HOW TO MANAGE A PATIENT ON SYSTEMIC CHEMOTHERAPY

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1 15th AISF PRE-MEETING COURSE Treatment of hepatocellular carcinoma Rome, February 20th HOW TO MANAGE A PATIENT ON SYSTEMIC CHEMOTHERAPY Dott. Massimo Iavarone 1 Division of Gastroenterology Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Università degli Studi di Milano Milano

2 Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione Speaking and teaching: Bayer Phase II and phase III trials: Bayer, Bristol Myers Squibb, Roche, Pfizer, Polaris Group, Lilly, Novartis, Daiichi Sankyo. e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

3 - Which patients to treat - How to predict survival - Pre-treatment - On-treatment - How to manage adverse events

4 Eligibility to treatment with sorafenib according to AIFA

5 Overall survival, time to progression and disease control by BCLC-stage BCLC B stage, 74 patients OS 20.6 months BCLC C stage, 222 patients, OS 8.4 months A.I.S.F.: Sorafenib is the recommended treatment for HCC patients with preserved liver function not amenable/responding to surgery and loco-regional treatments (1b-A). p< Bruix J et al J Hepatol 2012; Sofia Study Group Hepatology Bolondi L et al DLD 2013, in press

6 GIDEON second interim analysis: Patient characteristics and treatment-emergent safety data by Child-Pugh 1571 patients, 212 patients unclassified ECOG PS 0, % 1, % 2, % Child-Pugh A (n=957) Child-Pugh B (n=367) BCLC stage B, % C, % Dose interruption, % Dose reduction, % Drug-related AE, % SAE AE resulting in permanent discont Death, % Overall survival, months Time to progression, months Adapted from: Marrero J J Clin Oncol 2011 (abs 4001).

7 Impact of baseline Performance Status on sorafenib treatment in patients with advanced HCC and cirrhosis Patient Features Sharp Asia-Pacific Sofia Gideon (n=602) (n=226) (n=296) (n=1571) ECOG PS % 73% 44% 52% 2 Bruix J et al J Hepatol 2012; Llovet J et al NEJM 2008, Cheng AL et al Lancet Oncol 2009

8 Sarcopenia predicts dose-limiting toxicities of sorafenib in advanced HCC 40 Child-Pugh A patients, 11 (28%) sarcopenic 55% sarcopenic vs 17% non-sarcopenic started low dose sorafenib (p=0.004) Mir O et al PLoS ONE 2012 DLT. Dose-limiting toxicities

9 BASELINE STUDY OF THE PATIENT Vital signs Clinical laboratory tests: hematology coagulation dipstick routine chemistry including phosphorus, TSH, amylase/lipase, AFP. Imaging: contrast-enhanced CT/MRI (abdomen, chest); bone scan. WARNING: VEGFR TKIs are associated with an increased risk (RR % CI , p=0.023) of FAEs compared to controls (39/4679 patients) i.e. hemorrhage, myocardial infarction Shutz FAB et al J Clin Oncol 2012

10 Risk of bleeding in cirrhotic patients on sorafenib Most phase II and III studies with anti-angiogenic drugs in HCC lack EV pre-treatment. 59% of 108 cirrhotic patients on sorafenib (91% Child-Pugh A) had EV 8 (15% yearly) patients bled from EV after 64 (18-160) days of treatment Duffy A et al Hepatology 2012; Iavarone M et al AISF 2013

11 Cardiotoxicity in the Era of Target Therapy Sorafenib inhibits ~ 15 kinases off-target effect VEGFR: Angiogenesis is key to maintain cardiac homeostasis in response to pressure overload and ischemia RAF-1: role in remodeling in response to pressure overload During initial sorafenib exposure, arterial hypertension frequently occurs (5-18%) Baseline cardiac evaluation Daily monitoring arterial pressure (15-30 days) Therapy when appropriate with ACE-inhibitors (?) Sorafenib downdosing/interruption Zambelli A et al Breast 2012; Llovet J et al NEJM 2008; Cardinale D Circulation 2006; Khaled A ASCO GI 2013

12 - Which patients to treat - How to predict survival - Pre-treatment - On-treatment - How to manage adverse events

13 Baseline risk factors for overall mortality in HCC patients on sorafenib Predictor Univariate analysis Multivariate analysis HR (95% CI) P-value HR (95% CI) P-value ECOG Performance Status 1.8 ( ) < ( ) <.0001 Macroscopic vascular invasion 2.1 ( ) < ( ) Extrahepatic spread 1.7 ( ) ( ) 0.01 Sofia study group Hepatology 2011; Llovet J et al Clin Cancer Res 2012

14 Baseline biomarkers as predictive factors for sorafenib benefit (OS) p-value for biomarker treatment interaction = p-value for biomarker treatment interaction = Llovet J et al Clin Cancer Res 2012

15 VEGF genotyping to predict survival in HCC patients on sorafenib Polymorphisms: VEGFA rs and VEGFC rs Alleles PFS (mo) OS (mo) 0 favourable 3,4 8,8 1 favourable 5,6 15,1 2 favourable 11,4 22,7 p 0,0004 0,0001 Faloppi L et al ASCO GI 2013

16 - Which patients to treat - How to predict survival - Pre-treatment - On-treatment - How to manage adverse events

17 Overall survival in 85 patients by AFP response AFP response defined as 20% reduction at week 8 weeks in patients with baseline AFP>20 ng/ml 13.3 vs. 8.2 months, p=0.022 Personemi J et al Hepatol 2012

18 Overall survival in 41 patients treated with sorafenib, according to arterial hypertension development Estfan B et al Am J Clin Oncol 2012

19 Radiological response evaluation to predict survival in patients with HCC treated with sorafenib SOFIA study Lack of early radiological response (mrecist, month 2) = reduced survival Univariate analysis: HR 2.6 (95% CI ) p< Multivariate analysis: HR 1.6 (95% CI ) p<0.02 Overall survival in 53 patients treated with sorafenib according to RECIST and mrecist response (best response) OR=33.5 months SD=11.2 months (95%CI ) PD=4.2 months (95%CI ) p=0.002 OR=18.2 months (95%CI ) SD=9.7 months (95%CI ) PD=6.0 months (95%CI ) p=0.001 OR=17.1 months (95%CI ) SD=9.7 months (95%CI ) PD=3.7 months p=0.016 Sofia Study Group Hepatology 2011 Edeline J et al Cancer 2012

20 Symptomatic progression vs radiological progression in HCC patients on sorafenib SHARP allowed to keep patients on treatment beyond radiological progression, until clinical progression (PS and/or liver function deterioration). AIFA requests patient re-evaluation after 2 cycles stopping treatment if progression occurs BUT Early 1 st TTP (<5.9 months) vs. late 1 st TTP (>5.9) 11.7 vs 26.4 months, p= Survival Post 1 st Progression, N=96 Llovet J et al NEJM 2008; Reig M et al J Hepatol 2012 (S401)

21 - Which patients to treat - How to predict survival - Pre-treatment - On-treatment - How to manage adverse events

22 Early treatment/emergent adverse events recognition and management SOFIA study (field-practice) Liver function deterioration 15% (>2 points Child/Pugh score Monthly re-evaluation: clinical/blood test Discontinuation due to AEs Nutritional evaluation/support, stomatitis (6%) 45% Dose adjustment/discontinuation Dose reductions due to AEs Moisturizers, gel pad insert, cotton gloves, 54% clobetasol proprionate cream Dose interruptions due to AEs Dose adjustment/discontinuation 56% Symptomatic (loperamide ), probiotics Dose adjustment/discontinuation overall treatment duration 3.8 months overall mean sorafenib Don t daily forget dose 696 mg thyroid, hematological toxicities, increased amylase/lipase, proteinuria, surgical procedures and non-healing wounds, drug-drug interaction. Llovet J NEJM 2008; Mendez-Vidal MJ Cancer Metastasis Rev 2012; Iavarone Thyroids 2010; Sofia Study Hepatology 2011

23 Overall survival according to the prevalent dose of sorafenib in the SOFIA Study (post-hoc analysis) Full dose: patients who maintained full dosing or had a dose reduced for <70% of the treatment period 3 months (95% CI ) Half-dose: patients who received half-dose of sorafenib for 70% of the treatment period 6.8 months (95% CI ) Full dose, n=219 Half dose, n=77 Sorafenib 12-hour area under curve in patients with and without grade 3-4 toxicities 21.6 months (95% CI ) vs 9.6 months (95% CI ) Sofia study group Hepatology 2011; Boudou-Rouquette et al Oncologist 2012

24 TAKE HOME MESSAGES Full dose sorafenib is the SOC for patients with preserved liver function who are not amenable to or failed surgery and locoregional treatments. Careful pre-treatment patient evaluation mandatory. Careful patient monitoring of therapy efficacy and toxicity. Poor tolerance of full dose sorafenib can be managed by downdosing (400 mg/day) to prevent treatment withdrawal.