【正文】 ECOG PS 0–2 Primary end point ? Overall survival Secondary end points ? TTP ? Disease control rate ? Change in ECOG PS ? Change in QoL ? Safety Study start date: April 2022 Estimated final analysis: November 2022 方案 C: X vs 最佳支持治療 (BSC) 二線治療 ( Sorafenib失敗 ) Subject to PATH Program Disclaimer 總結(jié) ? 肝細胞肝癌在亞洲人群高發(fā) ? 分期多樣化， BCLC分期最為準確 ? 肝細胞肝癌中常常伴有細胞信號傳導通路異常 – 血管生成信號 – Ras/Raf/MEK/ERK – PI3K/Akt/mTOR – Wnt/β catenin ? Sorafenib 是目前唯一證實在晚期肝細胞肝癌患者生存的靶向治療藥物 1 ? 適應性耐藥或原發(fā)耐藥是未來研究重點 ? 一些新靶向藥物在 III期臨床研究中，期待結(jié)果 Subject to PATH Program Disclaimer JM et al. N Engl J Med 2022。 ECOG PS 0–2 Primary end point ? Overall survival Secondary end points ? TTP ? Objective response ? Disease control rate ? Safety Study start date: February 2022 Estimated final analysis: January 2022 R A N D O M I Z A T I O N Setting C: X vs placebo / BSC after sorafenib failure Subject to PATH Program Disclaimer R A N D O M I Z A T I O N 531 patients Everolimus + BSC Placebo + BSC Patients with advanced HCC。 sorafenib failure (or intolerance)。 Child–Pugh class A。 ECOG PS 01 Primary end point ? Overall survival Secondary end points ? TTP ? Objective response Study start date: October 2022 Estimated final analysis: February 2022 R A N D O M I Z A T I O N 方案 A: X vs sorafenib 一線治療 Subject to PATH Program Disclaimer 350 patients Sorafenib + placebo 350 patients Sorafenib + erlotinib Patients with advanced HCC。 no previous treatment。 Child–Pugh class A。 ECOG PS 01 Primary end point ? Overall survival Secondary end points ? PFS ? TTP ? Safety ? Health status Study start date: July 2022 Estimated final analysis: July 2022 R A N D O M I Z A T I O N 方案 A: X vs sorafenib 一線治療 Subject to PATH Program Disclaimer 525 patients Sorafenib 525 patients Brivanib Patients with advanced HCC。 no previous systemic treatment。 Child–Pugh class A。23:50948. Subject to PATH Program Disclaimer 隨機對比 II期臨床研究 60 patients Bevacizumab + erlotinib 60 patients Sorafenib Patients with advanced HCC。27:84350. Subject to PATH Program Disclaimer Thomas MB, et al. J Clin Oncol. 2022。9:14350. Subject to PATH Program Disclaimer 美國肝臟病研究協(xié)會（ AASLD）肝細胞肝癌臨床研究指南 Subject to PATH Program Disclaimer Llovet JM, et al. J Natl Cancer Inst. 2022。 2022 靶向治療前景 “在歐洲和美國已推薦 Sorafenib治療肝細胞肝癌的臨床應用，主要由于其能夠延長患者生存。 177。 STD 177。8:592603. Subject to PATH Program Disclaimer EACH 研究 : 試驗設計 ? 大型、開放、隨機對照、多中心的 Ⅲ 期臨床試驗，包括中國大陸、臺灣，韓國和泰國等 38家中心參與 Arm A (FOLFOX4): OXA 85mg/m2 iv. h0 – h2 Day 1 LV 200mg/m2 iv. h0 – h2 Day 1,2 5FU 400mg/m2 iv. bolus Day 1, 2 then 600 mg/m2 over 22 hours in Day 1 amp。8:592603. 腫瘤血管外周防御細胞增加 Subject to PATH Program Disclaimer Bergers G, Hanahan D. Nat Rev Cancer. 2022。8:592603. Subject to PATH Program Disclaimer Bergers G, Hanahan D. Nat Rev Cancer. 2022。27:331218. Table adapted from Llovet and Bruix, Hepatology 2022. Subject to PATH Program Disclaimer 抗血管生成藥物耐藥方式 適應性 (逃逸 ) 耐藥 原發(fā)無效 Bergers G, Hanahan D. Nat Rev Cancer. 2022。357:266676. 8. Escudier B, et al. N Engl J Med. 2022。353:12332. 6. Slamon et al N Engl J Med. 2022。350:233542. 3. Jonkers et al N Eng J Med 2022. 4. Sandler et al N Engl J Med. 2022。10:2534. Subject to PATH Program Disclaimer 不同靶向藥物治療在實體瘤帶來的獲益 Tumor type or randomized trial(s) Endpoint HR (95% CI) Hepatocellular carcinoma (advanced) ?Sorafenib (n=299) vs placebo (n=303)1 Survival TTP (–) (–) Renal cell carcinoma (advanced) ?Sorafenib (n=384) vs placebo (n=385)8,9 PFS Survival (–) (–) Colorectal cancer (metastatic) ?IFL + bevacizumab (n=402) vs IFL (n=411)2 ?Cetuximab (n=287) vs best supportive care (n=285)3 Survival Survival (NA) (–) Lung cancer ?Pac/carbo + bevacizumab (n=434) vs pac/carbo (n=444)4 ?Erlotinib (n=488) vs placebo (n=243)5 Survival Survival (–) (–) Breast cancer (advanced, HER2+ve) ?Chemo + trastuzumab (n=235) vs chemo (n=234)6 ?Paclitaxel + bevacizumab vs paclitaxel (n=326)7 TTP PFS (–) (–) 1. Llovet et al N Engl J Med. 2022。48:131227. Subject to PATH Program Disclaimer Sorafenib在晚期肝細胞肝癌為標準治療 ? Sorafenib 是第一個也是迄今為止唯一延長肝細胞肝癌患者生存的藥物 – 在西方和東方不同人種、不同病因中得到驗證 – 療效和安全性得到驗證 ? 早期肝細胞肝癌的研究在進行中 ? Sorafenib 在肝細胞肝癌患者的安全性是在可控范圍內(nèi)的 – 不良反應多為中度 – 可預料和可管理的 Llovet JM et al. N Engl J Med. 2022。 June 2022. 2. Llovet JM, et al. N Engl J Med. 2022。26. Abstract 4509. Updated from oral presentation at ASCO。359:37890. Survival probability 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Sorafenib (n=299) = months Placebo (n=303) = months Time from randomization (months) Probability of radiologic progression 0 1 2 3 4 5 6 7 8 9 10 11 12 Sorafenib (n=299) = months Placebo (n=303) = months Time from randomization (months) 0 HR = (95% CI: –) p 0 HR = (95% CI: –) p Overall survival Time to progression (independent central review) Subject to PATH Program Disclaimer Sorafenib p