【文章內容簡介】 PATH Program Disclaimer ? HBV ? HCV ? 酒精 ? 黃曲霉毒素 B1 損傷 干細胞增殖停止 星形細胞活化 慢性肝病 Liver cirrhosis Abnormal liver nodules Extensive scarring (collagen) 染色體不穩(wěn)定 染色體重度不穩(wěn)定 和 P53缺失 Hepatocellular carcinoma 幼稚細胞結節(jié) Hyperplastic nodule 分化好的 中等分化的 分化差的 增殖 壞死 Farazi PA, DePinho RA. Nat Rev Cancer. 2022。6:67487. 肝細胞肝癌的組織病理學和分子病理學特征 Subject to PATH Program Disclaimer 肝硬化 廣泛瘢痕形成 肝臟結節(jié)形成 結節(jié)增生 肝細胞肝癌 肝細胞肝癌的發(fā)病機制與多個信號傳導通路相關 細胞膜 cMYC cJUN Wnt 受體 BcLXL BAD ERK1/2 MEK1/2 βcatenin GSK3β GBP DSH HBx Akt mTOR Raf PKC NF?B Ras NF?B PLCε SHC GrB2 GEF PI3K PTEN p53 生存 l 轉錄和翻譯 βcatenin HBx RTK: FGFR EGFR IGFIR cMET 受體 r Adapted from Avila MA, et al. Oncogene. 2022。25:386684. Subject to PATH Program Disclaimer 肝 細 胞肝癌的分子學 發(fā) 病機制 ? 肝細胞肝癌的發(fā)病機制與多個信號傳導通路相關 – 肝細胞惡變是基于炎癥、細胞再生、細胞增生、肝硬化、遺傳、后天因素等 ? 肝 細 胞肝癌多伴有 細 胞信號通路失 調 ，主要包括： 1,2 – 血管生成信號 – Ras/Raf/MEK/ERK – PI3K/Akt/mTOR – Wnt/βcatenin 分子治療的主要靶點 1. Theirsson S, et al. Hepatology. 2022。43:S14550. 2. Avila MA, et al. Oncogene. 2022。25:386684. Subject to PATH Program Disclaimer 肝細胞肝癌靶向治療 :臨床研究 ? 肝細胞肝癌臨床研究全面展開 ? Sorafenib 的有效性，引發(fā)靶向治療臨床研究 ? 主要在早期和晚期患者臨床研究， 一線治療、二線治療及輔助治療方面的研究 Llovet JM , Bruix J. J Clin Oncol. 2022。27:83335. Subject to PATH Program Disclaimer Adapted from Tanaka S, Arii S. Cancer Sci. 2022。100:18. 臨床開發(fā) : 分子靶向藥物和其主要靶點 Agent 抗血管生存 抗增殖 VEGF VEGFR PDGFR EGFR Raf mTOR Bevacizumab ● Cediranib ● ● Thalidomide ● Erlotinib ● Gefitinib ● ABT869 ● ● Sorafenib ● ● ● Lapatinib ● Sunitinib ● ● Cetuximab ● Brivanib ● SU6668 ● ● Everolimus ● Subject to PATH Program Disclaimer Agent 抗生成血管 抗增殖 VEGF VEGFR PDGFR EGFR Raf mTOR Bevacizumab ● Cediranib ● ● Thalidomide ● Erlotinib ● Gefitinib ● ABT869 ● ● Sorafenib ● ● ● Lapatinib ● Sunitinib ● ● Cetuximab ● Brivanib ● SU6668 ● ● Everolimus ● III期臨床研究 :分子靶向藥物和其主要靶點 Sorafenib targets both tumorcell proliferation and angiogenesis in vitro KIT/Flt3/ RET Angiogenesis Raf Endothelial cell or pericyte Nucleus VEGFR2 PDGFRβ MEK Apoptosis Tumor cell Proliferation PDGF VEGF EGF Survival Wilhelm SM, et al. Cancer Res. 2022。64:7099109 . Ras Nucleus Ras ERK Raf MEK Apoptosis ERK PDGFβ VEGF Paracrine stimulation Sorafenib X X X X X X X X Subject to PATH Program Disclaimer Primary endpoints: OS, TTSP Secondary endpoints: TTP, DCR, safety Phase III SHARP and Asia–Pacific studies Eligibility ? Advanced HCC, ECOG PS 0–2, ChildPugh A, no prior systemic therapy Stratification ? MVS and/or EHS, ECOG PS (0 vs 1–2), geographic region RANDOMIZE 1:1 SHARP1 Asia–Pacific2 RANDOMIZE 2:1 Sorafenib 400 mg bid Placebo Sorafenib 400 mg bid Placebo Endpoints: OS, TTSP, TTP, DCR, safety (no primary endpoint defined) n=299 n=303 n=150 n=76 1. Llovet JM, et al. N Engl J Med 2022。359:37890. 2. Cheng AL, et al. Lancet Oncol 2022。10:2534. Subject to PATH Program Disclaimer Sorafenib consistently increased overall survival in different global patient populations HR = hazard ratio。 OS = overall survival。 SHARP = Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol. Llovet JM et al. N Engl J Med. 2022。359:37890. Cheng AL, et al. Lancet Oncol. 2022。10:2534. ?Survival probability Months 0 4 6 8 10 12 14 16 2 Sorafenib (n=299) Median OS: months Placebo (n=303) Median OS: months 18 ?HR = Survival probability Months 0 4 8 12 22 Sorafenib (n=150) Median OS: months Placebo (n=76) Median OS: months 2 6 10 14 16 18 20 HR = ?SHARP1 ?Asia–Pacific 2 Subject to PATH Program Disclaimer AsiaPacific (N=226) SHARP (N=602) Median age (range), years 51 (2386) 67 (2189) Sex (male), % 85 87 ECOG PS (0/1/2), % 26/69/5 54/38/8 MVI, % 35 38 EHS, % 69 51 BCLC stage (B/C), % 4/96 17/82 Hepatitis virus status (HBV/HCV), % 73/8 18/28 No. of tumor sites, % 1 11 44 2 35 31 3 20 12 ≥4 35 13 Sites of disease, % Lung 50 21 Lymph node 32 26 Asia–Pacific trial1 vs SHARP2: baseline patient characteristics 1. Cheng A, et al. J Clin Oncol. 2022。26. Abstract 4509. Updated from oral presentation at ASCO。 Chicago, IL。 June 2022. 2. Llovet JM, et al. N Engl J Med. 2022。359:37890. Subject to PATH Program Disclaimer SHARP: sorafenib prolongs OS by 44% and TTP by 74% in patients with advanced HCC Llovet JM, et al. N Engl J Med. 2022。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 prolongs OS by 47% and TTP by 74% in Asia–Pacific patients with advanced HCC Cheng AL, et al. Lancet Oncol. 2022。10:2534. Overall survival Time to progression Sorafenib Median: months (95% CI: –) Placebo Median: months (95% CI: – Sorafenib