《：胆道恶性肿瘤的靶点及耐药机制.docx》由会员分享，可在线阅读，更多相关《：胆道恶性肿瘤的靶点及耐药机制.docx（8页珍藏版）》请在taowenge.com淘文阁网|工程机械CAD图纸|机械工程制图|CAD装配图下载|SolidWorks_CaTia_CAD_UG_PROE_设计图分享下载上搜索。
1、iCCAFusiorn： APAlVRO31/ReT/NRG15MResistance mutationsFGFR2 fuskxn: FGFRm eg V$4F. N549HI0H1 muSRMa: lOtHm og 阳7N. QH2meCCA & GBCamp (1020%) 丫KRASGI2C5%PlK3CAm 10% XXX/ SO*MSIHTRK5%1.现有的可治疗的BTC靶点及已知的耐药突变最新：胆道恶性肿瘤的靶点及耐药机制胆道恶性肿瘤（BTCs ）通常按解剖部位分为胆囊癌、肝门部胆管癌、远端胆管癌和肝内胆管癌（iCCA）0然而，从综合组学分析中可以清 楚地看到，每种类型的BTCs都
2、有其独特的基因型和不同的肿瘤微环 境。来自加拿大玛格丽特公主癌症中心的Jennifer Knox教授、Grainne 0 Kane教授、Cha Len Lee博士对BTCs的治疗靶点及耐 药机制进行了阐述。肝内胆管癌（iCCA）的发病率正在增加，部分原因是诊断方法的改进。 在iCCA患者人群中，主要是在小导管iCCA人群，可发现大多数可操 作的基因改变，这些突变基因包括突变、FG尸/?2融合和几种肿 瘤不知情（Tumor-agnostic ）的生物标志物（图1 ）。与大导管iCCA 患者相比，这些患者的预后更佳，而大胆管iCCA突变谱类似于肝外 CCA （ eCCA ）,以7253失;舌突变和
3、突变为主。XXX/Mutations: IDH1 - 15-20% 8RAF 5-9% 8RCA 5% PIK3CA1OH MMR 90ng second line)HER2 amplificationsNCTO4466891 (HERIZON-BTC-01)2b, single armZanidatamab (ZW25)HER2 amplificationsNCT0341092/711/2, multicohortTAS0728HER2 amplificationsNCT036020791/2, multicohortA166HER2 amplificationsNCTO44307381b/
4、2, multicohortTucatinib + trastuzumabHER2 amplificationsNCT043294292, single armRC48-ADCAdditional targets2 Second lineNTRK 1/3 fusionsNCTO2576431 (NAVIGATE)2, multicohortLarotrectinibROS1 translocationsNCTO4439253 (MATCHY)2, multicohortCrizotinib2 Third linePTEN mutation/deletionNCT033453033, singl
5、e armBortezomibMDM2 amplification ( third line)MDM2 amplificationNCT05012397( MANTRA-2)1912, multicohortMilademetanm期ClarlDHy试验招募了 187例先前接受过治疗的突变iCCA患者，结果显示，接受抑制剂ivosidenib治疗组患者的无进展生存（PFS ）为2.7个月，而安慰剂组为1.4个月（HR 0.37 ; 95%CI : 0.25-0.54 ; A0.001）。重要的是，调整交叉治疗后的总生存得到改 善，与健康相关的生活质量也有所提高口叫令人失望的是Jvosideni
6、b在iCCA中似乎具有细胞抑制作用（总缓解率ORR为2%）,存在发 生早期耐药的风险（图1 ）。这一领域的药物开发主要集中在靶向多 个0A7/2突变的更有效的药物以及组合策略上。尸GFR2融合于2013年被首次描述 截至2022年9月，已有3种FGFR 抑制剂获得FDA批准。Pemigatinib （已获欧洲药品管理局批准）和 infigratinib是靶向FGFR1至FGEA3的选择性可逆性尸GFR2抑制剂， 但对尸3/7?4的抑制活性较弱【11,12,制造商将不再生产Infigratinb。Futibatinib是一种靶向FGFR1至FG尸7?4的不可逆的FGFZ?抑制剂， 于2022年9
7、月获得FDA批准口引。尸G尸应融合往往与98/?/尸突变不同时存在，但可与IDH1突变共同发生。靶向FG6?2融合的治疗ORR约为20%40%,+PFS 为59个月（表2 ） 口。-27。这些药物的副作用包括高磷血症、手足 综合征、指甲变化、轻度胃肠不适和眼病。与其他实体肿瘤的情况一 样，对这些酪氨酸激酶抑制剂的原发和获得性耐药比较常见。研究人 员已经证实FG尸应含有一种门控突变以及多克隆尸6尸/?2突变28,2叫 有趣的是，在ESMO 2022年会上公布的REFOCUS试验显示，17例 患者接受所推荐的RLY-4008的口期剂量治疗，其ORR为88%【21。 RLY-4008是一种高选择性和
8、不可逆的尸G6?抑制剂，靶向FGFR2融合和耐药机制，进一步的数据有待公布RI FG&?抑制剂目前正在一 线治疗中接受评估（表1）今叫表2.可采用FDA批准的二线药物治疗的生物标志物I Biomarkers wlh FDA approved agents available in 2 second-line settingBiomarkersAgentThal (study design)Outcomes in BTCPemigatin*)FIGHT-202 （2.小中皿尸；ORR 36%: OS 21 moFGFR2 fusion” mutatiomIMigratjnibCBGJ398X22
9、O4(2. tingto arm)FOENDMJCA2(2 singleORR 23%(production ends 04 2022)FutJbaUnibORR 42%: OS 22 moDH1 mutatxxisFvos denibClariD 用 (3placetxxontroledf01ORR 2%; OS 10 moBRAFVB006 mutationDabrafenib trame&nibbROAR4 (2. mufccohort) KEYNOTE-158 (2. smgte arm)l,s：ORR 51%MS中dKt乐Pombfolaumab1IORR 58%; OS 24 mo
10、DostarhmabGARNET(Lmutocohortp 电ORR 42%(pooled data across tumor types)TMB 10m ut/M)PembrolizumabKEYNOTE-158 (2. smgte arm)1 电ORR 5 8%; OS 24 moWTRK1/3KmkxwUrotrectm*LOXO-TRK-140011,7 . scouf1* (1/2, mufticohort)ORR 75%(pooled data evoked 2 CCA)EntrocbrMb STARTRK.1(NCT02097810).STARTRK-2NCTO2568267).
11、 (1/2. mufticohort)ORR 57%(pooled data invoked 1 CCA) RET ftjstonsSelpercatribLRCTTO-001(NCT03157120) (1/2. mulbcohort)ORR 44%; 03 18 mo (poolod data with 2 CCA)Additrool agents/biocnafkers with supported data in BTC in 2 second-line settingFGFR2 fusionfmut3tionsDerazantmibFDESXJ1,10 mut/mb )的BTCs患者
12、是PD-1抑制剂治 疗的候选人群，可能占所有病例的比例不到5%。NTRK和RET融合 同样代表了肿瘤不知情的生物标志物，FDA已批准拉罗替尼 (Larotrectinib )、恩曲替尼(Entrectinib )以及 selpercatinib 用 于该类肿瘤患者的治疗。04其他预测性生物标志物所报道的BTCs的其他融合基因包括ROS1/ALK和NRG1 ,所有这些都有可及的治疗方法。BRCA相关或同源重组缺陷的BTCs不常见， 这类BTCs类似于其他肿瘤类型，可能从粕类或PARP抑制剂治疗中 获益。Adagrasib (阿达拉西布)是一种KRAS G72U共价抑制剂，在含有这种罕见突变等位基
13、因的胰腺癌和胆道癌中显示出良好前景,RAS特异性和泛RAS抑制剂的开发已经取得了巨大进展26。未来机遇BTCs已被广泛定义为一种免疫“冷”肿瘤,在BTCs治疗中需要精确的 免疫肿瘤学方法的生物标志物。综合分析表明，在西方和亚洲的BTCs 人群中都有炎症聚集，这或许可以预测免疫检查点抑制剂治疗反应 31,32。值得注意的是，GBC可能比iCCA更容易有炎症反应，癌基因 驱动的iCCA毫无疑问具有较低的免疫细胞负担。多项正在进行的试 验正在评估免疫检查点抑制剂组合在BTCs中的疗效。未来我们将会看到更多的使用ctDNA来识别靶点，而且可能更早地 识别BTCs治疗的靶点。值得注意的是，如果不使用合适
14、的平台FGFR2 融合可能更难在ctDNA中识别33。更重要的是,ctDNA允许我们跟 踪其克隆进展随时间推移的变化，并可能成为基于耐药性改变的出现 而进行顺序治疗的一种途径。总结鉴于高达50%的胆道恶性肿痼BTCs )患者具有可操作的体细胞突变， 肿瘤或液体活检应常规用于BTCso三种尸GER2抑制剂和一种IDH1 抑制剂已获得美国食品药品管理局批准用于BTCs的治疗。BTCs靶向 治疗耐药极其常见，为取得BTCs治疗的更大进展，需要更有效的药 物以及组合或序贯治疗策略。了解与不同分子谱相关的肿瘤微环境可 能有助于开发新的免疫治疗策略。参考文献1 .Valle J, Wasan H, Pal
15、mer DH, et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.2.Oh D-Y, Ruth He A, Qin S, et al; TOPAZ-1 Investigators. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 202
16、2;1 (8):EVIDoa220001 5.3.Bunse L, Pusch S, Bunse T, et aL Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018;24(8):1192-1203.4.Bekaii-Saab TS, Valle JWZ Cutsem EV, et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced ch
17、ola ng iocarci noma with FGFR2 rearrangements. Future Oncol. 2020;16(30):2385-2399.5.Borad MJ, Bridgewater JA, Morizane C, et al. A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1 L) treatment for patients (pts) with advanced (adv) cholan
18、giocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3).J Clin Oncol. 2020;38(suppl 4):TPS600.6 .Ali A, DeRemer DL, Lee J-H, et al. Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neopla
19、sms (NCT03207347).J Clin Oncol. 2020;38(suppl 15):e22061.7 .Piha-Paul SA, Azaro A, Arkenau HT, et al.Invest New Drugs. 2021;39(5):1 324-1334.8 .Mansfield AS, Wei 乙 Mehra R, et al. Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.NPJ Precis Oncol. 2022;6(
20、1 ):13.9 .Dumbrava EE, Hanna GJ, Cote GM, et al. A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2).J Clin Oncol. 2022;40(suppl 16):TPS3165.10 .Zhu AX, Macarulla T, Javle MM, et al. Final overall surviva
21、l efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarlDHy trial.JAMA Oncol. 2021 ;7(11 ):1669-1677.11 .Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cho
22、langiocarcinoma: a multicentre, open-label, phase 2 study.Lancet Oncol. 2020;21 (5):671-684.12 .Javle M, Roychowdhury S, Kelley RK, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a m
23、ulticentre, open-label, single-arm, phase 2 study.Lancet Gastroenterol Hepatol. 2021;6(10):803-815.13 .Goyal Lf Meric-Bernstam F, Hollebecque A, et al. Updated results of the FOENIX-CCA2 trial: efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearr
24、angements.J Clin Oncol. 2022;40(suppl 16):4009.14 .Subbiah V, Lassen U, Elez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.Lancet Oncol. 2020;21 (9):1 234-1243.15 .Marabelle A, Le DT, A
25、scierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.J Clin Oncol. 2020;38(1):1-10.16 .0aknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti-
26、programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial.JAMA Oncol. 2020;6(11):1766-1772.17 .Hong DS, Bauer TM, Lee J J, et al. Larotrectinib in adult patients with solid tumours:
27、a multi-centre, open-label, phase I dose-escalation study.Ann Oncol. 2019;30(2):325-331.18 .Laetsch TS, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.Lancet Oncol. 2018;19(5):7
28、05-714.19 .Mazzaferro V, El-Rayes BF, Dit Busset MD, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cho la ng iocarci noma. Br J Cancer. 2019;120(2):165-171.20 .Guo Y, Yuan C, Ying J, et al. Phase I result of ICP-192 (gunagratinib), a highly selective
29、 irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations.J Clin Oncol. 2021;39(suppl 15):4092.21 .Hollebecque A, Borad M, Goyal L, et al. LBA12 Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangem
30、ent (f/r), FGFR inhibitor (FGFRi)-naTve cho la ng iocarci no ma (CCA): ReFocus trial.Ann Oncol. 2022;33(suppl 7):S1381.22 .Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positivez metastatic biliary tract cancer (MyPathway): a multicentrez open-label, phase 2a, multiple baske
31、t study.Lancet Oncol. 2021;22(9):1290-1300.23 .0hba A, Morizane C, Kawamoto Y, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase II study (HERB trial)J Clin Oncol. 20
32、22;40(suppl 16):4006.24 .Carrizosa DR, Burkard ME, Elamin YY, et al. CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions.J Clin Oncol. 2022;40(suppl 16):3006.25 .Schram AM, Drilon AE, Macarulla T, et al. A phase II basket study of MCLA-128, a bispecific antib
33、ody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors.J Clin Oncol. 2020;38(suppl 15):TPS3654.26 .Bekaii-Saab TS, Spira AI, Yaeger Rz et al. KRYSTAL-1: updated activity and safety of adagrasib (MRTX849) in patients (Pts) with unresectable or metastatic pancreatic cancer (PDAC
34、) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation J Clin Oncol. 2022;40(suppl 4):519.27 .Le DTZ Uram JN, Wang H, et aL PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015;372(26):2509-2520.28 .Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary FGFR2 mut
35、ations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive chola ng iocarci noma.Cancer Discov. 2017;7(3):252-263.29 .Vogel A, Segatto O, Stenzinger A, Saborowski A. FGFR2 inhibition in chola ng iocarci noma. Annu Rev Med. Published online September 28, 2022.30 .Meric
36、-Bernstam F, Beeram M, Hamilton E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.Lancet Oncol. 2022;23(12):1 558-1 570.31 Jusakul A, Cutcutache 1, Yong CH,
37、 et aL Whole-genome and epigenomic landscapes of etiologically distinct subtypes of chola ng iocarci no ma.Cancer Discov. 2017;7(10):1116-1135.32 .Mody K, Jain P, El-Refai SM, et al. Clinical, genomic/ and transcriptomic data profiling of biliary tract cancer reveals subtype-specific immune signatures.JCO Precis Oncol. 2022;6(6):e2100510.33 .Berchuck JE, Facchinetti F, DiToro DF, et al. The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer.Ann Oncol. Publi