Advances in Systemic Therapy Hepatocellular Carcinoma (HCC) Dr ZEE Ying Kiat HASLD Conference Ho Chi Minh City, 18 December 2016

Transcription

1 Advances in Systemic Therapy for Hepatocellular Carcinoma (HCC) Dr ZEE Ying Kiat HASLD Conference Ho Chi Minh City, 18 December 2016

2 Scope Background Staging and treatment strategies Current systemic therapy Future perspectives Conclusions

3 Background

4 HCC: A Deadly Tumour on the Rise HCC is the 6th most common cancer worldwide and is the 3rd leading cause of cancer-related mortality 1 Most cases of HCC arise as a result of chronic liver inflammation or injury 2 The incidence of HCC is increasing due to the long-term consequences of chronic hepatitis C and hepatitis B viral infections 3 Most patients newly diagnosed with HCC are not candidates for curative treatment because of gross vascular invasion, extrahepatic metastases and/or poor liver function 4 1. Parkin DM et al. CA Cancer J Clin. 2005;55: Moradpour D et al. Eur J Gastroenterol Hepatol. 2005;17: El-Serag HB, Mason AC. N Engl J Med. 1999;340(10): Llovet JM et al. Hepatology. 1999;30:

5 Staging and treatment strategies

6 HCC: BCLC Staging and Treatment Strategy Barcelona Clinic Liver Cancer Stage 0, PS 0, Child-Pugh A HCC Stage 1-2, PS 0-2, Child-Pugh A-B Stage 3, PS > 2, Child-Pugh C Very early stage (0) Single < 2 cm Carcinoma in situ Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Single 3 nodules 3 cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation RFA/PEI TACE Sorafenib Symptomatic (20%); survival Curative treatments (30%); 5-yr survival: 40%-70% RCTs (50%); 3-yr survival: 10%-40% < 3 mos 1. Llovet JM, et al. J Natl Cancer Inst. 2008;100(10):

7 Historically No Clear Benefit with Traditional Cytotoxic Therapies No standard systemic therapy for advanced HCC prior to Abou-Alfa GK. J Clin Oncol

8 Current systemic therapy

9 Systemic Therapy for Advanced Disease Sorafenib: Mechanism of action Induces tumour cell apoptosis or inhibits tumour cell proliferation by targeting the RAF/MEK/ERK pathway at the level of RAF kinase 8 Exerts an anti-angiogenic effect by targeting the receptor tyrosine kinases VEGFR-2, VEGFR-3 and PDGFR, and their associated signaling cascades 8 1. Strumberg D et al. Drugs Today. 2005;41(12): 773.

10 1. Llovet JM et al. N Engl J Med. 2008;359(4): Cheng AL et al. Lancet Oncol. 2009;10(1): Systemic Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies SHARP Clinical Trial Asia-Pacific Study

11 Systemic Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies Patients in the Asia-Pacific Study also had more prior locoregional therapies 1. Llovet JM et al. N Engl J Med. 2008;359(4): Cheng AL et al. Lancet Oncol. 2009;10(1):25-34.

12 Systemic Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies 1. Llovet JM et al. N Engl J Med. 2008;359(4): Cheng AL et al. Lancet Oncol. 2009;10(1):25-34.

13 1. Llovet JM et al. N Engl J Med. 2008;359(4): Cheng AL et al. Lancet Oncol. 2009;10(1): Systemic Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies One-third of patients required dose reductions due to toxicity

14 Systemic Therapy for Advanced Disease Failed Phase III studies Indication / Target Population Acronym Phase III Comparison (Active vs Control) Primary Outcome Child- Pugh First line / Advanced HCC BRISK-FL - Brivanib vs Sorafenib Linifanib vs Sorafenib A A - Sunitinib vs Sorafenib A SEARCH Sorafenib + Erlotinib vs Sorafenib A - Sorafenib + Cisplatin + 5FU vs Sorafenib A/B(7) SECOX Sorafenib + Capecitabine + Oxaliplatin vs Sorafenib A - Sorafenib + Doxorubicin vs Sorafenib A Second line / Advanced HCC EVOLVE-1 BRISK Everolimus vs Placebo Brivanib vs Placebo A A/B(7) BRISK-APS Brivanib vs Placebo A/B(7) Adjuvant / Early HCC post resection or ablation REACH Ramucirumab vs Placebo A/B(8) STORM Sorafenib vs Placebo RFS A

15 Systemic Therapy for Advanced Disease Second-line regorafenib: Phase III RESORCE study Pts with BCLC stage B or C HCC; documented PD on sorafenib 20 days at 400 mg/day; Child-Pugh A liver function; ECOG PS 0-1 (N = 573) Randomized 2:1 Primary endpoint: (ITT) Secondary endpoints: PFS, TTP, RR, DCR 4-wk cycles Regorafenib + BSC 160 mg PO daily Wks 1-3 (n = 379) Placebo + BSC PO daily Wks 1-3 (n = 194) All pts treated until PD, death, or unacceptable toxicity BSC, best supportive care; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; ITT, intent to treat; PD, progressive disease; PS, performance status; TTP, time to progression, RR, response rate. 1. Bruix J et al. ESMO GI Abstract LBA-03.

16 Systemic Therapy for Advanced Disease Second-line regorafenib: Phase III RESORCE study Endpoint Regorafeni b (n = 379) Placeb o (n = 194) Median, mos Median PFS, mos Median TTP 3.2* 1.5* ORR, % *HR 0.44; 95% CI: ; P <.001; P = % reduction in risk of death (HR: 0.62; 95% CI: ; P <.001) 54% reduction in risk of progression or death (HR: 0.46; 95% CI: ; P <.001) DCR (CR + PR + SD): 65.2% vs 36.1% (P <.001) DCR, disease control rate; SD, stable disease; TTP, time to progression. 1. Bruix J et al. ESMO GI Abstract LBA-03.

17 Systemic Therapy for Advanced Disease Second-line regorafenib: Phase III RESORCE study 1. Bruix J et al. ESMO GI Abstract LBA-03. Adverse Events, % Regorafeni b (n = 379) Placeb o (n = 194) Any grade 3 adverse events Hypertension Hand foot syndrome Fatigue Diarrhea Dose modifications due to adverse events Deaths occurring 30 days after last dose

18 Future perspectives

19 Cancer Immunotherapy Cancer evades immune cell recognition and destruction via several mechanisms 1-5 A Reduced presentation of tumour antigens to the immune system Downregulation of MHC expression Suppression of APC B Release of immunosuppressive factors Factors/enzymes directly or indirectly suppress immune response Tumour cell APC D T-cell immune checkpoint modulation C Recruitment of immunosuppressive cells Tumour microenvironment Tregs MDSCs Images adapted from Davies M. Cancer Manag Res. 2014;6:63-75 and reprinted from Mellman I et al. Nature. 2011;480(7378): BTLA = B- and T-lymphocyte attenuator; GITR = glucocorticoid induced tumour necrosis factor-related protein; HVEM = herpes virus entry mediator; LAG-3 = lymphocyte-activation gene 3; MDSC = myeloid-derived suppressor cell; TIM-3 = T-cell immunoglobulin domain and mucin domain-3; VISTA = V-domain immunoglobulin-containing suppressor of T-cell activation. 1. Mellman I et al. Nature. 2011;480(7378): Spranger S et al. J Immunother Cancer. 2013;1: Töpfer K, Kempe S, Müller N, et al. J Biomed Biotechnol. 2011;918471: Pardoll DM. Nat Rev Cancer. 2012;12(4): Ma Y et al. J Cancer. 2013; 4(1):

20 Cancer Immunotherapy Immune checkpoint inhibition: CTLA-4 and PD-1/PD-L1 Priming phase (lymph node) Dendritic cell T cell T-cell migration T cell Cancer cell Effector phase (peripheral tissue) MHC TCR TCR MHC Dendritic cell B7 CD28 CTLA-4 T cell T cell PD-1 PD-L1 Cancer cell Ipilimumab (Yervoy ) Pembrolizumab (Keytruda ) Nivolumab (Opdivo ) Atezolizumab (Tecentriq ) MHC = major histocompatibility complex; TCR = T-cell receptors; CTLA-4 = cytotoxic T-lymphocyte associated protein 4; PD-1 = programmed death protein 1; PD-L1 = programmed death protein ligand Ribas A. N Engl J Med. 2012;366:

21 Immunotherapy for Advanced Disease Immune checkpoint inhibition with PD-1 antibodies 1. El-Khoueiry AB et al. ASCO Abstract LBA101.

22 1. Sangro B et al. ASCO Abstract TPS4147. Immunotherapy for Advanced Disease Immune checkpoint inhibition with PD-1 antibodies Randomized, open-label, multicenter phase III trial Stratified by etiology, vascular invasion and/or extrahepatic spread, and geography Advanced HCC; no prior systemic therapy; not eligible for/progressed after locoregional therapy; C-P A; ECOG PS 0-1 (planned N = 726) Primary endpoint: time to progression, Secondary endpoints: ORR, PFS, PD-L1 expression Nivolumab 30 min IV Q2W Sorafeni b PO BID All pts treated until PD, unacceptable toxicity, or withdrawal of consent *Nonviral HCC, HBV-HCC (HBV infection resolved or controlled), or HCV- HCC (resolved or active HCV infection) ECOG, Eastern Cooperative Oncology Group; PD, progressive disease;, overall survival; ORR, overall response rate; PFS, progression free survival.

23 Select Ongoing First-line Phase III Trials in Advanced HCC First-Line Study N Population Primary Endpoint Lenvatinib vs sorafenib (NCT ) Nivolumab vs sorafenib (NCT ) Sorafenib ± SBRT (RTOG 1112; NCT ) Sorafenib ± TACE (NCT ) Sorafenib vs Y90 (NCT ) Notes 954 Unresectable HCC Open label 726 Unresectable or progressive advanced HCC 368 HCC with 1 liver lesion or vascular tumor thrombosis TTP, Biomarker analysis 246 Analysis of Advanced HCC prognostic (BCLC Stage C) value of AFP response 360 Locally advanced HCC (BCLC stage B or C without extrahepatic disease

24 Select Ongoing Second-line Phase III Trials in Advanced HCC Second-Line Study N Population Primary Endpoint( s) Tivantinib vs BSC (NCT ) Tivantinib vs placebo (NCT ) Cabozantinib vs BSC (NCT ) Ramucirumab vs BSC (REACH-2; NCT ) 368 Unresectable HCC after 1 prior therapy 160 c-met high HCC after sorafenib Considerations 760 All comers HCC with prior sorafenib with no c-met selection 399 HCC with elevated baseline AFP after first- line sorafenib Pembrolizumab vs BSC (KEYNOTE-240; NCT ) 408 HCC with progression on sorafenib PFS,

25 Conclusions

26 Conclusions Sorafenib is the only systemic agent approved for the first-line treatment of advanced HCC Regorafenib improves survival in patients with disease progression following sorafenib Immune checkpoint inhibition is an exciting therapeutic strategy Many Phase III studies are ongoing