Sorafenib in HCC. Discussion points

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1 Discussion points in Andrew X. Zhu, MD, PhD 214 CASL Meeting-Consensus, Controversies and Future Directions in -data from phase III trials ptimal Dosing Side effects and management strategies use in Child-Pugh B Liver Cancer Incidence: Sixth Most Common Cancer Worldwide 1 Targets Tumor Cell Proliferation and Angiogenesis Lung 1,549,121 Breast 1,31,867 Colon/Rectal 1,167,2 Stomach 1,66,543 Prostate 782,647 Liver 711,128 Cervix Uteri 559,94 Esophagus 529,283 Leukemia 33,963 Bladder 314,256 vary 23,555 Corpus Uteri 226,787 ral Cavity 2,774 on-hodgkin's Lymphoma 196,298 2, 4, 6, 8, 1,, 1,2, 1,4, 1,6, 1,8, is the most common primary liver malignancy in adults 2 RAF MEK ERK RAS Tumor Cell HGF Mcl-1 ucleus HIF Apoptosis HGF PDGF VEGF Proliferation Survival Autocrine loop Mitochondria Endothelial Cell or Pericyte Paracrine stimulation PDGFR-b Mitochondria Apoptosis PDGF-b RAF MEK ERK ucleus RAS VEGF VEGFR-2 Angiogenesis: Differentiation Proliferation Migration Tubule formation 1. Garcia M, et al. American Cancer Society, Accessed March 2, Perz JF, et al. J Hepatol. 26;45: HGF = hepatocyte growth factor. Avila MA, et al. ncogene. 26;25: ; Liu L, et al. Cancer Res. 26;66: ; Semela D, et al. J Hepatol. 24;41:864-88; Wilhelm SM, et al. Cancer Res. 24;64: Cl CF 3 : Inhibits Serine/Threonine and Tyrosine Kinases H Serine/threonine Kinases Kinase IC 5 (nm) Raf-1 6 B-Raf 25 B-raf V6E 38 p38 38 Mnk-2 15 ERK-1, MEK- 1, PKA, PKB, PKC, cdk1/cyclinb, pim-1 H >1, Wilhelm S et al. Cancer Res. 24;64:799 19; Riedl B et al. Poster presented at AACR March 21, ew rleans, LA *Determined on mouse enzyme # Carlomagno, F. et al. J atl. Cancer Inst. 26; 98 p H CH 3 Receptor Tyrosine Kinases Kinase IC 5 (nm) VEGFR-1 26 VEGFR-2 9 VEGFR-3* 2 FLT3 33 RET # 47 PDGFR-b * 57 C-KIT 68 FGFR-1 58 c-met, IGFR-1, EGFR, HER2, LCK >1, Phase III trial of in (SHARP): study design Eligibility Advanced ECG PS 2 Child Pugh A o prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECG PS ( vs 1 2) Geographic region R A D M I S E 1:1 n=299 n=33 Primary end points: S, TTSP (assessed by FHSI-8) Secondary end points: TTP (independent assessment) sorafenib 4mg b.i.d. SHARP = Assessment Randomized Protocol ECG PS = Eastern Cooperative ncology Group Performance Status S = overall survival; TTSP = time to symptomatic progression; TTP = time to progression FHSI-8 = Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index-8 Llovet JM, et al. Engl J Med 28;359:

2 Median verall Survival, Months SHARP Phase III Trial Randomized Phase III Trial of vs in Asian With Advanced : Study Design Eligibility Advanced ECG PS -2 Child Pugh A o prior systemic therapy Stratification MVI (portal vein) and/or EHS ECG PS ( vs 1-2) Geographic region R A D M I Z E 2:1 n=15 n=76 4mg bid End points S, TTSP (FSHI8-TSP), TTP, response (RECIST), and safety o primary end point defined Cheng A, et al. J Clin ncol. 28;26. Abstract 459. Updated from oral presentation at ASC; Chicago, IL; June 28. Asia-Pacific Phase III Trial SHARP vs Asia-Pacific Study: Efficacy Endpoint S SHARP 1 Asia-Pacific 2 vs Hazard Ratio (95% CI) P Value 1.7 vs 7.9 mo.69 ( ) <.1 vs Hazard Ratio (95% CI) P Value 6.5 vs 4.2 mo.68 (.5-.93).14 TTSP 1.8 ( ) ( ).5 TTP 5.5 vs 2.8 mo.58 ( ) < vs 1.4 mo.57 ( ) <.1 RR 2% vs 1% 3.3% vs 1.3% 1. Llovet JM, et al. Engl J Med. 28;359(4): Cheng AL, et al. Lancet ncol. 29;1(1): SHARP: Exploratory Subgroup Survival Analysis Prolongs Survival in Advanced Regardless of Patient Characteristics or Extent of Disease ECG PS ECG PS 1 & 2 o extrahepatic spread Extrahepatic spread o macroscopic vascular invasion Macroscopic vascular invasion o macroscopic VI and/or extrahepatic spread Macroscopic VI and/or extrahepatic spread. Favors Favors HR (95% CI) for Survival Llovet JM, et al. Engl J Med. 28;359: Exploratory Subgroup Analyses HR =.69 (95% CI: 2 HR =.79 HR =.75 HR =.58 HR =.76 HR =.68 HR =.71 HR =.77 HR = ) P<.1 verall Prior Prior HCV 3 Alcoholic ECG ECG MVI o MVI Population 1 Curative TACE 2 n = 178 Cirrhosis 4 PS 5 PS and/or and/or n = 62 Therapy 2 n = 176 n = 159 n = 325 n = 277 EHS 6 EHS 6 n = 158 n = 421 n = Llovet JM, et al. Engl J Med. 28;359(4): Galle PR, et al. EASL Bolondi L, et al. J Clin ncol. 28;25(suppl): Abstract Craxi A, et al. J Clin ncol. 28;25(suppl): Abstract Raoul J, et al. J Clin ncol. 28;25(suppl): Abstract Sherman M, et al. J Clin ncol. 28;25(suppl): Abstract

3 SHARP: Drug-Related Adverse Events (%) (n = 299) (n = 32) Treatment-related SAEs Drug-related SAEs 13 9 Grade 8, 7, 6, 5, Alpha-Fetoprotein Trend on 78,5 Drug-Related AEs Any 3/4 Any 3/4 Diarrhea 39 8/ 11 2/ Hand-foot skin reaction 21 8/ 3 <1/ Anorexia 14 <1/ 3 <1/ Alopecia 14 / 2 / ausea 11 <1/ 8 1/ Weight loss 9 2/ <1 / Pain (abdomen) 8 2/ 3 <1/ Bleeding 7 <1/ 4 <1/<1 Vomiting 5 1/ 3 <1/ Liver dysfunction <1 <1/ / 4, 3, 2, 1, 4, 2,581 2,727 11,3 6,8 1,152 3,356 14, Llovet JM, et al. Engl J Med. 28;359(4): Dosing Standard dose schedule: 4 mg bid Lack of prospective randomized trials to assess lower dose in comparison with standard dose Dose escalation scheme can be considered and often used in practice in patients with borderline PS and compromised hepatic function: start at 4 mg daily and increase as tolerated Hand-Foot Skin Reaction Hand-foot skin reaction is a group of symptoms affecting the hands and/or feet 1,2 Varying degrees of severity that tend to decrease during the course of therapy Side effects of anti-angiogenic therapies usually occur during the first few weeks of treatment 3 may require 2,3 : Topical treatments Temporary suspension of treatment or dose reduction until the episode resolves Permanent dose reduction (in severe or persistent cases) Grade 1 Incidence: 8%* *Incidence reported from the SHARP trial.[4] Grade 2 Incidence: 6%* Grade 3 Incidence: 8%* 1. Moldawer, Figlin R. ncol urs Forum.28;4:699-78; 2. Wood LS. Commun ncol. 26;3:558-62; 3. Alexandrescu DT, et al. Clin Exp Dermatol. 27;32:71-4; Photos courtesy of Elizabeth Manchen, R, MS, C. Management of Hand-Foot Skin Reaction Early intervention may prevent progression of symptoms and avoid treatment interruption or dose reduction 1 are advised to 1,2,3 : Wear comfortable soft-soled footwear (eg, gel insoles) Apply hydrating cream, preferably containing urea Bathe regularly in lukewarm water containing Epsom salts (magnesium sulphate) If possible, patients should consult a podiatrist before starting treatment 1. Wood LS. Commun ncol. 26;3:558-62; 2. Anderson R, et al. ncologist. 29; ; 3. Robert C, et al. Lancet ncol. 25;6: Fatigue ot always attributable to drug therapy Usually managed by educating the patient Advise patients to: Stay as active as possible because that will help them sleep better Maintain normal work and social schedules Take breaks as needed Tell their doctor or nurse if they cannot tolerate activity or if their fatigue worsens Wood LS. Commun ncol. 26;3:

4 Geometric mean plasma concentration (mg/l) AUC -12 /Dose (mg x h/l/mg) C max/dose (mg/l/mg) ptimizing the Management of AEs With Phase I Study of in Japanese With : Pharmacokinetics in patients with Child Pugh A and B Most AEs related to sorafenib are predictable and manageable Preventive measures can be taken to avoid dose reductions or treatment interruptions Treatment rarely needs to be permanently discontinued Good communication is vital among patients, clinicians, and nurses Advanced Solid Tumor (CP A) (CP B) Advanced Solid Tumor (CP A) (CP B) Furuse J, et al. Cancer Sci. 28;99: Phase II trial in Child Pugh A and B patients: plasma concentrations of in Child Pugh B 1 8 Child Pugh A Child Pugh B Time (hours) Abou-Alfa GK, et al. J Clin ncol 26;24: Abou-Alfa GK, et al. ASC 28, Chicago, IL, USA Phase II trial: safety by Child Pugh class C P A (%) (n=98) C P B (%) (n=38) AEs SAEs Fatigue HFSR 3 13 Diarrhoea Bilirubin increase 18 4* Ascites Encephalopathy 2 11 Length of therapy 24.9 weeks 12.9 weeks Dose reductions 31% 21% *Due to cirrhosis not associated with liver failure or an increase in liver enzymes SAEs = serious AEs Abou-Alfa GK, et al. J Clin ncol 26;24: Measure GIDE Study Marrero JA, et al. J Clin ncol. 211;29(suppl): Abstract 41. Child A (%) n = 965 (61%) Child B (%) n = 368 (23%) 8-mg starting dose, n (%) 738 (76) 261 (71%) Daily dose (median, mg) Treatment duration (median, weeks) discontinued due to AEs, n (%) (23) 139 (38) 4

5 safety in patients with mild to moderate liver impairment exposure values were comparable with those in patients without liver impairment o dose adjustment for sorafenib is required in patients with Child Pugh A or B status can be safely given in Child-Pugh B patients but have more frequent worsening of their liver cirrhosis and worse survival Lack of prospective randomized trials to assess the efficacy/safety in Child B patients-ongoing Italian randomized phase III trial Lessons From Development It has modest efficacy in advanced with Child A cirrhosis Toxicity management and dose adjustment is critical for clinical benefits utcomes vary depending on the etiology, geographic regions, and severity of underlying cirrhosis o validated predictive biomarkers for sorafenib in SEARCH: Study bjective and Design bjective To compare the efficacy and safety of sorafenib plus erlotinib with sorafenib plus placebo as first-line treatment in patients with advanced/unresectable Design Randomized, double-blind, placebo-controlled phase III trial conducted in 26 countries in Europe, orth and South America, and Asia Pacific Study aim: show a 33% increase in median S compared to sorafenib + placebo using a one-sided alpha of.25; a total of 521 events are required to achieve 9% power verall Survival* HR: % Cl:.781, 1.16 P =.24 (1-sided) + Erlotinib Median: 9.5 mo + Median: 8.5 mo *ITT Population Zhu AX, et al. Ann ncol. 212;23(suppl 9): Abstract Zhu AX, et al. Ann ncol. 212;23(suppl 9): Abstract Phase II Trial of Doxorubicin ± in : Study Design Clinical utcomes Eligibility Advanced ECG PS -2 Child Pugh A o prior systemic therapy o prior chemoembolization o history of organ allograft Primary objective TTP Secondary objectives RR, PFS, S, safety R A D M I Z E 1:1 n=47 n=49 Period 1 Period 2* Doxorubicin 6mg/m 2 + sorafenib 4mg bid q3w Doxorubicin 6mg/m 2 + placebo q3w 4mg bid Inhibition of the Ras/Raf/MEK/ERK pathway may prevent activation of the multidrug resistance pathway * or placebo continued until withdrawal, PD, or death in Period 2. q3w = once every 3 weeks. Abou-Alfa GK, et al. JAMA 21 TTP 6.4 vs 2.8 months; S 13.7 vs 6.5 months, and PFS 6. vs 2.7 months 5

6 Conclusions is first line therapy for patients with advanced due to portal vein invasion (PVI) or metastatic disease (BCLC stage C) or in patients who have progressed after TACE (BCLC stage B) [Level 1B]. should only be used in patients with preserved liver function (Child Pugh A) [Level 1B] with compromised PS and hepatic function should be considered for lower starting dose of sorafenib (Level 2B) Toxicity management and dose adjustment is critical for clinical benefits ovel agents and strategies are desperately needed 6