12 AISF Special Conference Sorafenib: magnitude of benefit, side effects and stopping rules 9 years after approval

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1 12 AISF Special Conference Sorafenib: magnitude of benefit, side effects and stopping rules 9 years after approval ARMANDO SANTORO Roma

2 SORAFENIB APPROVAL 29 OCTOBER 2007 Marketing authorization for NEXAVAR for the treatment of HCC (Italy: July 2008) 19 NOVEMBER 2007 NEXAVAR received FDA approval for the treatment of patients with unresectable HCC

3 SHARP TRIAL HCC : Advanced Disease

4 ASIA-PACIFIC TRIAL HCC : Advanced Disease

5 SORAFENIB 9 YEARS LATER BETTER USE OF SORAFENIB RESPONSE CRITERIA/ BIOMARKERS SIDE EFFECTS/ STOPPING RULES MAGNITUDE OF BENEFIT

6 BETTER USE OF SORAFENIB: SUBGROUP ANALYSIS

7 BETTER USE OF SORAFENIB: REAL LIFE STUDIES Study Design Setting Key outcomes GIDEON Single-arm safety study in unresectable HCC On label Safety profiles of sorafenib are broadly similar in Child-Pugh A and B HCC Median OS BCLC B: 15.6 months; BCLC C: 9.1 months Median TTP BCLC B: 6.3 months; BCLC C: 3.9 months GIDEON Italia Single-arm safety study in unresectable HCC Italian cohort of patients On label The safety profile of sorafenib is consistent to that observed in GIDEON global and in the pivotal registration studies. Median OS 14.4 months and TTP 6.2 months. Objective responses 5% with 3 complete responses (1%). Stable diseases of at least 6 weeks 41% with a 30% of disease control rate INSIGHT Single-arm multicenter observational study HCC (Germany, Austria) - Safety and efficacy of sorafenib in clinical practice On label Sorafenib is safe in routine daily practice Median OS BCLC B: 19.5; median OS BCLC C: 13.6 months SOFIA Single arm multicenter observational study in intermediate/adv HCC (Italy) - Efficacy and tolerability of sorafenib in clinical practice On label Median OS: 10.5 months Median OS BCLC B: 20.6; median OS BCLC C: 8.4 months STELLA Phase IV, prospective, noninterventional, multi-center study conducted in Italian centers On label OS at 12 months: 54%

8 BETTER USE OF SORAFENIB: REAL LIFE STUDIES

9 Better use of Sorafenib in Child-Pugh class A and B Pressiani T et al. Ann Oncol 2012

10 BETTER USE OF SORAFENIB : AGE Wong H et al. Oncologist 2011

11 SORAFENIB 9 YEARS LATER BETTER USE OF SORAFENIB RESPONSE CRITERIA/ BIOMARKERS SIDE EFFECTS/ STOPPING RULES MAGNITUDE OF BENEFIT

12 RESPONSE CRITERIA

13 BIOMARKERS FOR SORAFENIB Tissue biomarkers Nuclear perk overexpression associated with prolonged TTP in phase 2 1 Tissue perk staining was not associated with outcomes in phase 3 2 Circulating biomarkers High s-c-kit and low HGF at baseline showed a trend towards improved OS 3 Genomic Biomarkers FGF3/FGF4 amplification predicted response in small number of HCC patients 4 1. Abou-Alfa GK et al J Clin Onc 2006;24: Llovet JM et al N Engl J Med 2008;359: Llovet JM et al. Clin Cancer Res 2012; 18: Arao T et al, Hepatology 2013;57(4):

14 BIOMARKERS: Dermatological AE within 60 days (DAE60) OS and TTP according to DAE60 grade 2 (CTCAE) Prospective study, 147 BCLC B/C pts, C-P A 82%, median follow-up 11.6 mos, median treatment duration 6.7 mos DAE 60: 8.1 mo (IC 95%: ) No DAE 60: 3.9 mo (IC 95%: ) DAE 60: 18.2 mo (IC 95%: ) No DAE 60: 10.1 mo (IC 95%: ) Reig M et al. J Hepatol 2014

15 BIOMARKERS FOR SORAFENIB : AFP

16 REACH OS in pts with baseline AFP > or <400 ng/ml Zhu AX et al. GI ASCO 2015

17 BIOMARKERS IN HCC Ang2 and VEGF: independent predictors of survival None of the biomarkers significantly predicted response to sorafenib clinical or molecular biomarkers to identify who responds to sorafenib are virtually absent, whereas mounting evidence supports a possible role for AFP response

18 SORAFENIB 9 YEARS LATER BETTER USE OF SORAFENIB RESPONSE CRITERIA/ BIOMARKERS SIDE EFFECTS/ STOPPING RULES MAGNITUDE OF BENEFIT

19 SAFETY PROFILE FOR SORAFENIB Treatment-Emergent Adverse Events Reported for at least 10% of Patients in either Treatment Arm NEXAVAR (N=297) Placebo (N=302) P-value Adverse Event Any Grade 3 4 Any Grade 3 4 Any Grade Grade 3 or 4 Overall incidence, % Constitutional symptoms Fatigue, % < Weight loss, % < Dermatologic events Alopecia, % <0.001 NA Dry skin, % NA Hand foot skin reaction, % <1 0 <0.001 <0.001 Pruritus, % < Rash or desquamation, % Other, % < Llovet JM et al. N Engl J Med 2008

20 MANAGEMENT OF SIDE EFFECTS: GUIDELINES HEPATOLOGY, Vol. 53, No. 3, 2011 J Hepatol 2012; 56:

21 STOPPING RULES FOR SORAFENIB 2013 Abstract 2107 EFFICACY OF CONTINUED SORAFENIB TREATMENT AFTER RADIOLOGICAL CONFIRMATION OF DISEASE PROGRESSION IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA Wada Y, et al. Continued sorafenib treatment after radiological confirmation of disease progression improved survival in patients with advanced HCC, particularly those with an initial TTP of >4 months

22 STOPPING RULES: Phase II randomized dose escalation trial Rimassa L et al. Oncologist 2013

23 SORAFENIB 9 YEARS LATER BETTER USE OF SORAFENIB RESPONSE CRITERIA/ BIOMARKERS SIDE EFFECTS/ STOPPING RULES MAGNITUDE OF BENEFIT

24 MAGNITUDE OF BENEFIT: THE COMPETITORS Asia Pacific SHARP Endpoint HR (95% CI) p value HR (95% CI) p value OS TTP ( ) ( ) <0.001 ( ) ( ) <0.001 Cheng AL et al. Lancet Oncol 2009 Llovet JM et al. NEJM 2008

25 MAGNITUDE OF BENEFIT Tumor type Treatment (n) Primary End-Point Secondary HCC Sorafenib (n=299) Placebo (n=303) NSCLC Erlotinib (n=488) Placebo (n=243) Colon Chemo + bevacizumab (n=402) Chemo (n=411) Breast Chemo + trastuzumab (n=1672) Chemo (n=1679) OS TTP HR 0.68 ( ) HR 0.58 ( ) OS PFS HR 0.70 ( ) HR 0.61 ( ) OS PFS HR 0.66 HR 0.54 PFS OS HR 0.48 ( ) HR 0.67 ( )

26 MAGNITUDE OF BENEFIT: THE COMPETITORS ABOU-ALFA ET AL ASCO 2016 Cheng AL et al. JCO 2013 Johnson P et al. JCO 2013 Cainap C et al. JCO 2014 SORAFENIB Zhu AX et al. JCO VS 2014 SORAFENIB + ADI-PEG NEGATIVE RESULTS

27 MAGNITUDE OF BENEFIT: THE COMPETITORS Multicenter, randomized, phase III trials in patients with untreated advanced HCC Arms Principle Targets of Experimental Drug N of Patients Enrolled Median Overall Survival Data SUNITINIB VS SORAFENIB 1 VEGFR, PDGFR, others vs 10.2 months HR 1.30 ( ), p=0.001 BRIVANIB VS SORAFENIB (BRISK-FL) 2 >4.000 patients FGFR, VEGFR vs 9.9 months HR 1.07 ( ), p0.31 Sorafenib +/- erlotinib EGFR vs 8.5 months (SEARCH) 3 HR 0.93 ( ), p=0.41 LINIFANIB VS SORAFENIB 4 VEGFR, PDGFR, others No results vs 9.8 months HR 1.05 ( ) SORAFENIB +/ vs 10.5 months DOXORUBICIN 5 HR:1.06 (95%CI ) Total Cheng AL et al. JCO 2013; 2. Johnson PJ et al. JCO 2013; 3. Zhu AX et al. JCO 2014; 4. Cainap C et al. JCO 2014; 5. Abou-Alfa GK et al. GI ASCO 2016

28 HOPES FOR THE FUTURE? FIRST LINE LENVATINIB VS SORAFENIB CHECK-POINT INHIBITORS

29 IMMUNE-BASED APPROACHES IN HCC

30 NIVOLUMAB PHASE I/II CA209 (CHECKMATE)-040 STUDY El-Khoueiry et al. ASCO 2015,

31 NIVOLUMAB PHASE I/II (CHECKMATE)-040: Cohort 3 & 4

32 THE HOPE FOR NEW DRUGS TO COMBINE WITH SORAFENIB? SECOND LINE

33 THE HOPE FOR NEW DRUGS TO COMBINE WITH SORAFENIB? 2013 N=36 DCR (CR+PR+SD): 26 (72%) CR: 0; PR: 1 (3%); SD: 25 (69%) Median TTP 4.3 months Median OS 13.8 months

34 THE HOPE FOR NEW DRUGS TO COMBINE WITH SORAFENIB?

35 THE HOPE FOR NEW DRUGS TO COMBINE WITH SORAFENIB? Multicenter, randomized, phase III trials in patients with advanced HCC following first-line therapy with sorafenib Arms Principle Targets N of Patients Enrolled Median Overall Survival Data Brivanib vs placebo (BRISK-PS) 1 Everolimus vs placebo (EVOLVE-1) 2 Ramucirumab vs placebo (REACH) 3 VEGFR, FGFR vs 8.2 months HR 0.89 ( ), p=0.33 mtor vs 7.3 months HR 1.05 ( ), p=0.68 VEGFR vs 7.6 months HR 0.87 ( ), p= Llovet JM et al. JCO 2013; 2. Zhu AX et al. JAMA 2014; 3. Zhu AX et al. Lancet Oncol 2015

36 MAGNITUDE OF BENEFIT: NEW DRUGS TO COMBINE WITH S? SECOND LINE TIVANTINIB VS BSC CHECK-POINT INHIBITORS CABOZANTINIB VS BSC ENZALUTAMIDE

37 SORAFENIB IN EARLY STAGES: "THE DEFEAT

38 SORAFENIB IN EARLY STAGES: "THE DEFEAT Bruix J et al. Lancet Oncol 2015

39 SORAFENIB IN EARLY STAGES: "THE DEFEAT SPACE TRIAL: SORAFENIB +/- TACE OS

40 CONCLUSIONS SORAFENIB REMAINS THE ONLY DRUG WITH DEMONSTRATED EFFICACY IN FIRST LINE ADVANCED HCC REGORAFENIB WILL BE THE ONLY DRUG WITH DEMONSTRATED EFFICACY IN SECOND LINE ADVANCED HCC

41 PERSPECTIVES CONCLUSIONS BSC OS = 8 MOS SORAFENIB OS = 11 MOS S + REGORAFENIB OS = 14 MOS