Unmet Needs in the Treatment of Advanced Hepatocellular Carcinoma

Transcription

1 Unmet Needs in the Treatment of Advanced Hepatocellular Carcinoma Joong-Won Park Center for Liver Cancer National Cancer Center, Korea

2 Advanced HCC Definition - An abtract concept, Not clear, No consensus General meaning - Advanced stage in BCLC stage - Vascular invasion + Stage II, III, IVa, IVb in modified UICC stage Stage II, IIIA-C, IV in AJCC stage - Not indicated of curative treatments - Candidate of systemic chemotherapy

3 2009 Practice Guidelines for the Management of HCC KLCSG-NCC, Korea Modified UICC Staging of HCC * Stage T N M I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 IV-A T4 N0 M0 T1-3 N1 M0 IV-B T1-4 N0-N1 M1 13/35 T1 (3/3) T2 (2/3) T3 (1/3) T4 (0/3) 1 Number 1 2 Size < 2cm 3 Vascular invasion (-) Advanced HCC? * Adopted from LCSGJ; Ueno S, et al. Hepatol Res 2002;24:395

4 2009 Practice Guidelines for the Management of HCC KLCSG-NCC, Korea Treatment Plan for HCC (Korean J Hepatol 2009;15: )

5 Unmet Needs in the Treatment of Advanced Hepatocellular Carcinoma Key Reference HCC: Consensus Recommendations of the NCI Clinical Trials Planning Meeting Thomas MB, et al. J Clin Oncol 2010;28:

6 The NCI Clinical Trials Planning Meeting (CTPM): the Gastointestinal Cancer Steering Committee (GISC) To identify the critical clinical questions and unmet meeds in HCC To develop strategies for future clinical trials in HCC and to provide rationale for the recommendations To reach consensus on priority of clinical trials, both near term and longer term To facilitate collaboration among clinicians and scientists Thomas MB, et al. J Clin Oncol 2010;28:

7 The Greatest Unmet Need in HCC HCC staging system to compare clinical trials Molecular characterization of tumor to validate stratification of Pts Advanced HCC who will need systemic therapy Multistep hepatocarcinogenesis : numerous potential therapeutic target Optimal imaging to assess drug activity - MAPK pathway - PI3K/Akt/mTOR pathway - Growth Factor: EGFR, VEGF - A threshold for tumor size detection - Assessment of tumor pathology, vascular features, and biologic change Thomas MB, et al. J Clin Oncol 2010;28:

8 The Greatest Unmet Need in HCC HCC staging system to compare clinical trials Molecular characterization of tumor to validate stratification of Pts Advanced HCC who will need systemic therapy Multistep hepatocarcinogenesis : numerous potential therapeutic target Optimal imaging to assess drug activity - MAPK pathway - PI3K/Akt/mTOR pathway - Growth Factor: EGFR, VEGF - A threshold for tumor size detection - Assessment of tumor pathology, vascular features, and biologic change Thomas MB, et al. J Clin Oncol 2010;28:

9 The Greatest Unmet Need in HCC HCC staging system to compare clinical trials Molecular characterization of tumor to validate stratification of Pts Advanced HCC who will need systemic therapy Multistep hepatocarcinogenesis : numerous potential therapeutic target Optimal imaging to assess drug activity - MAPK pathway - PI3K/Akt/mTOR pathway - Growth Factor: EGFR, VEGF - A threshold for tumor size detection - Assessment of tumor pathology, vascular features, and biologic change Thomas MB, et al. J Clin Oncol 2010;28:

10 The Greatest Unmet Need in HCC HCC staging system to compare clinical trials Molecular characterization of tumor to validate stratification of Pts Advanced HCC who will need systemic therapy Multistep hepatocarcinogenesis : numerous potential therapeutic target Optimal imaging to assess drug activity - MAPK pathway - PI3K/Akt/mTOR pathway - Growth Factor: EGFR, VEGF - A threshold for tumor size detection - Assessment of tumor pathology, vascular features, and biologic change Thomas MB, et al. J Clin Oncol 2010;28:

11 Seven Priorities for Future Studies in Advanced HCC 1. Because of limited patients resource, agents with new mechanism of action should be given priority Thomas MB, et al. J Clin Oncol 2010;28:

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13 Multiple Cellular Signaling Pathways Implicated in Pathogenesis of HCC VEGFR, PDGFR FGFR, EGFR, IGF-IR c-met Tyrosin Kinase Receptor Cell membrane Wnt/ -catenin Receptor SHC GrB2 GEF Ras BAD Akt PI3K PTEN mtor PKC PLC Raf MEK1/2 DSH GBP GSK3 ERK1/2 BcL-XL NF-ҚB -catenin NF-ҚB c-myc c-jun -catenin p53 Proliferation, Survival Transcription/translation PTC SMO Avila MA, et al. Oncogene 2006;25:3866 Minguez B, et al. Curr Op Gastroenterol 2009;25:186 Cell differentiation Hedgehog pathway

14 Multiple Cellular Signaling Pathways Implicated in Hepatocarciogenesis Whittaker, et al. Oncogene 2010

15 June 2011

16 Molecular Targeted Agents for HCC with Trials in ClinicalTrials.gov Target Agent VEGF VEGFR PDGFR FGF FGFR EGFR Raf MEK mtor IGF1R TRAILR1 Heparanase Sorafenib O O O Sunitinib O O Brivanib O O Linifanib O O TSU-68 O O O Bevacizumab O Erlotinib O Gefitinib O Lapatinib O Cetuximab O AZD6244 O BAY O PI-88 O O O Mapatumumab O Everolimus O OSI-906 O Kim HY, Park JW. Dig Dis 2011

17 Seven Priorities for Future Studies in Advanced HCC 2. Clinical trial design parameters - Sorafenib as the control in first-line trials - Placebo as the control in second-line trials - TTP as a 1 end point in randomized ph II - Identification of stratification factors - Preclinical data for second-line therapy - Organ dysfunction studies during phase I/II - Tissue banking Thomas MB, et al. J Clin Oncol 2010;28:

18 Sorafenib and Beyond A good responder shows good results Who is a good responder? patients selection: biomarker, clinical factors Good response has some limitations How can we overcome secondary resistance? combination, adjuvant treatment, other first line trials There are many poor responders How can we overcome prim resistance and toxicities? Second line, combination treatment

19 Who is a good responder? :clinical variables predicting response Cheng AL, et al, Lancet Oncol 2009 Shim JH, Park JW, et al. JCRCO 2009

20 Seven Priorities for Future Studies in Advanced HCC 3. Studies to identify circulating biomarkers to complement analysis of HCC tissues Thomas MB, et al. J Clin Oncol 2010;28:

21 Clin Cancer Res; 17(4);

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23 Seven Priorities for Future Studies in Advanced HCC 4. Novel imaging correlative end points should be defined for HCC since RECIST is a suboptimal tool for HCC MTA study Thomas MB, et al. J Clin Oncol 2010;28:

24 mwho, RECIST, and mrecist Response Criteria in HCC: Imaging Diagnosis RFA MTT TACE HCC RECIST/mWHO CR SD SD mrecist CR PR CR

25 Example Case That Changed From PR by mwho to CR by mrecist in Brivanib Phase II Study 04 Jun 07 Baseline assessment 12 Dec 07 mwho: PR mrecist: CR 22 Jun 09 mwho: PR mrecist: CR This patient was initially assessed as having PR by mwho criteria. Upon scan reassessment by mrecist, PR changed to CR. Park JW, et al. Clin Cancer Res 2011; 17: 1-11

26 Seven Priorities for Future Studies in Advanced HCC 5. Novel imaging methods should be prospectively studied 6. Phase zero studies of imaging modalities Phase 0 - Human microdosing studies - To speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. - Administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics and pharmacokinetics. Thomas MB, et al. J Clin Oncol 2010;28:

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28 Park JW, et al. J Nucl Med 2008; 49:

29 Seven Priorities for Future Studies in Advanced HCC 7. Tumor markers screening at-risk populations and assessing treatment response Thomas MB, et al. J Clin Oncol 2010;28:

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31 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, 90 Y 1. Prospective phase II, III trials of TACE+ablation, TACE+ systemic therapy Thomas MB, et al. J Clin Oncol 2010;28:

32 Combination Treatment of TACE and Sorafenib in ClinicalTrials.gov Local therapy MTT Agents Study design Sites TACE (doxorubicin) Sorafenib II, randomized placebo -controlled International TACE (doxorubicin) Sorafenib II, single arm Korea (NCC) TACE (doxorubicin) Sorafenib II, single arm USA (John Hopkins) TACE (cisplatin) Sorafenib II, single arm USA (Pittsburgh) TACE (doxorubicin+mmc) Sorafenib II, single arm USA (New Jersey) TACE (doxorubicin) Sorafenib (2 wks before TACE) II, single arm Germany (Heinrich Hei ne) TACE (doxorubicin) Sorafenib (2 wks before TACE) I/II Italy TACE (doxorubicin) Sorafenib I Switzerland (Bern) SIR-Spheres (yttrium-90) Sorafenib I/II Singapore

33 12 Sept 2010 ILCA, Montreal Interim Analysis of a Phase II Study of the COmbination of TACE and Sorafenib in Patients with Unresectable HCC in National Cancer Center, Korea (COTSUN Korea Trial, NCT ) Joong-Won Park, Hwi Young Kim, Ju Hyun Shim, Sang Myung Woo, Joon-Il Choi, Hyun Beom Kim and Byung-Ho Nam 1 Center for Liver Cancer and Center for Clinical Trials 1, National Cancer Center, Korea

34 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, 90 Y 2. Evaluate the outcome of regional therapy versus systemic therapy in patients with N1 or M1 disease Thomas MB, et al. J Clin Oncol 2010;28:

35 Comparison of Survival in Patients with BCLC Stage C Advanced HCC: Sorafenib Vs. Other Treatments Hwi Young Kim, Joong-Won Park *, Byung-Ho Nam 1, Hyun Keun Kim, Joon-Il Choi, Tae Hyun Kim, Hyun Beom Kim and Chang-Min Kim Center for Liver Cancer, National Cancer Center, Korea ; Cancer Biostatistics Branch 1, National Cancer Center Research Institute, Korea Publication in process

36 Subgroup Analyses HR (95% CI) AFP <200 ng/ml 200 ng/ml P= ( ) ( ) Intrahepatic tumor Nodular Massive/infiltrative P= ( ) ( ) Macrovascular i nvasion Absent Present P= ( ) ( ) Extrahepatic spread Absent Present P= ( ) ( ) Modified UICC s tage I III IVA, IVB P= ( ) ( ) Sorafenib better Kim HW, Park JW, et al. J Gastroenterol Hepatol 2011 Apr epub Other treatments better

37 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, 90 Y 3. Design clinical trials approaches to clearly idendify the patients population being studied Thomas MB, et al. J Clin Oncol 2010;28:

38 Baseline Characteristics (n=50) No. (%) or median(range) Sex Male 42 (84.0) Age (years) 61.5 (29 76) Etiology of liver disease HBV 28 (65.1) HCV 8 (18.6) ECOG performance status 0 22 (44.0) Child-Pugh class A 47 (94.0) α-fp (ng/ml) 43.7 ( ) BCLC stage B 39 (78.0) C 11 (22.0) Modified UICC stage II 15 (30.0) III 24 (48.0) IVA 11 (22.0) Portal vein invasion 11 (22.0) Lymph node involvement 1 (2.0) Previous treatment(s) None 15 (30.0) Surgery 8 (16.0) RFA/PEI 12 (24.0) TACE 24 (48.0) Radiotherapy 3 (6.0)

39 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, Y Conduct comparison trials of TACE, DEB, and Y 90 to assess safety, efficacy, and cost-effectiveness end points Thomas MB, et al. J Clin Oncol 2010;28:

40 Drug Eluting Beads (DEB) vs Conventional TACE International, multicentre, randomised phase II study to assess the safety and efficacy of DC Bead uploaded with doxorubicin versus conventional TACE with doxorubicin-in-lipiodol emulsion followed by embolisation Patients randomised 1:1 (n=212) TACE with DC Bead Doxorubicin dose = 150mg Conventional TACE Doxorubicin dose = 50 75mg/m 2 (maximum 150mg) TACE repeated at 2 and 4 months TACE repeated at 2 and 4 months Primary endpoint: tumor response at 6 months (EASL criteria by blinded independent review of MR images) Secondary endpoints: safety (toxicity according to SWOG), TTP Lencioni R et al. ASCO GI 2009, San Francisco, CA 40

41 Progression free (%) PRECISION V: DC Bead did not improve overall TTP compared with ctace DC Bead ctace Days Lencioni R, et al. CIRSE 2008, Copenhagen, Denmark

42 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, Y Define the role of TACE in liver transplantation: - TACE response have an impact on the outcome in LT? - What is the efficacy of TACE as a bridge to LT? - Pre-LT TACE: survival gain?, downstaging feasibility? Thomas MB, et al. J Clin Oncol 2010;28:

43 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, Y Conduct prospective trials of regional therapy options: there would be numerous challenges, including standardization of technique Thomas MB, et al. J Clin Oncol 2010;28:

44 Seven Priorities for Clinical Evaluation of Regional Therapy: TACE, HAIC, DEB, Y ECOG 1208 trial, A phase III randomized, doubleblind trial of chemoembolization with or without sorafenib in unresectable HCC in patients with and without vascular invasion, is a priority study Thomas MB, et al. J Clin Oncol 2010;28:

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46 Three Priorities for Clinical Evaluation of Local Therapy: Resection, Ablation, EB Radiotherapy 1. Evaluate the outcome of adjuvant systemic therapy following resection or ablation: STORM trial 2. Conduct a phase II trial of adjuvant chemotherapy following regional therapy 3. Compare modalities, such as hepatic resection versus ablation Thomas MB, et al. J Clin Oncol 2010;28:

47 Two Priorities for Clinical Evaluation of Liver Transplantation 1. Downstaging therapy - can pts outside UNOS benefit? Which pts? - ph II, single arm, treated with TACE 2. Adjuvant therapy - can decrease post-lt recurrence in high risk pts? - randomized ph II, III trials with sorafenib Thomas MB, et al. J Clin Oncol 2010;28:

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