Hepatocellular Carcinoma

Transcription

1 Hepatocellular Carcinoma Ghassan K. Abou-Alfa Memorial Sloan Kettering Cancer Center Great Debates & Updates in GI Malignancies New York, NY March 28, 2015

2 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

3 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

4 Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C Mean Change from Baseline in Hepatitis C Virus (HCV) RNA Level during Treatment. Gane EJ et al. N Engl J Med 2013;368:34-44.

5 Mortality from Cancer According to Body- Mass Index for U.S. Men Cancer Prevention Study II, 1982 through 1998 Calle, E. E. et al. N Engl J Med 2003;348:

6 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

7 Child s Pugh Score of Liver Cirrhosis Parameter Points Albumin (g/dl) > < 2.8 Bilirubin (mg/dl) < > 3 Ascites Absent Slight Moderate Encephalopathy None I - II III - IV PT (INR) < > 2.3 Score A B C Points Pugh, RNH, et al. British Journal of Surgery. 60(8): , 1973

8 Scoring Systems: Comparison Table Parameter Child-Pugh Okuda CLIP CUPI TNM6 JIS GRETCH BCLC Albumin Bilirubin Ascites PT (INR) Encephalopathy Alkaline phosphatase Tumor extent/stage Portal vein thrombosis AFP Presenting with no sxs Performance status CLIP=Cancer of the liver Italian Project; CUPI=Chinese University Prognostic Index; TNM6=Tumor,Node, Metastases 6 th edition; JIS=Japan Integrated Staging; GRETCH=Groupe d Etude et de Traitement du Carcinome Hépatocellulaire; BCLC=Barcelona Clinic Liver Cancer; AFP=alpha fetoprotein; PT=prothrombin time; sxs=symptoms. Huitzil, FD, Abou-Alfa, GK. ASCO GI Abstract 210

9 Huitzil, DF, Abou-Alfa, GK, J Clin Oncol Jun 10;28(17): Best and Worst Scoring System (s) Rank c-index (95%CI) 1 CLIP 0.69 ( ) 2 CUPI 0.67 ( ) 3 GETCH 0.66 ( ) 4 Okuda 0.65 ( ) 5 JIS 0.63 ( ) 6 BCLC 0.58 ( ) 7 TNM ( )

10 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

11 Barcelona-Clinic-Liver-Cancer Staging HCC ECOG 0, Child A ECOG 0-2, Child A-B ECOG > 2, Child C Very early stage, Single <2 cm Single Early stage, 3, 3 cm, ECOG 0 Portal pressure/bilirubin Increased 3 nodules, 3 cm Associated diseases Intermediate stage multinod, ECOG 0 Advanced stage, portal inv. N1, M1, ECOG 1-2 Terminal stage Normal No Yes Resection Transplant PEI/RFA Chemoembo Sorafenib Curative Treatments Palliative Options BSC Adapted from Forner, A. et al. Semin Liver Dis Feb;30(1):61-74.

12 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

13 Phase III SHARP Trial Study Design Primary end-points: Overall survival Time to symptomatic progression (FHSI8-TSP) Secondary end-points: Time to progression (independent review) Stratification: Macroscopic vascular invasion and/or extrahepatic spread Sorafenib (n=299) 400 mg po bid Discontinue therapy Radiologic progression ECOG PS Geographical region 602 patients Placebo (n=303) 400 mg po bid AND FHSI8-TSP worsening Llovet JM, et al. N Engl J Med. 2008;359:

14 Survival Probability SHARP Overall Survival (ITT) Sorafenib Median: 46.3 weeks (10.7 months) (95% CI: 40.9, 57.9) Placebo Median: 34.4 weeks (7.9 months) (95% CI: 29.4, 39.4) Patients at risk Sorafenib: Placebo: Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87) P<0.001* Llovet JM, et al. N Engl J Med. 2008;359: Weeks *O Brien-Fleming threshold for statistical significance was P=

15 The Anti-Angiogenic Ceiling Median OS (months) Reference Phase II Phase III Sorafenib 9.2 Abou-Alfa, J Clin Oncol Llovet N Engl J Med Cheng, Lancet Oncol Cheng, J Clin Oncol Sorafenib + Erlotinib 8.5 Zhu, ESMO 2012 Sunitinib 9.8 Zhu, J Clin Oncol Faivre, Lancet Oncol Cheng, J Clin Oncol Bevacizumab 12.4 Siegel, AB J Clin Oncol Boige, V The Oncologist 2012 Bev + Erlotinib 13.7 Kaseb, A Oncology Philip, P Cancer 2012 Linifanib 10.4 Toh, J Clin Oncol Cainap, C, GI ASCO 2013 Brivanib 10 Park, Clin Cancer Res Johnson, P, JCO 2013 Lenvatinib Accrual Held Abou-Alfa, GK and Venook, AP, Lancet Oncol Jun;14(7):e283-8.

16 (1:1) Randomization (N~96) Randomized Phase II Dox+Sorafenib and Dox+Placebo Period 1 Period 2 Eligibility Child-Pugh A ECOG PS: 0, 1, 2 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Sorafenib 400 mg po bid Sorafenib 400 mg po bid Continue until withdrawal, PD, or death 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Placebo 2 tablets po bid Placebo 2 tablets po bid Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent Abou-Alfa GK. et al. JAMA. Vol. 304, No. 19, November 17, 2010 :

17 Doxorubicin +/- Sorafenib Exploratory Kaplan Meyer Curves Median TTP Median OS Median PFS Sorafenib 6.4 months Sorafenib 13.7 months Sorafenib 6 months Placebo 2.8 months Placebo 6.5 months Placebo 2.7 months p 0.02 p p Abou-Alfa GK, et al. JAMA. 2010;304(19):

18 Raf-1 Inhibits ASK-1 Alavi AS, et al. Cancer Res. 2007;67(6):

19 (1:1) Randomization (N~ ) CALGB Period 1 Period 2 Eligibility Child-Pugh A ECOG PS: 0, 1, 2 6 cycles of: Doxorubicin 60 mg/m 2 IV* Day 1 in 21-day cycles Sorafenib 400 mg po bid 6 cycles of: Sorafenib 400 mg po bid Sorafenib 400 mg po bid Sorafenib 400 mg po bid Continue until withdrawal, PD, or death Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent Approved circumstances: benefit from therapy and continues to have normal EF on MUGA

20 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

21 HCC Second Line Therapies Agent Phase Outcome Reference Brivanib Phase III versus Placebo 9.4 vs 8.2 months OS Llovet, JM, et al J Clin Oncol Aug 26 Everolimus Phase III versus Placebo 7.6 vs 7.3 months OS Zhu, AZ, et al. JAMA Jul 2;312(1):57-67 Ramicurumab ADI-PEG 20 Phase III versus Placebo Phase III versus Placebo 9.2 vs 7.6 months OS Zhu, AZ, et al. Annals of Oncology (2014) 25 (5): /annonc/mdu438 Accruing Glazer, JCO 2010:28, 2220 Cabozantinib Phase III versus Placebo Accruing Versylpe, C, et al. Abstract ASCO 2012 Tivantnib Phase III versus Placebo Accruing Santoro, A, Lancet Oncol Jan;14(1): LY II 93.1 vs 20.3 weeks AFP high responders vs non responders Doxorubicin II 10.1 months OS in retrospective work Faivre, S. JCO 32, 2014 (suppl 3; abstr LBA173) Abou-Alfa, GK JCO 30, 2012 (suppl 4; abstr 298)

22 Cabozantinib in HCC Schema PR Cabo 100 mg qd Measurable RECIST HCC Child-Pugh A One prior line of therapy Cabozantinib 100 mg qd 12 weeks lead-in. mrecist q 6 wks SD Cabo 100 mg qd Placebo POD Primary endpoints: : time to tumor progression Secondary endpoints: overall survival, progression-free-survival, response, safety Versylpe, C, et al. Abstract ASCO 2012

23 Proportion Overall Survival Cabozantinib Phase II Overall Survival (n=41) Median OS (95% CI) # Events 15.1 months (8.9, 18.3) OS (months) Versylpe, C, et al. Abstract ASCO 2012

24 Randomized Second Line Phase II Tivantinib versus Placebo Tivantinib PO BID Patients with advanced HCC, Child-Pugh A, ECOG PS 0-1, adequate organ function, with prior Rx 3 weeks 2:1 n=107 On PD Placebo PO BID Primary endpoints: TTP Stratification: met status, HBV vs HCV, and duration of prior therapy Santoro, A, et al. Lancet Oncol Jan;14(1):55-63.

25 Proportion of Patients Surviving MET as a Prognostic Factor Median OS Patients Events MET Dx Low MET Dx High HR: 2.94 (95% CI: ) Log Rank: P=0.02 Rimassa, L, et al. Abstract ASCO 2012

26 Tivantinib OS in MET Diagnostic High Tivantinib: 7 2 months (95% CI Placebo: 3 8 months ( ) (HR 0 38, 95% CI ; p=0 01 Santoro, A, et al. Lancet Oncol Jan;14(1):55-63.

27 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

28 Strebel, BM,; Dufour, JF. Expert Rev Anticancer Ther Nov;8(11): TACE and Sorafenib Theoretical Sequencing

29 SPACE Schema Inclusion Criteria Unresectable, multinodular, HCC Child-Pugh A without ascites or encephalopathy ECOG PS of 0 Exclusion Criteria Vasc. invasion, extrahepatic spread (VI/EHS) Planned liver transplantation Previous local therapy to target lesion Prior TACE, prior systemic therapy n=307 R A N D O M I Z E Sorafenib 400mg bid Matching Placebo Imaging TACE (optional) Cycle no (=4 weeks) n=154 n=153 Primary Endpoint Time to progression (by central review) Secondary Endpoints Overall survival Time to VI/EHS Time to untreatable progression Safety First TACE with doxorubicin-eluting beads performed 3-7 days after start of treatment with sorafenib or placebo Subsequent TACE with doxorubicin-eluting beads performed on day 1 (±4 days) of cycles 3, 7, and 13, and every 6 cycles thereafter Patients allowed optional TACE with doxorubicin-eluting beads sessions between cycles 7 and 13 and cycles 13 and 19, if deemed necessary by the investigator Lencioni, R J Clin Oncol 30, 2012 (suppl 4; abstr LBA154^)

30 SPACE Overall Survival Secondary Endpoint HR: % Cl: 0.606, 1.33 P = Sorafenib Median: NR 95% Cl: 554 days, NR Placebo Median: NR 95% Cl: 562 days, NR Lencioni, R J Clin Oncol 30, 2012 (suppl 4; abstr LBA154^) 30

31 Epidemiology Scoring and staging Agenda Curative and therapeutic options First line systemic therapy Second line systemic therapy Integrating systemic therapy with local treatment Molecular approaches Conclusion

32 Mutations identified in 48 genes in HCC cohort TERT CTNNB1 APC NOTCH2 NOTCH3 SMAD3 SMAD4 GNA S KDR FGF19 ERBB3 CCND1 CDKN1A CDKN1B RB1 TP53 PTEN ASXL1 ARID1A ARID1B ARID5B PARP1 MSH6 PMS1 IDH2 NFEL2L2 EXH2 MCL1 IRS SF3B1 NCOR1 PBRMT1 SUZ PNRC1 NSD1 RECQL4 DIS3 BRD4 KDM5A FAM46C PI3CG WT1 PTPRD PTPRT CIC FOXL2 SPEN BTK Recurrent alterations observed in TERT promoter (36%), β-catenin /APC (36%) and ASXL1 (18%) Wild-type Point Mutation frameshift mutations Amplification Deletion splice mutations

33 MSKCC HCC Global Initiative Country Etiology Ethnicity Region Tissue and Data USA Mixed Etiology Mixed Western Hemisphere USA Hawaii HBV Pacific Islanders 50 Pacific 76 Hong Kong China HBV Asian Southeast Asia 37 Singapore HBV Asian and Malaysian Southeast Asia 18 Taiwan HBV Asian Southeast Asia 58 Korea HBV Japan-Korea Japan-Korea Japan HCV Japan-Korea Japan-Korea UK HCV English Western Hemisphere Egypt HCV Middle Eastern Africa 52 Saudi Arabia HCV HBV Middle Eastern Middle East

34 Summary HCC incidence trends are still of concern in many parts of the world Scoring and staging are an integral part of clinical management for HCC Sorafenib remains the sole standard of care therapy for HCC The anti-angiogenic ceiling may have been reached or never been there Doxorubicin plus sorafenib work is ongoing Work in the second line setting is multi-faceted No local therapeutic roles for sorafenib yet Molecular understanding of HCC is underway