ESMO GI Cancer Preceptorship 15 November 2017 Singapore First-line therapy for unresectable HCC: an oncologist s viewpoint Chiun Hsu, MD, PhD G raduate I n stitute of Oncology, National Taiwan Univers ity (NTU) College of Medicine Department of Oncology, NTU Hospital NTU Cancer Cente r
Conflict of interest disclosure Research grant Ministry of Science and Technology (Taiwan), Celgene, YongLin Healthcare Foundation Honorarium (speaker/advisor/travel) AstraZeneca, Bayer, Bristol-Myers Squibb/ONO, Eli Lilly, MSD, Novartis, Roche, TTY Biopharm 2
Liver-directed therapy used to be the major player Ablation therapy, trans-catheter arterial chemoembolization (TACE) Hepatic arterial infusional chemotherapy (HAIC), selective internal radiation therapy (SIRT), external radiation therapy Systemic therapy In 2017 (and beyond) More weapons for a more heterogeneous population The gap between guidelines/evidence and practice 3
An example of practice guidelines: The AASLD 2017 update (10 key questions for health care providers) Sorafenib? 10. The AASLD recommends Score? Cause? the use of systemic therapy over no therapy for patients with Child Pugh A cirrhosis or wellselected patients with Child s B cirrhosis plus advanced HCC with macrovascular invasion and/or metastatic disease. The Gaps BCLC stage? Optimal dosage? The criteria of well-selected patients with Child B cirrhosis? The changing landscape of advanced-stage disease? Heimbach J, et al. Hepatology 2017 (E pub online) 4
The optimal dosage of systemic therapy: Experience in sorafenib treatment (1) Prospective observation (296 patients) Child A: 260 (88%) BCLC stage C: 222 (75%) Starting dose: 800 mg/day Sorafenib treatment interruption ECOG PS, Disease progression: 103 albumin, (44%) Adverse event: 95 (40%) bilirubin, age Liver decompensation: 38 (16%) 97 (33%) discontinued without previous adjustment (75% due to AE) 77 (26%) patients received half-dose sorafenib for 70% of the treatment period (median of 6.8 months (95% CI 4.2-9.4)) Independent predictors of survival: ECOG PS, MVI, EHS, full dose sorafenib Full dose Full dose BCLC B Adjusted dose BCLC C Adjusted dose Iavarone M, et al. Hepatology 2011; 54: 2055-63. Camma C, et al. Hepatology 2013; 57: 1046-54 5
Experience in sorafenib treatment (2) Start from half-dose? BC Cancer Agency chart review (2008-2010), 800 mg/day (n=33) 400 mg/day (n=66) 14 Japanese Red Cross Hospitals (2008-2013) 800 mg/day (n=183) 400 mg/day (n=254) Propensity score match (Age, BW, Sex, PS, Child) Median OS 7.8 (f) vs. 7.1 (h) mon (p=0.14) Median OS 9.2 (f) vs. 9.7 (h) mon (p=0.35) Shingina A, et al. Can J Gastroenterol 2013; 27: 393-6. Nishikawa H, et al. Int J Oncol 2014; 45: 2295-302 6
Experience in sorafenib treatment (3) were the patients well-selected? 128 US Veterans Affairs Hospitals (2006-2015) 800 mg/day (n=3094) <800 mg/day (n=1809) 800 mg/ day Median age 63.6 64.1 Cirrhosis co-morbidity index 1 1 ECOG 3-4 (%) 4 5 Child B/C (%) 34/3 44/7 BCLC D 6 11 Active alcohol use (%) 8 10 < 800 mg/ day HR 0.92 (95% CI 0.83-1.01, p ni <0.001) Median OS about 7 mon Propensity score match Reiss KA, et al. J Clin Oncol 2017; 35: 3575-81 7
Systemic therapy for advanced-stage HCC: concerns about the underlying liver diseases Patients with Child B cirrhosis were more susceptible to treatment-related adverse events, dose reduction, or discontinuation Correlation between efficacy and adverse events? Antiviral therapy, alcohol abstinence Score 7 vs. score 8-9 Child B associated with underlying liver disease vs. Child B associated with tumor progression 8
The landscape of advanced-stage HCC The BCLC definition: Macrovascular invasion and/or extra-hepatic spread ECOG score 1 or 2 Patients refractory to loco-regional (liver-directed) therapy Definition of TACE-refractoriness 2 consecutive ineffective responses of treated tumors (viable lesions >50%) or 2 consecutive progressive increases in total tumor count CT or MRI at 1 3 months after a selective TACE treatment. Continuous elevation of tumor marker levels New emergence of vascular invasion and extrahepatic spread Arizumi T, et al. Liver Cancer 2015; 4: 253-62 9
The trend to start systemic therapy earlier? Lenvatinib (body weight 60 kg: 12 mg/day; < 60 kg: 8 mg/day) vs. Sorafenib 400 mg twice daily Primary endpoint: overall survival (OS), 1:1 randomization (predefined non-inferiority margin 1.08) Patients with main portal vein thrombi or tumors occupying 50% of liver volume were excluded. Median OS, mos (95% CI) Lenvatinib Sunitinib 13.6 (12.1 14.9) 7.9 (7.4 9.2) Sorafenib 12.3 (10.4 13.9) Sorafenib 10.2 (8.9 11.4) Brivanib 9.5 (8.3 10.6) Sorafenib 9.9 (8.5 11.5) Linifanib 9.1 (8.2 10.2) Sorafenib 9.8 (10.4 13.9) Asian (%) 67 77 62 66 BCLC stage C (%) 74.2 85.2 78.0 84.2 Cheng AL, et al. ASCO 2017 (abstr#4001). Cheng AL, et al. J Clin Oncol 2013; 31: 4067-75. Johnson PJ, et al. J Clin Oncol 2013; 31: 3517-24. Cainap C, et al. J Clin Oncol 2015; 33; 172-9 10
The future of systemic therapy for HCC: multikinase inhibitors vs. checkpoint inhibitors Major targets Immune modulatory effects Combination trials with checkpoint inhibitors (clinicaltrials.gov, accessed on 05 Nov 2017) Sorafenib Regorafenib Lenvatinib Cabozantinib VEGFR, PDGFR, RAF family, KIT, RET, FGFR VEGFR, TEK, KIT, RET, RAF family, PDGFR, FGFR VEGFR, FGFR, PDGFR, KIT, RET CD8+ T cells/ Treg/ MDSC, etc. T cell trafficking, adhesion, function Yes Yes Yes Yes Yes No Yes Yes VEGFR2, MET, RET, KIT, AXL, FLT3 11
The future roles of liver-directed therapy? Chow P, et al. Kudo M, et al. Vilgrain V, et al. Patient population Locally advanced HCC, Child A/B7 Advanced HCC Locally advanced HCC, Child A/B7 Tx (patient no.) Sorafenib (162) SIRT (130) Sorafenib (102) Sorafenib + HAIC (88) Sorafenib (206) SIRT (174) Median OS, mos (95% CI) 10.41 (8.57 13.83) 11.27 (9.17 13.57) 11.8 (NR) 11.8 (NR) 9.9 (NR) 9.9 (NR) Median PFS, mos (95% CI) ORR (%) 5.22 (NR) 1.9 6.28 (NR) 23.1-17.1-36.3 3.7 (NR) 11.6 4.3 (NR) 19.0 Chow P, et al. ASCO 2017 (abstr#4002); Kudo M, et al. EASL 2016 (abstr# LB04); Vilgrain V, et al. EASL 2017. 12
Clinical trials with multiple primary endpoints When all of 2 or more distinct endpoints should be met to show treatment effects (co-primary endpoints) e.g., migraine treatment (control of pain + individually specified symptoms (photophobia, nausea, etc.) e.g., Alzheimer s disease (cognition + functional improvement) At least 1 of several primary endpoints is sufficient e.g., overall survival, progression-free survival, response rate e.g., Treatment of burn (wound closure, scarring) Composite endpoints (when the incidence of individual events is too low) e.g., anti-platelet therapy (prevention of MI, stroke, or death) FDA draft guidance 2017 13
Summary The Present A bigger and more heterogeneous patient population Tumors, liver function, prior therapy Multi-disciplinary team care More options are emerging The Future Combination therapy Partners, dosage, sequence Bridging the gaps between evidence and practice 14
Thank you very much! 感謝盧建宏醫師提供 15