美国临床肿瘤学会（ ASCO ）年会已经是集参会规模、学术水平和权威性于一体的全球最顶级临床肿瘤学会议。2021年的ASCO年会将于6月4日-8日召开，众多国际前沿和备受关注的临床肿瘤学科研成果和临床数据将进行披露，此前已经公开了大约4600条摘要标题，其中大多数摘要则在今天挂网公布了具体内容。

让我们聚焦ASCO2021，感受全球药物临床研究最新动态和突破进展吧。限于篇幅，本文选取各药物领域部分值得关注的研究进展50篇，更多深度内容分析，将在ASCO2021会议期间通过医药魔方的视频号进行分享和直播。

小分子药物

在小分子药物领域，SHP2和KRAS研发动态在当前备受关注。在ASCO2021大会上， SHP2抑制剂TNO155终将披露初步数据，作为全球首个进入临床的SHP2研究药物，诺华开发的TNO155在临床结果披露方面落后于Revolution的RMC4630，本次TNO155的结果将为我们再次验证SHP2靶标成药性，或许我们也能一窥SHP2抑制剂活性高低对于临床结果的影响。

在KRAS领域，多次吸睛的Sorasasib（AMG510）也将在近期迎来监管决议。其关键临床II研究（CodeBreaK 100）的早期数据已经披露，在ASCO2021上，Sorasasib将为我们带来总生存在和探索性亚组的分析结果等最新临床动态，adagrasib(MRTX849)也不甘寂寞，继续披露III期研究计划。

Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors.

Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutatednon-small cell lung cancer.

Trial in progress: A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, as monotherapy in non-small cell lung cancer(NSCLC) with brain metastasis and in combination with other anticancer therapies in advanced solid tumors (CodeBreaK 101).

KRYSTAL-12: A randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer(NSCLC) with KRASG12C mutation.

EGFR抑制剂一直是关注焦点，特别是奥希替尼的成功，带动了国内新药研发浪潮。阿美替尼作为首个国产EGFR三代药物，ASCO2021会议上将首次披露阿美替尼 vs 吉非替尼的一线PK详细数据。届时，我们在之前的二线对比分析基础上，也将再次对比阿美替尼 vs 奥希替尼一线PK的优劣。

EGFR exon 20抑制剂的开发竞争也日益激烈。武田的TAK-788和Spectrum公司的波齐替尼均已提交了上市申请并被授予快速通道，TAK-788也获得中美双突破性疗法药物认证。国内公司方面，迪哲医药将在ASCO2021首次披露DZD9008的临床数据，再鼎拥有权益的TAS6417也将亮相，君实和微境开发的AP-L1898已经获得国内临床默示许可。

Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).

Preliminary safety and efficacy results from phase 1 studies of DZD9008 in NSCLC patients with EGFR Exon20 insertion mutations.

Safety and activity of CLN-081 (TAS6417) in NSCLC with EGFR Exon 20 insertion mutations (Ins20).

在小分子BTK抑制剂方面，百济神州泽布替尼在美国的成功上市标志着中国创新药走向新阶段。然而，遗憾的是，在两项头对头研究中（WM、CLL）尚未显示PFS优势（CLL中观察到ORR积极信号）。高选择性在安全性上带来的回报能否实现适应症患者群体相较伊布替尼和阿卡替尼的扩增，将进一步决定商业销售的增长；此外，BTK未来的竞争或许也将在药物治疗的经济学评价中展开。

作为第二款上市的BTK抑制剂，阿卡替尼同样未能摆脱伊布替尼的压制，头对头的研究不可避免。而作为“带头大哥”，伊布替尼在ASCO2021也将发布长达7年的随访结果，能否被超越，仍待验证。

Up to seven years of follow-up in the RESONATE-2 study of first-line ibrutinib treatment for patients with chronic lymphocytic leukemia.

First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia.

Abstract e18856: Cost-effectiveness of zanubrutinib versus ibrutinib inadult patients with Waldenström macroglobulinemia in the United States

Abstract e19506: Preliminary results of the phase 2 study of zanubrutinib in patients with previously treated B-cell malignancies intolerant to ibrutinib and/or acalabrutinib.

CDK4/6抑制剂领域，辉瑞的哌柏西利和礼来的阿贝西利均已在国内上市，恒瑞的SHR6390则在2021年4月成为首个申报上市的国产CDK4/6抑制剂；并且，SHR6390也被授予突破性治疗药物，上市申请同步纳入优先审评。突破性治疗药物是国家药监局执行的适用于药物临床试验期间，对防治严重危及生命的疾病或者严重影响生存质量，且尚无有效防治手段或者与现有治疗手段相比有充分证据表明具有明显临床优势的创新药或改良型新药，授予该认证是对疗效的认可荣誉。SHR6390，早期仅公告了取得阳性结果而未披露详细数据，在本届ASCO会议上，或将一起见证突破性进展。

2020年底，阿贝西利在国内获批上市，虽然晚于哌柏西利，但得益于其在早期乳腺癌中的临床获益得到验证，ASCO2021会议期间,也将披露中国亚组的临床研究数据，或许将展现不一样的风采；哌柏西利和瑞波西利继续更新临床Ⅲ期研究的OS数据。除此之外，乳腺癌领域多个选择性ER降解剂药物（LY3484356、G1T48、AZD9833、SAR439859、GDC-9545等），也将亮相ASCO2021。

Dalpiciclib versus placebo plus fulvestrant in HR+/HER2- advanced breastcancer that relapsed or progressed on previous endocrine therapy (DAWNA-1): Amulticenter, randomized, phase 3 study.

Efficacy and safety analysis of Chinese patients in monarchE: Abemaciclib combined with adjuvant endocrine therapy for high risk HR+, HER2- early breast cancer.

Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3.

Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer(ABC) treated with fulvestrant (FUL) ± ribociclib (RIB).

上述药物之外，百济神州近期获批的PARP抑制剂帕米帕利也将发布2项临床研究数据、信达引进的FGFR抑制剂Pemigatinib中国患者数据以及更新的胆管癌FIGHT-202研究数据也将亮相、诺诚健华的ICP-192首次披露相关研究数据。

在成熟靶标之外，ASCO2021也将公布多个创新靶标研究药物的临床动态，包括复星弘创靶向IRE1的First-in-calss药物ORIN1001、RAD51抑制剂CYT-0851、PARP7抑制剂RBN-2397、SAE抑制剂TAK-981、ALK5抑制剂vactosertib、RSK抑制剂PMD-026以及肝癌新靶标PPT1抑制剂GNS561等。

ADC药物

ADC药物已经全面进入发力阶段，药物进展应接不暇。ASCO2021上的ADC药物必将引人瞩目。

1. Her2 ADC

Enhertu（trastuzumabderuxtecan，DS-8201、T-Dxd）的成功将ADC带入新高度，适应症开发也是涉及了乳腺癌、肺癌、胃癌、结直肠癌、三阴乳腺癌和尿路上皮癌等多个瘤种。在ASCO2021上，Enhertu也是带来多项研究进展，其中不乏首次或最终数据，仍然值得围观。

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01).

Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breastcancer with brain metastases: A subgroup analysis of the DESTINY-Breast01 trial.

Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced ormetastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07).

Trastuzumabderuxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric orgastroesophageal junction (GEJ) adenocarcinoma: Final overall survival(OS) results from a randomized, multicenter, open-label, phase 2 study(DESTINY-Gastric01).

Aphase 2, multicenter, open-label study evaluating trastuzumab deruxtecan(T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01).

Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2study (DESTINY-CRC02)

恩美曲妥珠、Enhertu之外，国内Her2 ADC药物也渐入佳境。荣昌生物的纬迪西妥单抗（RC48）成为国内第二款提交上市的Her2 ADC药物，东曜药业的TAA013也已进入Ⅲ期研究、新码生物的ARX788已经突破性疗法公示，石药（DP303c）、恒瑞（SHR-A1811/SHR-A1201）、科伦博泰（A166）、美雅珂等也有相关布局。在ADC药物和技术突破之时，国内ADC药物临床数据也在登上国际舞台。

RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: Apooled analysis of two studies.

RC48-ADC combined with toripalimab, an anti-PD-1 monoclonal antibody(Ab), in patients with locally advanced or metastatic urothelial carcinoma(UC): Preliminary results of a phase Ib/II study

Safety of trastuzumab emtansine (T-DM1) in patients (pts) withHER2-positive locally advanced or metastatic breast cancer (mBC): Final resultsfrom KAMILLA Cohorts 1 (global) and 2 (Asia)

A phase 1 multicenter, dose expansion study of ARX788 as monotherapy inpatients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma (ACE-Gastric-01)

Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC,in heavily pretreated patients with HER2-overexpresing solid tumors: Resultsfrom two phase 1 clinical trials.

Phase I study of A166 in patients with HER2-expressing locally advancedor metastatic solid tumors.

2. TROP2 ADC

虽然第一三共的DS-1062已经不是首个上市的TROP2 ADC药物，但将TROP2靶标带进公众视野，DS-1062也有一份功劳。ASCO2021会议上，将再次公布DS-1062临床进展。而首个上市的TROP2 ADC药物戈沙妥组单抗，也将在ASCO舞台再次亮相。

A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) versus docetaxel in previously treated advanced or metastatic non-small celllung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01).

TROPION-PanTumor01: Dose analysis of the TROP2-directed antibody-drugconjugate (ADC) datopotamab deruxtecan (Dato-DXd, DS-1062) for the treatment(Tx) of advanced or metastatic non-small cell lung cancer (NSCLC).

Phase III postneoadjuvant study evaluating sacituzumab govitecan, anantibody drug conjugate in primary HER2-negative breast cancer patients withhigh relapse risk after standard neoadjuvant treatment: SASCIA

3. Her3 ADC

Her3 ADC在研药物较少，第一三共的U3-1402彰显不俗潜力，尤其在对EGFR抗性治疗中。早期的研究数据已经展现了针对不同EGFR 抗性机制的治疗效果，包括C797S。ASCO2021会议上，patritumab deruxtecan（U3-1402，HER3-DXd）再次公布临床动态。

Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC).

HERTHENA-Lung01: A randomized phase 2 study of patritumab deruxtecan(HER3-DXd) in previously treated metastatic EGFR-mutated NSCLC.

Cldn18.2、Muc1和FRα也是ADC药物涉及较多的靶标，特别是FRα，在本届会议上将有多个药物披露动态，包括华东医药拥有国内权益的mirvetuximabsoravtansine (IMGN853)。

在ADC领域，解决了技术问题之后，最关键的将是创新靶标的发现，并为全身暴露存在缺陷的药物提供新的技术路线。不过，新技术的发展并不会停歇，抗体偶联药物之后，多肽偶联药物也在不断出现，不妨在ASCO一睹风采。

A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) endometrial cancer (EC)

Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients(pts) with platinum-agnostic ovarian cancer: Final analysis.

Phase 1 dose-escalation study of STRO-002, an antifolate receptor alpha(FRα) antibody drug conjugate (ADC), in patients with advanced, progressive platinum-resistant/refractory epithelial ovarian cancer (EOC).

Preliminary results from a phase 1/2 study of BDC-1001, a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), in patients(pts) with advanced HER2-expressing solid tumors.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

Association of combined phase I/II study of a novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies with Nectin-4expression.

A phase 1 study of TAK-164, an anti-guanylyl cyclase C (GCC)antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal(GI) cancers expressing GCC.

A phase 1b, open-label, single-arm study of cofetuzumab pelidotin (aPTK7-targeting antibody-drug conjugate) in patients with PTK7-expressing, recurrent non-small cell lung cancer (NSCLC).

抗体药物

PD-1/L1药物无疑为抗体领域最为成功的药物代表，也难免引来红海竞争，全球药企对创新靶标的渴望与日俱增。近期，百时美施贵宝（BMS）2亿美元首付款引进双特异性抗体AGEN1777，再次将TIGIT引入大众视野。然而，TIGIT 抗体的单药活性仍令人怀疑，继去年罗氏ASCO会议之后，百济神州的Ociperlimab等药物能否在今年ASCO会议再次证明TIGIT等创新靶标；ICOS激动药物在vopratelimab 和Feladilimab失败之后，是否仍有曙光，静待药物进展为我们揭秘。总之，PD-1/L1之后，创新靶标路途之艰难，不免略感路漫漫其修远兮之悲壮。

AdvanTIG-302: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (OCI) plus tislelizumab (TIS) versus pembrolizumab (PEM) in programmed death ligand-1(PD-L1) selected, previously untreated, locally advanced, unresectable ormetastatic non-small cell lung cancer (NSCLC)

A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, inadult patients with advanced malignancies.

Abstract e16228: Safety, tolerability and preliminary efficacy of CAN04, a first in class monoclonal antibody against IL1RAP, in combination with nab-paclitaxel and gemcitabine (NG) in subjects with pancreatic cancer

双特异性抗体（Bispecific Antibody，双抗）是利用一个抗体分子结合两种不同抗原或同一抗原的两个不同表位，实现的一种新的创新药物形式。早期的双抗药物，甚至在贝林妥欧单抗上市之后，也未太多激起双抗药物的研发热情。反倒是，PD-1药物的红海竞争以及可能的双机制协同作用，加速了双抗药物的研发热情，而Amivantamab的成功再次注下强心剂。不过，在TGFBR2/PDL1抗体融合药物Bintrafusp alfa（M7824）的接连失败之后，PD-1/L1与各种创新机制联合的双抗药物能否走出阴霾，仍待进一步临床验证。

ASCO2021会议上，Amivantamab、zenocutuzumab、Zanidatamab等也将带来新的数据分析或临床研究动态。

A large real-world study on the effectiveness of the combined inhibition of EGFR and MET in EGFR-mutant advanced non-small cell lung cancer (NSCLC).

Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: PALOMA, an open-label, multicenter, dose escalation phase 1b study.

Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small celllung cancer (NSCLC) and potential biomarkers for response.

Amivantamab compared with real-world therapies in patients with NSCLCwith EGFR Exon 20 insertion mutations who have progressed after platinumdoublet chemotherapy.

Efficacy and safety of zenocutuzumab in advanced pancreas cancer andother solid tumors harboring NRG1 fusions.

Zanidatamab, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

A phase I/II, multicenter, open-label study of REGN5668 (mucin [MUC]16 xCD28 bispecific antibody [bsAb]) with cemiplimab (programmed death [PD]-1 Ab) or REGN4018 (MUC16 x CD3 bsAb) in recurrent ovarian cancer (rOVCA)

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