HCC: Epidemiology. Update on treatment of advanced hepatocellular carcinoma. Incidence of HCC is increasing

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1 Update on treatment of advanced hepatocellular carcinoma Jean-Luc Raoul Centre E Marquis Rennes, Brittany France HCC: Epidemiology Europe - USA: C virus, alcohol obesity, iron Europe: 4 deaths / year 6 - M cases / year Asia: 4 deaths / year Asia Africa: B virus, aflatoxin Bosch FX et al Gastroenterology 24 Incidence of HCC is increasing In most western countries : st cause of death among cirrhotic = HCC, New etiologies: HCV induced HCC will peak in 25 NASH: Obesity, diabetes, Immigration. But also in some high incidence countries

2 BCLC staging system: linking staging to treatment (BCLC) 5-year overall survival = 4 à 7% Median overall survival 6 à 6 months Survival < 3 months Treatment of advanced HCC Progress OLT, down-staging and advanced HCC Radiological techniques Intra-arterial Percutaneous 2 Systemic treatments Hormone therapies Chemotherapies Targeted treatments Liver Transplantation, down-staging and advanced HCC 2

3 Down staging prior to LT () Prospective study of patients with tumour stage >T2 (22 7) Eligibility for down staging LN: 5 8cm 2 3 LN: one >3cm, all <5cm, total <8cm 4 5 LN: none >3cm, total <8cm Transplantation if UCSF criteria met LN: <6.5cm 2 3 LN: none >4.5cm, total <8cm Follow-up period >3 months after down staging Down-staging treatments (n=6) TACE (n=5) RFA (n=) TACE + RFA/percutaneous ablation (n=29) resection (n=6) Yao FY et al, Hepatology 28 Down staging prior to LT (2) Down staging to within conventional criteria can be achieve in the majority of patients with an excellent outcome Yao FY et al, Hepatology 28 Radiological techniques 3

4 Treatment for advanced HCC: transarterial embolisation/chemoembolisation Patients with unresectable HCC Transarterial embolisation administered with/without chemotherapy (e.g. doxorubin, cisplatin) Only given to patients with well-preserved liver function (Child A) good Performance Status (PS ) no tumour-related symptoms no extrahepatic spread or vascular invasion Severe side effects common Llovet JM. J Gastroenterol 25;4: Meta-analysis: 2-year survival with TACE/embolisation versus supportive care for unresectable HCC Study Number of patients Odds ratio (95% CI) in random effects model Lin, et al GETCH Bruix, et al Pelletier, et al Lo, et al Llovet, et al 22 2 Overall 53 p= Heterogeneity p=.4 Favours treatment Favours control CI = confidence interval Modest survival benefit with TACE/embolisation (median OS: 6 to 2 mo) Not a standardized treatment Llovet JM, et al. Lancet 23;362:97 7 Chemoembolization Use of reproducible treatment : DC bead: controled drug delivery system, Promising results in phase II, Phase III: PRECISION V: TACE with doxo: Pts vs DC bead + doxo: Pts Primary objective: ORR at 6 mo Lammer J, et al CIRSE 28 4

5 PRECISION V TRIAL Conclusions: In overall, DC bead has: Greater objective response rate NS:. Lower SAE & AE DC bead has a significant advantage in: ORR in more advanced patients.38 DCR in more advanced patients.26 Reduction in doxo SAE. in all patients Lammer J, et al CIRSE 28 Chemoembolization + RFTA Chemoembolization, RFTA, combination: < 3 lesions, 3 7,5 cm, Child A, 29 Pts TACE 2 weeks rest then RFA New Standard? Cheng BQ et al. JAMA 28 RFA: +/- PEI RFTA: with percutaneous ethanol injection 33 patients CHC: solitary < 7 cm 2 ou 3 nodules: < 3 cm Randomisation: RFA (n = 67) PEI then ( min) RFA (n = 66) Stratification / size (< 3, 3 5, > 5 cm) Zhang YJ et al. Radiology 27 5

6 All < 3 cm P =.4 NS P =.3 NS 3 5 cm > 5 cm New Standard? 2 Systemic treatments Hormone therapies Hormone therapies anti-androgens tamoxifen somatostatin analogues No survival advantage over symptomatic treatment. Llovet JM, et al. Lancet 23;362:97 7 FFCD double blind trial: LA SMS vs placebo? Survival probabilities Number at risk Octreotide Placebo Kaplan-Meier survival estimates Time in months Barbare JC, submitted Octreotide Placebo 6

7 Systemic chemotherapies Phase II studies Single-agent therapies : doxorubicin, cisplatin, 5-FU, Pegylated liposomal doxorubicin and nolatrexed Combination regimens : PIAF 2 XELOX 3 and GEMOX 4 objective response rates < 2 25 % substantial toxicity reported (e.g. HBV re-activation) 5 Conclusion: «promising, manageable toxicity». Nowak AK, et al. Eur J Cancer Yeo W, et al. J Natl Cancer Inst Boige V, et al. Br J Cancer Louafi S, et al. Cancer Yeo W, et al. Ann Oncol 24 Systemic chemotherapy for advanced HCC Phase III studies: PIAF Variable Doxorubicin n=94 PIAF n=94 p value Overall response rate, % Grade 3 4 toxicities Treatment-related deaths, % 3 9 NS Median OS, months NS OS = overall survival Yeo W, et al. J Natl Cancer Inst 25 7

8 Systemic chemotherapy for advanced HCC Phase III studies: nolatrexed Variable Doxorubicin n=222 Nolatrexed n=222 p value Overall response rate, % 4..4 Grade 3 4 toxicities Median progression-free survival, weeks 2 NS Median OS, weeks Gish RG, et al. J Clin Oncol 27 Chemotherapy for unresectable HCC in non-cirrhotic liver Chemotherapy for HCC/cirrhotic liver is toxic and poorly effective Retrospective analysis of 24 patients (7 years) HCC with normal or fibrous (F, F2) liver treatments: ECC/ECF (n=2), FOLFOX (n=3), FOLFIRI (n=) toxicity sudden death grade 4 cardiac (n=), grade 3 neutropenia (n=5) efficacy 5 PR (ORR 22%) surgical resection in 2 (alive after 6 and 2 years) median OS 9 months (-/3-year survival 5/9%) Chemotherapy for HCC/non-cirrhotic liver poorly effective, but Edeline J, WJG 29 8

9 Systemic treatments Molecular pathogenesis of HCC Multiple mechanisms implicated in hepatocarcinogenesis Liver cirrhosis following tissue damage Mutations occurring in oncogene or tumor suppressor gene Cellular signaling pathways that are often dysregulated in HCC include 2 : Angiogenic signaling EGF/EGFR PI3K/Akt/mTOR Ras/Raf/MEK/ERK Key targets for molecular therapy Wnt/β-catenin P3K = phosphoinositide 3-kinase; Akt = protein kinase B; mtor = mammalian target of rapamycin; Raf = serine-threonine protein kinase (c-raf); Ras = small GTPase; MEK = mitogen-activated protein kinase; ERK = extracellular signalregulated kinase; Wnt = secreted signaling protein. Thorgeirsson S, et al. Hepatology 26; 2. Avila MA, et al. Oncogene 26. Major pathways dysregulated in HCC Villanueva A Semin Liver Dis 27 9

10 Systemic treatments Targeted therapies Multiples agents (Ph II):Single agent or in combination; : positive phase III trials Bevacizumab: mab anti VEGF Responses but side effects Erlotinib: EGFR TKI stabilizations Sunitinib: multi TKI Responses But toxicities? Brivanib: multi TKI Biological responses Good Tolerance All are entering in Phase III RCT Bevacizumab Phase II study, n = 46 ORR: 3 % PFS 6 mo = 65% Reduction in tumor enhancement Decrease in VEGF level Toxicity: SAE Hypertension (5 %), thrombosis (6%, arterial = 4%) GI bleedings ( %) Siegel AB, et al J Clin Oncol 28 Sunitinib MTKI, targets: VEGFR, PDGFR, c-kit, RET, FLT3 Sunitinib: oral HCC patients; SU 5mg/d, 4/2 schedule 37 pts, PS (5%), Child-P A (84%) Toxicities Gr 3 4: Plat 43%, PMN 24%, CNS 24%, asthenia 22%, Hemorrhage 4% 4 deaths: ascites, edema, bleeding, drowsyness, encephalopathy Efficacy: PR (3%) and 39% SD Recap: dose or schedule modification improving Pt selection Faivre SJ, et al ASCO 27 # 3546

11 Sunitinib SU: 37.5 mg/d 4/2 schedule DCE MRI to assess changes in tumor permeability 9 Pts, ECOG /: 7/2 Toxicity: PMN 2%, Lym: 6%, plat: % transa 6%, fatigue %, rash: %, Efficacy: PR, 8 SD Tumor permeability: 52% decrease Changes in angiogenic markers Zhu AX et al ASCO 27 # 4637 Brivanib Targets FGFR and VEGFR Phase II: 55 Pts ORR = 6 %, DCR = 47 % Decrease in AFP: 49 % Toxicity: fatigue, hypertension, diarrhea Park JW, ILCA mm 92 mm June, 4th, 27 AFP = Nl Initiation of Brivanib Tt

12 Nov th, 28 7 months of Brivanib 63 mm 23 mm 92 mm 65 mm Baseline June, 4th, 27 targets tumor cell proliferation and angiogenesis Tumor cell Endothelial cell or pericyte (vascular) RAS HGF Apoptosis Autocrine loop Paracrine stimulation PDGFR-β PDGF-β RAS VEGF VEGFR-2 RAF Mcl- Mitochondria MEK ERK HIF HGF PDGF VEGF Nucleus Proliferation Survival RAF Mitochondria MEK Apoptosis ERK Nucleus Angiogenesis: Differentiation Proliferation Migration Tubule formation Avila MA, et al. Oncogene 26; Liu L, et al. Cancer Res 26; Semela D, et al. J Hepatol 24; Wilhelm SM, et al. Cancer Res 24. Phase II trial of sorafenib in HCC: study design Eligibility Advanced HCC ECOG PS Child-Pugh Class A or B No prior systemic therapy N=37 4 mg bid Primary end points Tumor response (modified WHO) Safety (NCI-CTC v2.) ECOG PS = Eastern Cooperative Oncology Group Performance Status; NCI-CTC = National Cancer Institute-Common Toxicity Criteria; WHO = World Health Organization. Abou-Alfa GK, et al. J Clin Oncol 26 2

13 Phase II trial: one-third of patients with advanced HCC achieved stable disease Best response (independent assessment) n (%) [total N=37] PR 3 (2.2) MR 8 (5.8) SD ( 6 weeks) 46 (33.6) PD (by radiologic assessment) 48 (35.) Not available for independent review 32 (23.4) Median TTP, mo. Median OS, mo PR = partial response; MR = minor response; SD = stable disease; PD = progressive disease; TTP = time to tumor progression; OS = overall survival. Abou-Alfa GK, et al. J Clin Oncol 26 Phase II trial: conclusions has antitumor activity PR/MR: 8% of patients SD for 6 weeks in 34% of patients Tumor necrosis, increasing with time; Median TTP: 5.5 months (independent assessment) Median OS: 9.2 months is generally well tolerated Common AEs: diarrhea, HFSR and fatigue Safety profiles for Child-Pugh Class A and B patients were similar Abou-Alfa GK, et al. J Clin Oncol 26 Phase III SHARP Design Eligibility criteria Advanced HCC Child Pugh A status ECOG PS 2 Life expectancy 2 weeks Randomization 4mg b.i.d. n=299 Placebo n=33 Primary endpoints OS TTSP Double-blind, versus placebo; ratio : Secondary endpoints TTP tolerance Llovet J, N Engl J Med 28 3

14 Phase III SHARP Trial: Baseline Characteristics of Patients Placebo Characteristics (n=299) (n=33) Age (median, years) Male/Female (%) Region (Europe/N America/others) (%) Etiology (%) Viral Hepatitis (HCV/HBV) Alcohol/other Child Pugh (A/B; %) Prior therapies (%) Surgical resection Loco-regional therapies 65 87/3 88/9/3 29/9 26/26 95/ /3 87//3 27/8 26/29 98/2 2 4 Llovet J, N Engl J Med 28 Phase III SHARP Trial: Baseline Characteristics of Patients Placebo Characteristics (n=299) (n=33) BCLC stage 2 (%) Stage B (intermediate stage) Stage C (advanced stage) ECOG PS (%) 2 Macroscopic vascular invasion (portal vein) and/or extrahepatic spread (%) Present Absent Llovet J, N Engl J Med 28 Results 4

15 Survival probability Patients at risk : Placebo: Phase III SHARP Trial: OS (Intention-to-treat) Hazard ratio (S/P):.69 (95% CI:.55.88) p=.58* Median: 46.3 weeks (.7 months) (95% CI: ) Placebo Median: 34.4 weeks (7.9 months) (95% CI: ) 44 % 33 % Weeks Llovet J, N Engl J Med 28 Progression-free probability Phase III SHARP Trial: TTP (Independent Central Review) Median: 24. weeks (5.5 months) (95% CI: 8. 3.) Placebo Median: 2.3 weeks (2.8 months) (95% CI:.7 7.).25 Hazard ratio (S/P):.58 (95% CI:.44.74) p= Patients at risk Time (Weeks) : Placebo: Llovet J, N Engl J Med 28 Phase III SHARP Trial: Response Assessment (RECIST; Independent Review) and TTSP (FSHI8-TSP) Overall response CR PR SD PD Progression-free rate at 4 months Duration of treatment (median, weeks) (n=299) 7 (2.3%) 2 (7%) 54 (8%) 62% 23 Placebo (n=33) 2 (.7%) 24 (67%) 73 (24%) 42% 9 FSHI8-TSP: no significant differences between treatment groups (p=.77) RECIST = Response Evaluation Criteria In Solid Tumors Llovet J, N Engl J Med 28 5

16 Phase III SHARP Trial: Safety Events Treatment-emergent serious adverse events (SAE, %) Drug-related treatment-emergent SAE (%) Drug-related adverse events (%) Diarrhea Pain (abdomen) Weight loss Anorexia Nausea HFSR Vomiting Alopecia Liver dysfunction Bleeding All < 7 (n=297) 52 3 Grade 3 4 8/ 2/ 2/ </ </ 8/ / / </ </ All 3 < Placebo (n=32) 54 9 Grade 3 4 2/ </ / </ / </ </ / / </< Llovet J, N Engl J Med 28 Phase III SHARP Trial: Conclusions prolonged overall survival versus placebo in advanced HCC Median OS.7 mo versus 7.9 mo Hazard ratio:.69, p=.58 44% increase in OS prolonged TTP versus placebo Median TTP 5.5 mo vs 2.8 mo Hazard ratio:.58, p=.7 73% prolongation in TTP was well tolerated with manageable side effects Llovet J, N Engl J Med 28 SHARP Study Design Schema for Subanalyses MVI/EHS Present MVI/EHS Absent n=29 n=9 Eligibility Advanced HCC ECOG PS -2 Child-Pugh class A No prior systemic therapy Stratification MVI (portal vein) and/or EHS ECOG PS ( vs -2) Geographic region R A N D O M I Z E : Primary end points: OS, TTSP (FHSI-8) Secondary end points: TTP (independent assessment) * 4 mg bid n=299 Placebo* n=33 *Repeated 6-week cycles until both radiologic progression AND symptomatic progression criteria were met, or unacceptable toxicity or death. n=22 n=9 ECOG PS ECOG PS - 2 n=6 n=38 n=64 n=39 Raoul JL, ILC 28 6

17 Overall Survival by MVI and/or EHS MVI/EHS Present MVI/EHS Absent. (n=29) Median: 8.9 mo 95% CI: (n=9) Median: 4.5 mo 95% CI: 4.-N/E Survival Probability Placebo (n=22) Median: 6.7 mo 95% CI: Survival Probability Placebo (n=9) Median:.2 mo 95% CI: HR (95% CI):.77 (.6-.99) Months HR (95% CI):.52 ( ) Months TTP by MVI and/or EHS (Independent Assessment) MVI/EHS Present MVI/EHS Absent. (n=29) Median: 4. mo 95% CI: (n=9) Median: 9.6 mo 95% CI: 6.9-N/E Progression-Free Probability Placebo (n=22) Median: 2.7 mo 95% CI: Progression-Free Probability Placebo (n=9) Median: 4.3 mo 95% CI: HR (95% CI):.64 ( ) Months HR (95% CI):.4 (.23-.7) Months Overall Survival by ECOG PS ECOG PS ECOG PS -2. (n=6) Median: 3.3 mo 95% CI: 9.9-N/E. (n=38) Median: 8.9 mo 95% CI: Survival Probability Placebo (n=64) Median: 8.8 mo 95% CI: Survival Probability Placebo (n=39) Median: 5.6 mo 95% CI: HR (95% CI):.68 (.5-.95) Months HR (95% CI):.7 ( ) Months 7

18 TTP and TTSP by ECOG PS Favors Favors Placebo TTP ECOG PS ECOG PS -2 TTSP ECOG PS ECOG PS Hazard Ratio Conclusions is the first systemic treatment to demonstrate efficacy in patients with advanced HCC is the only systemic therapy approved by the FDA and EMEA for the treatment of patients with HCC prolonged survival in HCC patients, regardless of their MVI/EHS or ECOG PS status, thereby confirming the effectiveness of sorafenib in a broad range of patients was well tolerated, regardless of ECOG PS status or MVI/EHS presence at baseline in HCC patients from the Asia Pacific Region 8

19 Asia-Pacific study: Design Eligibility Advanced HCC ECOG PS 2 Child-Pugh Class A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS ( vs 2) Geographic region R A N D O M I Z E 2: n=5 n=76 4 mg bid Placebo End points: Overall survival, time to symptomatic progression (FSHI8-TSP), time to progression, response (RECIST), and safety No primary end point defined Cheng A, et al. J Clin Oncol 28;26: abstract 459. Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. Asia-Pacific study: Baseline patient characteristics Median age (range), y Male, % ECOG PS, % 2 Macroscopic vascular invasion, % No Yes Extrahepatic spread, % No Yes BCLC Stage C, % (n=5) 5 (23 86) Placebo (n=76) 52 (25 79) Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. Asia-Pacific study: Baseline patient characteristics No. of tumor sites, % Sites of disease, % Lung Lymph node Hepatitis virus status, % HBV HCV Child-Pugh Class A, % Liver cirrhosis (clinical), % AFP > ULN (laboratory), % (n=5) Placebo (n=76) Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 9

20 Survival probability Patients at risk Placebo Asia-Pacific study: Overall survival.25 HR S/P:.68 95% CI:.5,.93 p= Months (n=5) Median OS: 6.5 mo. 95% CI: 5.6, 7.6 Placebo (n=76) Median OS: 4.2 mo. 95% CI: 3.7, 5.5 Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL Survival probability Asia-Pacific study: Time to progression HR S/P:.57 95% CI:.42,.79 P<. (n=5) Median TTP: 2.8 mo. 95% CI: 2.6, 3.6 Placebo (n=76) Median TTP:.4 mo. 95% CI:.3,.5 Patients at risk 5 Placebo Months Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. Asia-Pacific study: Response by RECIST ORR (CR+PR), % CR PR SD, % PD, % DCR*, % (n=5) Placebo (n=76) *Independent review by Response Evaluation Criteria in Solid Tumors (RECIST). DCR = complete response (CR) + partial response (PR) maintained for 4 weeks + stable disease (SD) documented at least 2 weeks from baseline. Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 2

21 Asia-Pacific study: Adverse events occurring in % of patients Treatment-related SAEs, % Drug-related SAEs, % Drug-related AEs*, % Hand-foot skin reaction Diarrhea Alopecia Fatigue Rash/desquamation Hypertension Anorexia Nausea (n=49) 48 9 Any / Grade Placebo (n=75) 45 Any / 4 Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. Asia-Pacific study: Subset analyses Favors sorafenib Favors placebo Age 65 Yes (n=32) No (n=94) Macroscopic vascular invasion (MVI) Yes (n=8) No (n=46) Extrahepatic spread (EHS) Yes (n=55) No (n=7) MVI and/or EHS Yes (n=79) No (n=47) ECOG PS (n=59) /2 (n=67) Hazard ratio for OS Cheng A, et al. J Clin Oncol 28;26: abstract 459; Adapted from poster presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. Conclusions significantly prolonged OS over placebo in advanced HCC Median OS: 6.5 vs 4.2 months Hazard ratio:.68, P=.4 47% increase in OS prolonged TTP over placebo Median TTP: 2.8 vs.4 months Hazard ratio:.57, P<. 74% prolongation in TTP was well tolerated and had manageable side effects is effective in patients with HCC from the Asia-Pacific region 2

22 in combination with doxorubicin in HCC Phase II trial of doxorubicin ± sorafenib in HCC: study design Period Period 2* Eligibility Advanced HCC ECOG PS -2 Child-Pugh Class A No prior systemic therapy No prior chemoembolization No history of organ allograft R A N D O M I Z E n = 47 n = 49 : Primary objective TTP (independent assessment) Secondary objectives ORR, PFS, OS, safety Doxorubicin 6 mg/m 2 + sorafenib 4 mg bid q3w Doxorubicin 6 mg/m 2 + placebo q3w 4 mg bid Placebo * or placebo continued until withdrawal, PD, or death in period 2. q3w = once every three weeks; TTP = time to progression; ORR = overall response rate; PFS = progression-free survival; OS = overall survival Abou-Alfa GK, et al. Eur J Cancer Suppl. 27;5(4):259; updated from abstract 28. Poster and oral presentation at ASCO-GI; Orlando, FL; January 28. Phase II trial of doxorubicin ± sorafenib in HCC: TTP (independent assessment). Doxorubicin + sorafenib Median: 8.6 months (95% CI: 4.8, 2.6) Progression-free probability HR D+S/D+P =.6 p =.76 Doxorubicin + placebo Median: 4.8 months (95% CI: 2.2, 8.) Censored treatment Months Abou-Alfa GK, et al. Eur J Cancer Suppl. 27;5(4):259; updated from abstract 28. Poster and oral presentation at ASCO-GI; Orlando, FL; January

23 Phase II trial of doxorubicin ± sorafenib in HCC: OS Survival probability HR D+S/D+P =.45 p =.5 Doxorubicin + sorafenib Median: 3.7 months (95% Cl:.4 NA) Doxorubicin + placebo Median: 6.5 months (95% Cl: ) Months from randomisation Definitive analysis (data from March 27 cut-off, 5 events). NA = value can not be estimated due to censored data. Abou-Alfa GK, et al. Eur J Cancer Suppl. 27;5(4):259; updated from abstract 28. Poster and oral presentation at ASCO-GI; Orlando, FL; January 28. Phase II trial of doxorubicin ± sorafenib in HCC: AEs with % grade 3/4 incidence Fatigue Neutropenia Diarrhea Elevated bilirubin Abdominal pain HFSR Left ventricular dysfunction Hypertension Febrile neutropenia Doxorubicin + sorafenib (n = 47) Any grade Grades 3/ Doxorubicin + placebo (n = 49) Any grade Grades 3/ Abou-Alfa GK, et al. Eur J Cancer Suppl. 27;5(4):259; updated from abstract 28. Poster and oral presentation at ASCO-GI; Orlando, FL; January 28. Phase II trial of doxorubicin ± sorafenib in HCC: conclusion has shown promising efficacy and tolerability when combined with doxorubicin in the phase II setting in patients with advanced HCC Abou-Alfa GK, et al. Eur J Cancer Suppl. 27;5(4):259; updated from abstract 28. Poster and oral presentation at ASCO-GI; Orlando, FL; January

24 In conclusion is the new standard of care in a palliative setting Improving OS by % And TTP by % Without worsening QoL Well tolerated Combinations are promising. Future of targeted therapies, in advanced HCC Head to head comparisons in st line / sorafenib Sunitinib, Brivanib, Bevacizumab + Erlotinib Phase III: sorafenib vs sorafenib + erlotinib Second line treatments (brivanib, retinoids, ) Phase II trials of combinations: Chemotherapy? M-TOR inhibitors,? Future of targeted therapies, in HCC: Combination with TACE Simultaneously «adjuvant» after Response Adjuvant to surgery / RFA Waiting period / OLT 24

25 BCLC staging and treatment strategy HCC Very early stage () Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D) Single HCC Portal pressure/ bilirubin Increased Normal 3 nodules 3cm Associated diseases No Yes Extrahepatic disease No Yes Resection Liver transplantation PEI/RFA Chemoembolisation New agents Curative treatments? Randomised controlled trials Symptomatic +? treatment PEI = percutaneous ethanol injection RFA = radiofrequency ablation Llovet JM, et al. Lancet 23;362:97 7 Does sorafenib really work? Does sorafenib work? : PALLIATIVE TREATMENT Goal: to improve Overall survival Time to progression, Without impairing QoL Objective response rate = 2 3 % Then, goal of surveillance: To ensure that tumor is not progressing To find some signs of efficacy: 25

26 92 mm Aug 8th, 27 4th months of Brivanib June, 4th, 27 AFP = Nl Initiation of Brivanib Tt 8 mm EASL criteria in use in HCC particularly with biodrugs WHO RECIST EASL PR PR NC PR 26

27 EASL criteria in use in HCC particularly with biodrugs WHO EASL: RECIST VIABLE PR PR NC PR How to manage toxicities? Toxicities: not very severe, but => QoL We need: preventive measures patient s education in order: to avoid or limit toxicity to give full dose => full benefit How to manage toxicities? Diarrhea: avoid spicy food, milk, loperamide, then codeïne, eventually: 4 mg / d until resolution Asthenia, anorexia: alimentary support, check for anemia, hypo phosphosphatemia, 27

28 How to manage toxicities? Hand Foot Syndrome: Prevention Roomy shoes, moisturizing cream, Avoid hot temperatures Specific soles, Soft podiatry How to manage toxicities? Treat as soon as possible: Urea containing creams, corticoid creams Decrease dose => 4 mg/d to reevaluate on a weekly basis Back to 8 mg/d when major improvement (Gr -) If not: stop sorafenib for > 2 weeks When resolved: 4 mg every day or Every 2 days if it recurred. /// 28

29 Guidelines : hand foot skin reaction Occurrence Grade Grade 2 Grade 3 Institute supportive st measures immediately occurrence & continue sorafenib treatment Institute supportive measures & consider a decrease in sorafenib dose to 4 mg daily for 28 days If toxicity returns to If toxicity does not grade after dose OR return to grade reduction despite dose reduction Institute supportive measures & interrupt sorafenib treatment for a minimum of 7 days & until toxicity has resolved to grade All occurrences Increase sorafenib to full dose after 28 days Interrupt sorafenib treatment for a minimum of 7 days, until toxicity has resolved to grade When resuming treatment after dose interruption, resume sorafenib at reduced dose of 4 mg daily for 28 days If toxicity is maintained at grade at reduced dose When resuming treatment after dose interruption, resume sorafenib at reduced dose of 4 mg daily for 28 days If toxicity is maintained at grade at reduced dose Increase sorafenib to full dose after 28 days Increase sorafenib to full dose after 28 days 2 nd occurrence 3 rd occurrence 4 th occurrence As for st occurrence but, upon resuming sorafenib treatment, decrease dose to 4 mg daily indefinitely As for 2 nd occurrence Decision whether to discontinue sorafenib treatment should be made based on clinical judgement and patient preference As for st occurrence but decrease sorafenib dose to 4 mg daily indefinitely Decision whether to discontinue sorafenib treatment should be made based on clinical judgement and patient preference 29