2003;349:

16 Different treatment possibilities Sorafenib (Nexavar) Sunitinib (Sutent) Temsirolimus (Torisel) Pazopanib (Votrient) Everolimus (Afinitor) Axitinib (Inlyta)

17 What is important to discuss Indication the drug is studied Mode of action Results of trial : PFS (progression free survival) OS (overal survival) Side effects Administration Possible interactions

18 Different treatment possibilities Sorafenib (Nexavar) second line Sunitinib (Sutent) Temsirolimus (Torisel) Pazopanib (Votrient) Everolimus (Afinitor) Axitinib (Inlyta)

19 Jan 2007

20 Nexavar Targets both Tumor-Cell Proliferation and Angiogenesis Tumor cell Endothelial cell or Pericyte EGF RAF MEK ERK RAS Nucleus VHL HIF-2 Apoptosi s Autocrine loop Mitochondria EGF PDGF VEGF Proliferation Survival PDGF- Paracrine stimulation PDGFR- Mitochondria RAS RAF MEK ERK Apoptosi s Nucleus VEGF VEGFR-2 Angiogenesis: Differentiation Proliferation Migration Tubule formation Nexavar Wilhelm S et al. Clin Cancer Res. 2004;64:

21 Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs) Eligibility criteria Histologically/cytologically confirmed, unresectable and/or metastatic RCC Clear cell histology Measurable disease Failed one prior systemic therapy in last 8 months ECOG PS 0 or 1 Good organ function No brain metastasis Poor-risk MSKCC (Motzer) group excluded Stratification MSKCC (Motzer) criteria Country Randomisation (1:1) n~903 Sorafenib 400mg b.i.d. Placebo Major endpoints OS ( =0.04) PFS ( =0.01) ECOG PS = Eastern Cooperative Oncology Group Performance Status MSKCC = Memorial Sloan-Kettering Cancer Center OS = overall survival Escudier B, et al. ECCO 2005, Paris, France

22 TARGETs: clinical benefit was achieved by 84% of patients receiving sorafenib Objective responses*, n (%) Best response (RECIST) Sorafenib (n=451) Placebo (n=452) Complete response (CR) 1 (<1) 0 (0) Partial response (PR) 43 (10) 84% clinical 8 (2) Stable disease (SD) 333 (74) benefit 239 (53) 55% clinical benefit Progressive disease (PD) 56 (12) 167 (37) Missing data 18 (4) 38 (8) *Investigator-assessed Patients randomised at least 6 weeks before data cut-off at 31 May 2005 RECIST = Response Evaluation Criteria In Solid Tumors Escudier B, et al. ECCO 2005, Paris, France

23 TARGETs: sorafenib significantly prolonged PFS compared with placebo 100 PFS (% patients) Median PFS* Placebo = 12 weeks Sorafenib = 24 weeks Hazard ratio (HR) = 0.51 p< Placebo Sorafenib Censored observation Time from randomisation (months) *Based on investigator assessment Escudier B, et al. ECCO 2005, Paris, France

24 TARGETs: sorafenib has a predictable and manageable side-effect effect profile Incidence of adverse events* (%) Sorafenib (n=451) Placebo (n=451) Any grade Grades 3 4 Any grade Grades 3 4 Diarrhoea Rash/desquamation <1 Fatigue Hand foot skin reaction Hypertension <1 Dyspnoea Decreased haemoglobin Bone pain Tumour pain QOL : not worse in sorafenib group No hematological toxicity

25 Sorafenib Oral administration 800 mg a day : 2 x 400 mg a day Not with fatty meals 200 mg tablets available Continuously until disease progression

26 Sorafenib - interactions DRUGS CYP 344 inhibitors (macrolides, azoles, verapamil, dilthiazem, ) Risk QT-prolongation prolongation (Chinolones, sulfamethoxazole-trimethoprim, trimethoprim, amiodarone, lumefantrine, chloroquine, sotalol, propafenon, disopyramide, methadon, quetiapine, pimozide, lopinavir, fluoxetine, ) CYP 3A4 Induction (Carbamazepine, fenyto (Carbamazepine, fenytoïne, ne, oxcarbamazepine, fenobarbital, rifampicine, ritonavir, nevirapine, efavirenz, primidone, midone, )

27 Sorafenib - interactions DRINKS and HERBS Juice grapefruit /pomelo s Saint John s s Wort Echinacea (Urgenin,, Echinacin )

28 Different treatment possibilities Sorafenib (Nexavar) Sunitinib (Sutent) first line Temsirolimus (Torisel) Pazopanib (Votrient) Everolimus (Afinitor) Axitinib (Inlyta)

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30 Sunitinib Multitarget thyrosine kinase inhibitor Bergers G et al. J Clin Invest. 2003;111: ; Sulzbacher I et al. Am J Clin Pathol. 2003;120: ; Tsuchiya N et al. Tohoku J Exp Med. 2001;19:

31 Sunitinib in first line Eligibility Criteria Metastatic RCC with clear cell histologic component No prior systemic therapy Measurable disease ECOG Performance Status 0 or 1 Adequate organ function No brain metastasis No uncontrolled hypertension or clinically significant cardiovascular event/disease in last 12 months At least 18 years old Randomization 1:1 N=750 Stratification LDH (>1.5 vs.?1.5 ULN) ECOG PS (0 vs. 1) Previous nephrectomy Sunitinib 50 mg po daily (schedule 4 wks on, 2 wks off) IFN- administered TIW (3 MU 9 MU) Primary endpoint Progression-free survival Secondary endpoints Objective response rate (RECIST) Overall survival Patient-reported outcomes Safety Motzer R, et al. N Engl J Med. 2007;356:

32 Sunitinib in first line 11-month median PFS for SUTENT vs 5 months for IFN Progression-free survival probability 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 Hazard ratio = (95% CI: 0.320, 0.539) P< SUTENT (n=375) Median PFS: 11 months (95% CI: 10, 12) Time (months) Number of subjects at risk SUTENT IFN IFN (n=375) Median PFS: 5 months (95% CI: 4, 6) Motzer R, et al. N Engl J Med. 2007;356:

33 Bone marrow suppression Hypertension Asthenia Side effects sunitinib > 10 %, Fatigue severe side effects are rare Bullous skin lesions Hand-foot skin reaction Yellow discoloration of skin Hypothyroidism Diarhea Mucositis Peripheral edema Laboratory anomalies

34 Oral administration Sunitinib 50 mg a day : 1 x 50 mg, 4 weeks on, 2 weeks off 12,5, 25 and 50 mg tablets available Continuously until disease progression

35 Sunitinib - interactions DRUGS CYP 344 inhibitors (macrolides, azoles, verapamil, dilthiazem, ) Risk QT-prolongation prolongation (Chinolones, sulfamethoxazole-trimethoprim, trimethoprim, amiodarone, lumefantrine, chloroquine, sotalol, propafenon, disopyramide, methadon, quetiapine, pimozide, lopinavir, fluoxetine, ) CYP 3A4 Induction (Carbamazepine, fenyto (Carbamazepine, fenytoïne, ne, oxcarbamazepine, fenobarbital, rifampicine, ritonavir, nevirapine, efavirenz, primidone, midone, )

36 Sunitinib - interactions DRINKS and HERBS Juice grapefruit /pomelo s Saint John s s Wort Echinacea (Urgenin,, Echinacin )

37 Different treatment possibilities Sorafenib (Nexavar) Sunitinib (Sutent) Temsirolimus (Torisel) first line Pazopanib (Votrient) Everolimus (Afinitor) Axitinib (Inlyta)

38 The target - mtor complexes

39 Trial Design Stratification by: Geographical Regions: EU + AU + CA (21%) US (29%) Other (50%) Nephrectomy: Yes No R A N D O M I S E 626 pts IFN-α escalating to 18 MU SC 3 times weekly (n=207) Torisel 25-mg IV once weekly (n=209) Torisel 15-mg IV once weekly plus IFN-α 6 MU 3 times weekly (n=210) Hudes et al. N Engl J Med. 2007;356:

40 Main Inclusion Criteria: Prognostic Risk Factors Patients with unfavourable prognosis (> 3 out of 6 prognostic risk factors ) Karnofsky performance status 60 or 70 (<80) Less than 1 year from time of initial RCC diagnosis to randomization Hemoglobin less than the lower limit of normal (LLN) Lactate dehydrogenase > 1.5 times the upper limit of normal (ULN) Corrected serum calcium > 10 mg/dl More than 1 metastatic organ site of disease Hudes et al. N Engl J Med. 2007;356:

41 Probability of Survival Primary Endpoint Median Overall Survival Treatment with temsirolimus was associated with a 49% increase in median OS compared with IFN-α Torisel IFN-α Median Overall Survival 10.9 months 7.3 months P value Hazard ratio (95% CI) 0.73 ( ) Time From Registration, Months Temsirolimus (N=209) Temsirolimus + IFN-α (N=210) IFN-α (N=207) Hudes et al. N Engl J Med. 2007;356:

42 Serious Adverse Reactions Associated With Temsirolimus The following serious adverse reactions have been associated with temsirolimus in clinical trials: Hypersensitivity reactions Hyperglycemia/glucose intolerance Infections Interstitial pneumonitis Hyperlipemia This is not an exhaustive list, other side effects have also been observed. Data on file, Wyeth Pharmaceuticals Inc.

43 Temsirolimus IV weekly / day clinic 25 mg a week fixed dose Vials of 30 mg / 1,2 ml Continuously until disease progression

44 Temsirolimus- interactions DRUGS CYP 344 inhibitors (macrolides, azoles, verapamil, dilthiazem, ) CYP 3A4 Induction (Carbamazepine, fenyto (Carbamazepine, fenytoïne, ne, oxcarbamazepine, fenobarbital, rifampicine, ritonavir, nevirapine, efavirenz, primidone, midone, )

45 Temsirolimus - interactions DRINKS and HERBS Juice grapefruit /pomelo s Saint John s s Wort Echinacea (Urgenin,, Echinacin )

46 Different treatment possibilities Sorafenib (Nexavar) Sunitinib (Sutent) Temsirolimus (Torisel) Pazopanib (Votrient) first line Everolimus (Afinitor) Axitinib (Inlyta)

47 Phase III study: VEG Stratification ECOG performance status 0 versus 1 Prior nephrectomy Treatment naïve (n=233) versus one cytokine failure (n=202) Patients with advanced/ metastatic RCC (N=435) Randomization 2:1 Pazopanib 800 mg once daily (n=290) Matching placebo (n=145) Option to receive pazopanib via an open label study at progression Clinicaltrials.gov identifier NCT Sternberg et al. J Clin Oncol 2010;DOI: /JCO

48 Pazopanib versus placebo: progression free survival Median PFS (months) Proportion progression-free Placebo 4.2 Pazopanib 9.2 Hazard ratio (95% CI) 0.46 (0.34, 0.62) p value (1 sided) < % reduction in risk of progression or death with pazopanib treatment compared with placebo 0.0 Pazopanib Placebo Number at risk, n Pazopanib Placebo Time (month) In the overall study population, PFS was significantly greater in pazopanib versus placebo treated patients (p<0.0001) Sternberg et al. J Clin Oncol 2010;DOI: /JCO

49 Progression free survival in the treatment naïve subpopulation 1,2 1.0 Median PFS (months) Proportion progression-free Placebo 2.8 Pazopanib 11.1 Hazard ratio (95% CI) 0.40 (0.27, 0.60) p value (1 sided) < % reduction in risk of progression or death with pazopanib treatment compared with placebo 0.0 Pazopanib Placebo Number at risk, n Pazopanib Placebo Time (month) In the treatment naïve subpopulation, PFS was significantly greater in pazopanib versus placebo treated patients (p<0.0001) Sternberg et al. J Clin Oncol 2010;DOI: /JCO

50 Progression free survival in the cytokine pretreated subpopulation 1,2 1.0 Median PFS (months) Proportion progression-free Placebo 4.2 Pazopanib 7.4 Hazard ratio (95% CI) 0.54 (0.35, 0.84) p value (1 sided) < % reduction in risk of progression or death with pazopanib treatment compared with placebo 0.0 Pazopanib Placebo Number at risk, n Pazopanib Placebo Time (month) In the cytokine pretreated subpopulation, PFS was significantly greater in pazopanib versus placebotreated patients (p<0.001) Sternberg et al. J Clin Oncol 2010;DOI: /JCO

51 Overall response rate 1 p<0.001 Pazopanib Placebo Overall response rate (%) Overall population (n=435) Treatment-naïve (n=155) Cytokine pretreated (n=78) 1. Sternberg et al. J Clin Oncol 2010;DOI: /JCO

52 Pazopanib common adverse events* in Phase II and III studies *experienced by 10% of patients Adverse event VEG VEG Pazopanib (n=225), % Pazopanib (n=290), % Placebo (n=145), % All grade Grade 3 Grade 4 All grade Grade 3 Grade 4 All grade* Grade 3 Grade 4 Diarrhoea <1 9 <1 0 Hypertension <1 0 Hair colour changes < Nausea 42 < < Anorexia 24 < <1 0 Vomiting 20 < < Fatigue ALT increased 14 5 < <1 0 AST increased 12 3 < < Asthenia Abdominal pain Headache *In study VEG105192, 4 and 3% of patients in the pazopanib and placebo arms, respectively, had Grade 5 adverse events 1. Hutson et al. J Clin Oncol 2010;28: Sternberg et al. J Clin Oncol 2009;27(15S):Abstract 5021 and oral presentation.

53 Selected class effects associated with TKIs in the Phase III study (VEG105192) 1 Pazopanib (n=290) Placebo (n=145) Adverse event All grades, % All grades, % Proteinuria 9 0 Hypothyroidism 7 0 Hand foot syndrome 6 <1 Mucositis/stomatitis 4/4 <1/0 Arterial thromboembolic 3* 0 *2% of arterial thromboembolic events were Grade 3 or worse in severity 1. Sternberg et al. J Clin Oncol 2009;27(15S):Abstract 5021 and oral presentation.

54 Common haematological and biochemical abnormalities* in the Phase II and III studies of pazopanib *experienced by 10% of patients Adverse event All grade VEG VEG Pazopanib (n=225), % Pazopanib (n=290), % Placebo (n=145), % Grade 3 Grade 4 All grade Grade 3 Grade 4 All grade Grade 3 Grade 4 Haematological parameters Anaemia 26 < < <1 Lymphopenia < Neutropenia 27 < < Thrombocytopenia 26 < <1 <1 5 0 <1 Leukopenia Clinical chemistry measures ALT 53 9 < AST 54 6 < <1 0 Hyperglycaemia 41 < TBL increase 28 < < <1 Hypocalcaemia <1 Hyponatraemia Hypoglycaemia 17 0 < Hutson et al. J Clin Oncol 2010;28: Sternberg et al. J Clin Oncol 2009;27(15S):Abstract 5021 and oral presentation. 54

55 Elevated levels of aminotransferases and bilirubin were common with pazopanib treatment 1 Proportion of subjects, % Pazopanib (n=290) Placebo (n=145) All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 ALT increase AST increase 53 7 <1 19 <1 0 TBL increase 36 3 < <1 Alkaline phosphatase 27 1 < Over 50% of patients treated with pazopanib experience elevations in aminotransferase levels 1. US FDA. Available from: (Last accessed February 2010).

56 Alanine aminotransferase elevations occurred early during the course of pazopanib treatment Cumulative incidence ALT >5X ULN (N=586) Weeks Elevations in ALT levels were detected in the first 18 weeks of pazopanib treatment in the vast majority of subjects who developed such abnormalities 1. US FDA. Available from: (Last accessed February 2010).

57 Pazopanib Oral administration 800 mg a day, 1 x a day Not with food 200 mg and 400 mg tablets available Continuously until disease progression

58 DRUGS Pazopanib - interactions CYP 344 inhibitors (macrolides, azoles, verapamil, dilthiazem, ) Risk QT-prolongation prolongation (Chinolones, sulfamethoxazole-trimethoprim, trimethoprim, amiodarone, lumefantrine, chloroquine, sotalol, propafenon, disopyramide, methadon, quetiapine, pimozide, lopinavir, fluoxetine, ) CYP 3A4 Induction (Carbamazepine, fenyto (Carbamazepine, fenytoïne, ne, oxcarbamazepine, fenobarbital, rifampicine, ritonavir, nevirapine, efavirenz, primidone, midone, ) Delta ph (antacida, Hé-antihistaminica, H PPIs)

59 Pazopanib - interactions DRINKS and HERBS Juice grapefruit /pomelo s Saint John s s Wort Echinacea (Urgenin,, Echinacin )

60 Different treatment possibilities Sorafenib (Nexavar) Sunitinib (Sutent) Temsirolimus (Torisel) Pazopanib (Votrient) Everolimus (Afinitor) from 2nd line on Axitinib (Inlyta)

61 RAD 001 plus BSC vs. BSC in patients with metastatic RCC, that has h progressed on VEGFR-TKI therapy: results from a randomized, double blind, multicentre phase III study (1/3). Abstr Motzer et al. N=410 Stratification Prior VEGFr TKI: 1 or 2 MSKCC risk group: favorable, intermediate, or poor R A N D O M I Z A T I O N 2:1 Interim analysis Everolimus + BSC (n=272) Upon Disease Progression Placebo + BSC (n=138) Interim analysis = Final analysis 410 patients randomized between September 2006 and October 2007 Second interim analysis cut-off: October 15, 2007, based on 191 PFS events Independent Data Monitoring Committee receommended termination of study Everolimus (RAD001) : PO, 10 mg once daily continuously

62 RAD 001 plus BSC vs. BSC in patients with metastatic RCC, that has h progressed on VEGFR-TKI therapy: results from a randomized, double blind, multicentre phase III study (2/3). Abstr Motzer et al. Prior treatments Prior Treatmment Everolimus (n=272) % Placebo (n=138) % Nephrectomy Radiotherapy VEGFr-TKI therapy Sunitinib Sorafenib % Both Other systemic therapy Interferon Interleukin Chemotherapy Bevacizumab 9 10

63 RAD 001 plus BSC vs. BSC in patients with metastatic RCC, that has h progressed on VEGFR-TKI therapy: results from a randomized, double blind, multicentre phase III study (3/3). Abstr Motzer et al. PFS by treatment central radiology review Probability, % Hazard ratio = % CI [0.22, 0.40] Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo Log rank P value <0.001 Everolimus (n=272) Placebo (n=138) 0 Patients at risk Everolimus 272 Placebo Months

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66 Everolimus Oral administration 10 mg a day, 1 x a day 5 mg and 10 mg tablets available Continuously until disease progression

67 Everolimus - interactions DRUGS CYP 344 inhibitors (macrolides, azoles, verapamil, dilthiazem, ) CYP 3A4 Induction (Carbamazepine, fenyto (Carbamazepine, fenytoïne, ne, oxcarbamazepine, fenobarbital, rifampicine, ritonavir, nevirapine, efavirenz, primidone, midone, )

68 Everolimus- interactions DRINKS and HERBS Juice grapefruit /pomelo s Saint John s s Wort Echinacea (Urgenin,, Echinacin )

69 Different treatment possibilities Sorafenib (Nexavar) Sunitinib (Sutent) Temsirolimus (Torisel) Pazopanib (Votrient) Everolimus (Afinitor) Axitinib (Inlyta) 2nd line

70 AXIS: Study design and endpoints AXIS: International (175 sites in 22 countries), multicentre, randomised, controlled (active comparator), open-label, Phase III study 1,2 723 patients with mrcc Disease progression following one 1st-line therapy including: Sunitinib (54%) Cytokines (35%) Bevacizumab + IFN-α (8%) Temsirolimus (3%) Randomisation INLYTA 5 mg twice daily * n=361 Sorafenib 400 mg twice daily ** n=362 Chart adapted from references 1 and 2. IFN = Interferon. *Dose could be increased or decreased after initiation. ** Dose could be decreased after initiation. 1. Rini BI et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: INLYTA Summary of Product Characteristics, October CONTENTS PRESCRIBING INFORMATION

71 INLYTA : Greater efficacy in extending patient ITT PFS vs. sorafenib in 2nd-line mrcc therapy 1 AXIS primary endpoint: ITT PFS assessed by blinded independent central review 1,2 95% CI Proportion progression-free Sorafenib 4.7months INLYTA 6.8 months INLYTA mpfs = 6.8 months (ITT, n=361) Sorafenib mpfs = 4.7 months (ITT, n=362) HR=0.67 (95% CI: ); p< Time (months) Subjects at risk, n INLYTA Sorafenib Graph adapted from references 1 and 2. mpfs refers to the intention-to-treat (ITT) population. As determined by independent radiology review. CI, confidence interval; HR, hazard ratio. Cut-off date: 3 June INLYTA Summary of Product Characteristics, October Data on file. Pfizer. 3. Rini BI et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: CONTENTS PRESCRIBING INFORMATION

72 INLYTA : Significantly greater objective response rate (ORR) than sorafenib 1 The AXIS trial ORR, as assessed by blinded independent central review 1 AXIS secondary endpoint: ORR 1 25 p= Patients with objective response (%) % INLYTA (n=361) Over 100 % improvement in ORR 9.4% Sorafenib (n=362) Graph adapted from reference 1. ORR refers to the ITT population. ORR is derived from complete and partial responses as per Response Evaluation Criteria in Solid Tumors (RECIST), as determined by independent radiology review. Adapted from Pfizer Inc. INLYTA SmPC Cut-off date: 31 August INLYTA Summary of Product Characteristics, October Rini BI et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: CONTENTS PRESCRIBING INFORMATION

73 INLYTA (n=359) Sorafenib (n=355) Side effects All grades (%)Grades 3 (%) All grades (%)Grades 3 (%) Diarrhoea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysaesthesia* Weight decreased Vomiting Asthenia Constipation Hypothyroidism 19 <1 8 0 Cough Mucosal inflammation Arthralgia Stomatis <1 Rash 13 < Alopecia Graph adapted from reference 1. *Hand-foot syndrome = HFS. Highlighted boxes indicate the most common side effects occurring in both INLYTA and sorafenib 1. Rini BI et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: CONTENTS PRESCRIBING INFORMATION

74 INLYTA (n=359) Sorafenib (n=355) Side effects All grades (%)Grades 3 (%) All grades (%)Grades 3 (%) Diarrhoea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysaesthesia* Weight decreased Vomiting Asthenia Constipation Hypothyroidism 19 <1 8 0 Cough Mucosal inflammation Arthralgia Stomatis <1 Rash 13 < Alopecia Graph adapted from reference 1. *Hand-foot syndrome = HFS. Highlighted boxes indicate the most common side effects occurring in both INLYTA and sorafenib 1. Rini BI et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: CONTENTS PRESCRIBING INFORMATION

75 INLYTA 5 mg twice daily 5 mg and 1 mg film-coated tablets AVAILABLE CONTINUOUSLY UNTIL DISEASE PROGRESSION INLYTA should be taken orally twice daily, with or without food IN absence of hypertension : increase of dosage!! 1. INLYTA Summary of Product Characteristics, October CONTENTS PRESCRIBING INFORMATION

76 Axitinib- interactions DRUGS CYP 344 inhibitors (macrolides, azoles, verapamil, dilthiazem, ) CYP 3A4 Induction (Carbamazepine, fenyto (Carbamazepine, fenytoïne, ne, oxcarbamazepine, fenobarbital, rifampicine, ritonavir, nevirapine, efavirenz, primidone, midone, )

77 Axitinib - interactions DRINKS and HERBS Juice grapefruit /pomelo s Saint John s s Wort Echinacea (Urgenin,, Echinacin )

78 ESMO guidelines

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81 Toxicities Dose reductions often needed mtor Pneumonitis Hyperglycemia Hyperlipidemia TKI Stomatitis Hand foot syndrome Hypothyroidism Hypertension Diarrhea / Nausea / Taste Hypromellose 2 g Propyleenglycol 10 g Lidocaine HCl 400 ml Nilstat spec. 30 ml Natrena liquidum 5 ml aroma vanillae 1 ml aqua RO ad 500 ml