A Randomized, Phase 3 Study of Poziotinib in Previously Treated Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring HER2 Exon 20 Mutations (PINNACLE)

The primary purpose of this study is to compare the progression-free survival (PFS) in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) exon 20 mutations when treated with poziotinib versus docetaxel.

开始日期2022-05-12

申办/合作机构

Spectrum Pharmaceuticals, Inc.

NCT05045404

/ Withdrawn临床2期IIT

A Phase II Study of Poziotinib and Ramucirumab in EGFR Exon 20 Mutant Advanced Non-small Cell Lung Cancer (NSCLC)

This phase II trial tests whether poziotinib and ramucirumab work to shrink tumors in patients with EGFR Exon 20 gene mutant stage IV non-small cell lung cancer. Poziotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ramucirumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving poziotinib and ramucirumab may help to control the disease.

开始日期2021-06-16

申办/合作机构

The University of Texas MD Anderson Cancer Center

100 项与波齐替尼相关的临床结果

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100 项与波齐替尼相关的转化医学

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100 项与波齐替尼相关的专利（医药）

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163

项与波齐替尼相关的文献（医药）

2026-01-01·Journal of Thoracic Oncology

Loss of Payload Sensitivity and Other Mechanisms of Resistance to T-DXd in HER2-Mutant NSCLC: Implications for Subsequent Responsiveness to HER2 TKIs

Article

作者: Kittler, Ralf ; Kumar, Ashwani ; Heymach, John V ; Esfahani, Mohammad Shahrokh ; Jun, Soyeong ; Kang, Xiaoman ; Poteete, Alissa ; Shibata, Yuji ; Wakelee, Heather ; Wang, Jing ; Mutter, Jurik ; Huo, Xiaofang ; Ren, Xiaoyang ; Sugio, Takeshi ; Wang, Rui ; Oguchi, Kei ; Le, Xiuning ; Soltys, Scott ; Diehn, Maximilian ; Liu, Ximeng ; Tran, Hai ; Almanza, Diego ; Minamiguchi, Kazuhisa ; Nilsson, Monique B ; Huang, Qian ; Yu, Xiaoxing ; He, Junqin ; Xi, Yuanxin ; Alizadeh, Ash A ; Hong, Lingzhi ; Moran, Cesar ; Weipert, Caroline M

INTRODUCTION:

Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.

METHODS:

Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches.

RESULTS:

We determined that acquired resistance to T-DXd could occur through multiple mechanisms including payload resistance which could be mediated by SFLN11 loss and copy number gains in the efflux pump ABCC1/MRP1. Moreover, T-DXd resistance could be mediated by secondary HER2 extracellular mutations in domain IV, the trastuzumab binding site. Tumor cells with acquired payload resistance or domain IV mutations maintained HER2 signaling and remained sensitive to HER2 TKIs, including zongertinib or poziotinib. Likewise, patients with HER2-mutant NSCLC treated with poziotinib demonstrated similar response rates regardless of prior T-DXd.

CONCLUSIONS:

In patients with HER2-mutant NSCLC, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.

2025-07-28·Cureus Journal of Medical Science

Targeted Therapy in HER2 Exon 20-Mutant Non-small Cell Lung Cancer With Leptomeningeal Disease: A Case-Based Approach to Treatment Decision-Making

Article

作者: Elzaafarany, Osama

A rare and clinically challenging case of leptomeningeal disease (LMD) secondary to HER2-mutated non-small cell lung cancer (NSCLC), marked by both exon 20 insertion and gene amplification, is presented. In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, treatment was initiated with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. The patient, a 69-year-old woman with good performance status, developed LMD following prior systemic therapy and local CNS treatments. MRI and CSF cytology confirmed the diagnosis. Given the lack of approved therapies for HER2-mutant NSCLC with LMD, the treatment strategy was informed by available clinical data and supporting literature on the CNS activity of Enhertu. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations.

2025-07-15·Cancer Research and Treatment

Clinical Impact of TP53 Mutations in Patients with Head and Neck Cancer Who Were Treated with Targeted Therapies or Immunotherapy

Article

作者: Hye Ryun Kim ; Sang-Gon Park ; Keun-Wook Lee ; Yun-Gyoo Lee ; Sung-Bae Kim ; Hwan Jung Yun ; Sangwoo Kim ; Seung Taek Lim ; Seong Hoon Shin ; Min Kyoung Kim ; Hyun Woo Lee ; Eun Joo Kang ; Yoon Hee Choi ; Jong-Kwon Choi ; Shinwon Hwang

Purpose Tumor suppressor p53 (TP53) mutations are common in head and neck squamous cell carcinoma (HNSCC). We evaluated their clinical impact in patients treated with targeted agents or immunotherapy in the KCSG HN15-16 TRIUMPH trial.Materials and Methods We analyzed clinical characteristics and outcomes of patients with TP53 mutations in the TRIUMPH trial, a multicenter, biomarker-driven umbrella trial in Korea. Patients were assigned to treatment groups based on genomic profiles: group 1, alpelisib; group 2, poziotinib; group 3, nintedanib; and group 4, abemaciclib. If there was no identifiable target, the patients were allocated to group 5 (durvalumab±tremelimumab).Results TP53 mutations were detected in 116/179 patients (64.8%), more frequently in human papillomavirus–negative and non-oropharyngeal cancers. Patients with TP53 mutations exhibited shorter progression-free survival than TP53 wild-type in all the patients (1.7 vs. 3.8 months, p=0.002) and in those who received targeted treatments (2.5 vs. 7.3 months, p=0.009). Furthermore, TP53 mutations were strongly associated with poor overall survival than TP53 wild-type in all the patients (11.1 vs. 28.8 months, p=0.005) and in group 5 (8.1 vs. 33.0 months, p=0.001).Conclusion TP53 mutations were associated with aggressive clinical characteristics and poor survival, particularly in HNSCC patients treated with immunotherapy.

107

项与波齐替尼相关的新闻（医药）

2026-06-12

·DMH数字医健科创

【文献解读107】HER2突变非小细胞肺癌的治疗：下一个突破点

导语 HER2基因突变曾长期被视为非小细胞肺癌（NSCLC）中的“冷门”靶点，发生率仅约1%-4%，且其特征性的第20号外显子插入突变导致了对传统非选择性酪氨酸激酶抑制剂（TKI）的原发性耐药。长期以来，含铂化疗是其标准治疗，患者预后不佳。近年来，随着以T-DXd（DS-8201）为代表的新一代抗体药物偶联物（ADC）的出现，HER2突变NSCLC的治疗格局迎来了革命性的转机。本文将基于2022年发表于《循证医学》的述评文章[1]，系统梳理该领域的研究进展、核心挑战与未来方向。一、 HER2变异：不仅是乳腺癌的专利1.1 独特的生物学特性与耐药根源 HER2属于EGFR家族成员，在NSCLC中其变异形式以基因突变为主，这与乳腺癌/胃癌中常见的基因扩增和过表达截然不同。高达90%以上的HER2突变表现为第20号外显子框内插入突变（exon20ins），其中尤以p.A775_G776insYVMA（YVMAins）最为常见。这种特定的氨基酸序列插入会改变激酶区的构象，导致药物结合口袋变窄，形成空间位阻，从而阻挡了大多数非选择性HER-TKI的结合，这是造成原发性耐药的核心结构基础。1.2 临床流行病学特征 HER2突变在NSCLC中的发生率约为1%~4%，常见于不吸烟、女性、肺腺癌患者。此外，HER2扩增（原发性发生率约1%-3%；继发性在EGFR-TKI耐药后发生率可达8%-15%）和蛋白过表达（发生率报道不一）也是重要的变异形式，但其靶向治疗的探索历程更为曲折。二、靶向治疗：从小分子TKI到ADC的演进2.1 选择性HER-TKI：疗效提升与毒性挑战为克服构象障碍，新一代选择性HER-TKI应运而生。吡咯替尼作为我国自主研发的不可逆TKI，在后线治疗中显示出活性。一项II期研究显示，其治疗经治患者ORR达30.0%，中位PFS为6.9个月，中位OS为14.4个月[2]。另一项研究中，初治患者的中位PFS可达8.9个月[3]。Poziotinib凭借其小分子特性，能部分克服空间位阻。ZENITH20研究队列2（经治）报告ORR为35.1%，中位PFS为5.5个月[4]。然而，这些药物的毒性问题突出：Poziotinib治疗中，≥3级治疗相关不良事件（TRAE）发生率高达83.3%，导致近77%的患者需要减量[4]。药物研究/线数 ORR 中位PFS (月) ≥3级TRAE 吡咯替尼 Zhou等 II期/后线 30.0% 6.9 28.3% 吡咯替尼 Song等 II期/总人群 19.2% 5.6 - Poziotinib ZENITH20-2 /后线 35.1% 5.5 83.3% Poziotinib ZENITH20-4 /一线 50% 5.6 -2.2 ADC药物的破局者：T-DXd的卓越数据 ADC药物的迭代为HER2突变NSCLC带来了真正的突破。第一代ADC T-DM1在小样本研究中显示一定活性（ORR可达44%-50%），但疗效持续时间短（中位PFS约5个月），临床获益有限[5-6]。T-DXd（DS-8201）通过其高药物抗体比、可裂解连接子和膜通透性载荷，实现了疗效的飞跃。里程碑式的DESTINY-Lung01研究队列2显示，在91例经治HER2突变患者中，T-DXd治疗的ORR高达55%，疾病控制率（DCR）达92%，中位PFS和中位OS分别达到8.2个月和17.8个月，中位缓解持续时间（DoR）为9.3个月[7]。这一数据远超此前任何靶向药物。然而，疗效的飞跃伴随显著的毒性挑战。该研究中，≥3级TRAE发生率为46%，最需警惕的是间质性肺病（ILD），发生率达26%，并导致2例死亡[7]。目前，对比T-DXd单药与帕博利珠单抗联合化疗一线治疗的III期研究DESTINY-Lung04正在进行，结果将决定其能否进入一线。此外，借鉴乳腺癌经验，曲妥珠单抗联合帕妥珠单抗及多西他赛的三联方案（R2D2研究）也在后线探索中显示出活性（ORR29%，中位DoR达11.0个月），且安全性相对可控[8]，提供了另一种联合治疗思路。三、免疫治疗：争议中探索免疫检查点抑制剂（ICI）在HER2突变NSCLC中的角色尚不明确。回顾性研究显示，一线ICI联合化疗的ORR可达52%，中位PFS为6个月，与驱动基因野生型人群相似[9]。但另一项大型回顾性研究（POLISH研究）提示，对于初治患者，ICI联合化疗相比单纯化疗在PFS上并无显著获益（中位PFS 5.20个月 vs. 4.03个月，P=0.20），而抗血管生成药物联合化疗则显示出PFS优势（5.63个月 vs. 4.03个月，P=0.006）[10]。临床前研究指出，HER2变异可能通过抑制STING通路而削弱抗肿瘤免疫应答[11]，这为ICI在此人群的低效提供了理论解释。因此，免疫治疗在HER2突变NSCLC中的定位仍需前瞻性研究澄清。四、核心挑战与未来展望联合治疗是必然趋势：临床前研究表明ADC药物与选择性HER-TKI或ICI具有协同作用。基于T-DXd的联合方案（如联合ICI或TKI）是当前研究的热点（如NCT04686305等），有望进一步提升疗效。耐药机制亟待破解：TKI的耐药与EGFR、MET等旁路激活有关。ADC的耐药机制更为复杂，可能涉及靶点丢失、药物内化转运障碍、载荷耐药等，是未来研究的关键方向。脑转移治疗能力需提升：约6%-37%的患者发生脑转移。小分子TKI和T-DXd对无症状脑转移显示一定活性，但颅内控制能力仍有限。T-DXd的DESTINY-Lung01研究未系统评估颅内疗效，其真正的入脑能力有待专项研究阐明。 ADC技术的持续优化：T-DXd的成功源于ADC技术的进步。国内多家创新药企（如荣昌生物、恒瑞医药等）研发的HER2-ADC（如RC48、SHR-A1811等）正在积极开展临床试验，有望诞生更有效、更安全的下一代药物。核心要点总结 HER2突变NSCLC曾长期缺乏有效靶向治疗，以T-DXd为代表的新一代ADC药物实现了历史性突破，后线ORR>50%，中位OS近18个月，已成为该领域的治疗基石。选择性HER-TKI（吡咯替尼、Poziotinib等）虽有临床活性（ORR约30-50%），但受限于中等的疗效持续时间和显著的不良反应，尤其需关注皮肤毒性和ILD风险。免疫治疗在HER2突变人群中的价值尚不明确，回顾性数据存在矛盾，联合化疗可能不优于抗血管联合化疗方案，其地位需前瞻性试验验证。未来研究方向聚焦于：T-DXd的前线应用及联合治疗策略、ADC/TKI耐药机制的探索、针对脑转移患者的药物研发以及新一代ADC技术的优化。临床实践中，应常规对晚期NSCLC患者进行HER2基因检测（尤其是ex20ins）。对于后线患者，T-DXd应作为优先考虑的选择，但需密切监测并管理ILD等不良反应。参考文献： [1] 喻莹, 范云. HER2突变非小细胞肺癌的治疗：下一个突破点. 循证医学, 2022, 22(4): 193-197. [2] Zhou C, et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy. J Clin Oncol, 2020, 38(24): 2753-2761. [3] Song Z, et al. Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations. BMC Med, 2022, 20(1): 42. [4] Le X, et al. Poziotinib in non-small cell lung cancer harboring HER2 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. J Clin Oncol, 2022, 40(7): 710-718. [5] Hotta K, et al. A phase II study of trastuzumab emtansine in HER2-positive non-small cell lung cancer. J Thorac Oncol, 2018, 13(2): 273-279. [6] Li BT, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol, 2018, 36(24): 2532-2537. [7] Li BT, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med, 2022, 386(3): 241-251. [8] Mazieres J, et al. Combination of trastuzumab, pertuzumab, and docetaxel in patients with advanced non-small cell lung cancer harboring HER2 mutations. J Clin Oncol, 2022, 40(7): 719-728. [9] Saalfeld FC, et al. Efficacy of immune checkpoint inhibitors alone or in combination with chemotherapy in NSCLC harboring ERBB2 mutations. J Thorac Oncol, 2021, 16(11): 1952-1958. [10] Yang G, et al. First-line immunotherapy or angiogenesis inhibitor plus chemotherapy for HER2-altered NSCLC: a retrospective real-world POLISH study. Ther Adv Med Oncol, 2022, 14: 175883592210823. [11] Wu S, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat Cell Biol, 2019, 21(8): 1027-1040.

2026-06-12

·上海丰能数字健康技术研究院

【文献解读171】抗体偶联药物在晚期非小细胞肺癌中的研究进展

——基于《肿瘤防治研究》2022年第49卷第8期综述的深度解读导语：晚期非小细胞肺癌（NSCLC）的治疗在靶向与免疫治疗时代取得了长足进步，但获得性耐药仍是横亘在临床疗效前的核心障碍。当标准治疗线用尽，后线治疗选择有限且疗效有限时，临床亟需新的作用机制药物。抗体偶联药物（ADC）以其“精准投递”细胞毒药物的独特模式，正成为破局的新锐力量。本文将基于陈雅蕊、王江涛等作者在《肿瘤防治研究》（2022, 49(8): 855-860）上发表的综述，系统梳理ADC在晚期NSCLC各靶点的研究进展，并分析其临床潜力与挑战。一、 ADC：重塑肿瘤治疗范式的“生物导弹” 抗体偶联药物（ADC）由三个核心部件构成：特异性单克隆抗体、连接子和高活性细胞毒性载荷。其设计原理类似于精确制导的“生物导弹”：抗体负责识别并结合肿瘤细胞表面的特定抗原，通过内吞作用进入细胞内部；随后，在溶酶体环境下，连接子断裂释放细胞毒药物，从而在肿瘤细胞内“引爆”，实现高效杀伤。与传统化疗相比，ADC旨在降低全身毒性，提高治疗窗口。1.1 ADC的“三驾马车” 抗体：通常选用人源化IgG，需具备高特异性、高亲和力及低免疫原性。连接子：其稳定性至关重要，分为可切割型（允许药物在靶细胞外发挥“旁观者效应”）和不可切割型（降低脱靶毒性）。细胞毒载荷：多为微管抑制剂（如美坦辛衍生物）或DNA损伤剂（如拓扑异构酶I抑制剂），需在皮摩尔级别即有强效毒性。1.2 理想靶点的甄选一个合格的ADC靶点需满足：在肿瘤组织高表达/特异性表达，而在正常组织低表达；能被抗体有效结合并介导内化；具备高效的细胞内转运途径。在NSCLC领域，HER2、Trop-2、MET、HER3等已成为明星靶点，相关药物研发进展迅速。二、 HER2靶向ADC：从乳腺癌到肺癌的跨越式突破 HER2靶点在肺癌中的应用最初受启发于其在乳腺癌的成功。研究发现，HER2突变而非单纯扩增，能促进受体内化，为ADC治疗提供了更佳的生物学基础。2.1 T-DM1：开创先河的探路者作为首个在HER2阳性晚期NSCLC中测试的ADC，T-DM1（曲妥珠单抗-美坦辛）在一项II期研究中，针对HER2突变/扩增患者，取得了客观缓解率（ORR）51%，中位无进展生存期（PFS）5个月的疗效，且安全性可控。基于此，NCCN指南推荐其用于治疗HER2突变NSCLC（2A类证据）。2.2 DS-8201：树立新标杆的明星药物 DS-8201（德曲妥珠单抗）是新一代抗HER2 ADC，其采用拓扑异构酶I抑制剂作为载荷，并具有更高的药物/抗体比（DAR），从而增强了抗肿瘤活性。关键的DESTINY-Lung01II期临床研究结果令人瞩目：在42例经治HER2突变NSCLC患者中，ORR高达61.9%，中位PFS长达14个月。基于此，FDA于2020年批准其用于经治的转移性HER2突变NSCLC，并已纳入NCCN指南。对比研究显示，DS-8201在HER2突变队列的疗效显著优于HER2过表达队列（PFS 14月 vs. 5.4月）。药物研究阶段患者人群关键疗效数据 T-DM1 II期 HER2突变/扩增 ORR: 51%; PFS: 5个月 DS-8201 II期 (DESTINY-Lung01) HER2突变 (经治) ORR: 61.9%; PFS: 14个月 DS-8201 II期 (DESTINY-Lung01) HER2过表达 (经治) PFS: 5.4个月三、多靶点并进：Trop-2、MET与HER3的探索除了HER2，针对其他在NSCLC中高表达的靶点，ADC药物也在积极布局。3.1 Trop-2靶向：SG与DS-1062 Sacituzumab govitecan (SG)针对难治性NSCLC的I/II期研究显示，中位PFS为4.4个月，中位OS为7.3个月，且疗效与Trop-2表达水平无关。DS-1062（Datopotamab deruxtecan）的I期研究证实了其安全性，并已启动III期临床，对比多西他赛，并探索与PD-1抑制剂的联合一线治疗。3.2 MET靶向：克服信号通路耐药 Teliso-V是抗MET的ADC。I期研究显示其单药或联合EGFR-TKI在MET阳性NSCLC中具有抗肿瘤活性，其机制可能绕过EGFR TKI耐药中常见的MET扩增。然而，后续在鳞状NSCLC的II期研究因疗效不佳和毒性问题而提前终止，提示MET靶向ADC的临床开发需更精准的患者筛选。3.3 HER3靶向：克服EGFR TKI耐药的新策略 HER3是EGFR TKI耐药的重要旁路激活机制。Patritumab Deruxtecan (HER3-DXd)在EGFR突变NSCLC的I期研究中显示良好安全性。临床前研究表明，EGFR TKI可上调HER3表达，从而增强HER3-DXd的疗效。此外，HER3-DXd与PD-1抑制剂的联合也展现出协同抗肿瘤活性。靶点代表药物当前最高阶段核心发现/优势 Trop-2 SG II期 (篮式试验) 疗效与Trop-2表达水平无关，为泛癌种应用提供可能 Trop-2 DS-1062 III期单药与联合PD-1抑制剂的临床研究同步推进 MET Teliso-V II期 (已终止) 单药/联合EGFR-TKI在MET阳性患者中显示活性；鳞癌研究失败 HER3 HER3-DXd I期高内化率；与EGFR TKI和免疫治疗均有协同潜力四、探索中的新兴靶点与未来策略除上述靶点外，针对EGFR（MRG003）、B7-H3（MGC018）、PTK7（Cofetuzumab Pelidotin）、NaPi2b（XMT-1536）等靶点的ADC药物也处于I/II期临床研究阶段，初步数据展示了安全性与一定的抗肿瘤活性。值得注意的是，部分药物（如MGC018）的高级别治疗相关不良事件发生率较高，凸显了ADC毒性管理的重要性。未来ADC的发展将聚焦于：1.载荷优化：开发具有更强效、不同作用机制或可穿透血脑屏障的新型载荷。2.联合治疗：与免疫检查点抑制剂、靶向药物或其他ADC联用，以克服耐药、增强疗效。3.伴随诊断：寻找能精准预测ADC疗效的生物标志物，实现个体化治疗。核心要点总结与展望 ADC为耐药晚期NSCLC提供了全新治疗范式：以DS-8201为代表的HER2靶向ADC已在HER2突变患者中确立了卓越疗效和标准治疗地位。靶点探索呈现多元化格局：Trop-2、MET、HER3等靶点ADC药物研究活跃，各有优势与挑战，尤其HER3-DXd在克服EGFR TKI耐药方面潜力突出。临床应用需平衡疗效与毒性：ADC的安全性特征（如血液学毒性、间质性肺炎）需密切关注，精准的患者筛选和不良反应管理是成功应用的关键。联合治疗是未来重要方向：ADC与靶向、免疫等药物的联合方案正在积极探索，有望进一步提升疗效并扩大获益人群。伴随诊断与个体化治疗不可或缺：明确ADC的疗效预测标志物，实现“对号入座”，是未来研究的核心课题。临床实践启示笔者认为，ADC的临床应用策略应基于循证医学证据分层展开：对于HER2突变的经治晚期NSCLC患者，DS-8201是优先考虑的治疗选择之一。对于其他靶点（如Trop-2、HER3），目前多数药物仍处于临床研究阶段，鼓励符合条件的患者积极参与相关临床试验。在临床实践中，需对患者进行全面的基因检测（包括HER2、MET等），并充分评估患者的体能状态和既往治疗史。治疗过程中，应密切监测并及时处理ADC相关不良反应，尤其是与载荷相关的特异性毒性。参考文献： [1] Herbst RS, Morgensztern D, Boshoff C. 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2026-06-09

·DMH数字医健科创

【文献解读017】2021年度肺癌治疗进展

基于张婵媛等《2021年肺癌临床研究新进展》一文的深度解读与延展分析导语回首2021年，尽管全球仍笼罩在新冠疫情的阴影之下，但肺癌领域的临床研究并未停滞。相反，从可手术的早期患者到晚期复发难治人群，从非小细胞肺癌（NSCLC）到小细胞肺癌（SCLC），一系列重磅研究结果的公布，正在重塑我们的治疗格局。由广东省人民医院吴一龙教授团队发表的这篇年度综述，系统梳理了过去一年的关键进展。本文将以此为基础，选取核心数据与观点，结合笔者的临床视角，为您呈现一幅更立体、更富深度的2021肺癌研究图景。一、早期肺癌：手术基石稳固，围术期治疗迎来革新1.1 根治性治疗：SABR挑战手术地位的启示对于ⅠA期NSCLC，手术切除仍是NCCN指南的首选。2021年ASCO年会公布的修订版STARS研究结果，为不适合手术或拒绝手术的患者提供了重要依据。该研究将立体定向消融放疗（SABR）与倾向性匹配的电视辅助胸腔镜手术（VATS）肺叶切除术进行比较。关键数据显示，SABR组与手术组的3年OS率分别为91% vs. 91%，5年OS率为87% vs. 84%（HR 0.86， P=0.65），两者无统计学差异。PFS方面同样无显著差异（HR 1.38， P=0.35）。这表明，对于特定的早期患者，SABR可以作为一种疗效不劣于手术的根治性选择，但其应用需严格把握适应症，并强调多学科讨论（MDT）和个体化决策。1.2 围术期靶向治疗：从PFS获益到OS探索靶向治疗正深度介入可手术患者的围术期管理。经典的CTONG 1103研究（新辅助厄洛替尼 vs. 化疗，针对ⅢA-N2期EGFR突变患者）最终OS数据公布，厄洛替尼组中位OS为42.2个月，化疗组为36.9个月（HR 0.83， P>0.05），PFS优势未能转化为OS获益。这提示我们，一、二代TKI在围术期的应用可能面临天花板。然而，三代TKI的探索带来了新希望。由北京大学肿瘤医院杨跃教授发起的NEOS研究（奥希替尼新辅助治疗可切除Ⅱ-ⅢB期EGFR突变腺癌）中期结果令人振奋。在28例可评估患者中，客观缓解率（ORR）高达71%，疾病控制率（DCR）达100%。更重要的是，55%的患者实现了病理降期，40%的术前N2患者降期为N0，且安全性良好。这为三代TKI用于新辅助治疗提供了强有力的初步证据。在术后辅助治疗方面，ADAURA研究（奥希替尼辅助）已确立标准地位。而针对ⅢA期人群，由吴一龙教授主导的EVAN研究更新了OS数据：厄洛替尼组与化疗组的中位OS分别为84.2个月 vs. 61.1个月，5年OS率分别为84.8% vs. 51.1%。这是首个在ⅢA期EGFR突变人群中显示术后靶向辅助治疗带来显著OS获益的研究，临床意义重大。研究名称治疗模式核心疗效数据主要启示 STARS (修订版) SABR vs.手术 (ⅠA期) 5年OS：87% vs. 84% (P=0.65) SABR可作为特定早期患者的根治性选择 EVAN 术后辅助 (厄洛替尼vs. 化疗，ⅢA期) 中位OS：84.2 vs. 61.1个月；5年OS率：84.8% vs. 51.1% ⅢA期EGFR+患者术后辅助靶向带来显著OS获益 NEOS (中期) 新辅助 (奥希替尼，Ⅱ-ⅢB期) ORR 71%，病理降级率55% 三代TKI新辅助治疗潜力巨大，需Ⅲ期研究验证二、局部晚期NSCLC：免疫巩固治疗格局拓宽 PACIFIC研究确立了同步放化疗后免疫巩固治疗在不可切除Ⅲ期NSCLC中的标准地位。2021年更新的5年随访数据显示，度伐利尤单抗组与安慰剂组的5年OS率分别为42.9% vs. 33.4%，证实了持久的生存获益。 2021年的重磅进展当属GEMSTONE-301研究。这项由吴一龙教授牵头的Ⅲ期研究，关键性地将获益人群从同步放化疗患者扩展至序贯放化疗患者。结果显示，舒格利单抗组对比安慰剂组，中位PFS分别为9.0个月 vs. 5.8个月（HR 0.64， P=0.0026），显著降低了36%的疾病进展或死亡风险。这为临床上大量接受序贯放化疗的患者提供了标准巩固治疗方案，填补了重要的证据空白。此外，免疫治疗“前移”的探索也在进行。KEYNOTE-799研究（帕博利珠单抗联合同步放化疗）显示了惊人的疗效：鳞癌/非鳞癌队列ORR分别达到70.5%和70.6%，1年OS率均超过80%。尽管是Ⅱ期研究，但其数据强度提示，免疫治疗介入时机前移或能带来更深的缓解，值得期待后续Ⅲ期结果。三、晚期NSCLC靶向治疗：通路成熟与罕见靶点破局3.1 EGFR与ALK：联合策略的得与失 EGFR-TKI单药治疗已高度成熟。探索联合策略是重要方向。ARTEMIS-CTONG1509研究证实，贝伐珠单抗联合厄洛替尼较单药显著延长PFS（17.9个月 vs. 11.2个月， HR 0.55），但OS无差异，且L858R突变和脑转移亚组获益更明显。然而，三代TKI联合抗血管生成治疗却遇到挫折，WJOG9717L研究显示奥希替尼联合贝伐珠单抗并未带来PFS获益，反增毒性。同样，NEJ009研究（吉非替尼联合化疗）虽改善PFS，但同样未转化为OS获益且毒性增加。笔者认为，对于EGFR通路，未来联合治疗的突破点可能在于更精准的生物标志物筛选和毒性管理。 ALK融合突变（“钻石突变”）的治疗长生存趋势愈发明显。日本J-ALEX研究68个月随访数据显示，克唑替尼与阿来替尼的5年OS率分别为64.11% vs. 60.85%（允许后线交叉）。而eXalt3研究则显示，恩沙替尼的中位PFS（25.8个月）显著长于克唑替尼（12.7个月， HR 0.51）。ALK-TKI序贯治疗模式为患者赢得了长期生存的机会。3.2 罕见靶点：从“无药可用”到“精准可及” 2021年是罕见靶点治疗取得里程碑式进展的一年。• EGFR exon20ins：约占2%，传统EGFR-TKI疗效有限。Mobocertinib整体ORR为35%，中位OS达24个月；双抗Amivantamab的ORR为40%。• HER2突变：新型ADC药物DS-8201表现惊艳，ORR高达55%，但≥3级不良反应发生率达46%，安全性是临床应用的关键考量。• MET exon14跳跃突变：国产药物赛沃替尼历经5年研发，ORR达49.2%，于2021年获批上市，填补了国内空白。最长OS超过4年。• RET融合：普拉替尼在初治患者中ORR高达80%，已成功上市。Selpercatinib的ORR也达到66.0%。靶点/药物 ORR 中位PFS/OS 备注 EGFR ex20ins/Mobocertinib 35% PFS 7.3月；OS 24月经治患者 HER2 / DS-8201 55% PFS 8.2月；OS 17.8月高ORR，但毒性显著（≥3级AE 46%） MET ex14 / 赛沃替尼 49.2% PFS 6.8月中国获批，脑转移患者亦可获益 RET / 普拉替尼初治 80%；经治 66.7% - 已获批，覆盖初治人群四、晚期NSCLC免疫治疗：联合模式深化与耐药后探索免疫联合化疗已成为驱动基因阴性晚期NSCLC的一线标准。2021年，联合治疗的探索向更优组合和耐药后人群深入。针对EGFR-TKI耐药后的患者，ORIENT-31研究取得突破。该研究证实，信迪利单抗联合贝伐珠单抗及化疗（四药方案）对比单纯化疗，可显著延长PFS（6.9个月vs. 4.3个月，HR 0.57）。这是全球首个证实PD-1抑制剂联合方案在EGFR-TKI耐药后患者中PFS获益的Ⅲ期研究，为这一难治人群提供了新的标准治疗选择。在免疫治疗新靶点方面，CITYSCAPE研究（Ⅱ期）探索了抗TIGIT抗体tiragolumab联合阿替利珠单抗。在PD-L1 TPS≥50%的亚组中，联合治疗对比单药的ORR为66% vs. 24%，中位PFS为16.6个月 vs. 4.1个月（HR 0.29）。这提示TIGIT可能是一个极具前景的联合靶点，有待Ⅲ期研究进一步验证。此外，CheckMate 9LA和CheckMate 227研究的长期随访数据更新，进一步巩固了双免疫联合（纳武利尤单抗+伊匹木单抗）在不同PD-L1表达和组织学类型患者中的持续生存获益地位。五、小细胞肺癌：免疫延长生存，新靶点带来曙光免疫治疗为SCLC带来了突破。CASPIAN研究更新的3年随访数据显示，度伐利尤单抗联合化疗组的3年OS率达到17.6%，证实了免疫治疗带来的持久生存获益。然而，SCLC的整体预后仍不理想，亟需新机制药物。AMG 757是一种靶向DLL3的双特异性T细胞衔接器（BiTE）。DLL3在SCLC细胞高表达，而在正常组织低表达，是理想的治疗靶点。其Ⅰ期临床研究结果令人鼓舞：ORR为20%，且应答持久，中位PFS达到8.7个月，安全性可控。该研究首次证明了DLL3作为SCLC治疗靶点的可行性，为这类难治肿瘤开辟了全新的治疗方向。六、总结与展望：精准化、个体化、慢病化 2021年的肺癌研究，在各个治疗阶段均取得了实质性进展，共同勾勒出未来肺癌管理的清晰路径：精准化、个体化和慢病化。核心要点总结 1. 早期肺癌：根治性治疗选择更多元，围术期靶向治疗（特别是三代TKI）展现出巨大潜力，有望改变未来治疗格局。 2. 局部晚期NSCLC：免疫巩固治疗的获益人群从同步放化疗扩展至序贯放化疗，免疫治疗前移的探索初见成效。 3. 晚期NSCLC靶向治疗： EGFR/ALK通路趋于成熟，联合策略需谨慎；EGFR ex20ins、HER2、MET ex14、RET等罕见靶点迎来多个高效靶向药，精准治疗实现“破局”。 4. 晚期NSCLC免疫治疗：在TKI耐药后和PD-L1高表达人群中，新型联合方案（四药、双抗）取得积极进展。 5. 小细胞肺癌：免疫治疗奠定了持久生存获益的基础，靶向DLL3等新机制药物为攻克这一堡垒带来新曙光。未来研究方向笔者认为，未来的研究将聚焦于：1) 围术期治疗的最佳药物选择、时长及联合模式；2) 基于生物标志物的联合治疗患者筛选策略；3) 克服靶向和免疫治疗耐药的新机制药物研发；4) 将长生存转化为高质量生存的支持治疗与全程管理。5）肺癌的治疗已进入“百花齐放”的时代。随着多学科协作（MDT）模式的深入和临床研究的不断推进，肺癌正逐步走向“慢性病化”，让更多患者实现“活得更长、活得更好”的目标。参考文献 [1] National Comprehensive Cancer Network. The NCCN Guidelines for Non-Small Cell Lung Cancer (version 1.2022). [2] CHANG J Y, et al. Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): Long-term results of a single-arm, prospective trial. Lancet Oncol, 2021. [3] WU Y L, et al. CTONG1103: Final overall survival analysis. J Clin Oncol, 2021. [4] LYU C, et al. Osimertinib as neoadjuvant treatment for resectable stage II-IIIB EGFR mutant lung adenocarcinoma (NEOS). J Clin Oncol, 2021. [5] YUE D, et al. Updated overall survival (OS) from the randomized phase II EVAN study. J Clin Oncol, 2021. [6] SPICER J, et al. Surgical outcomes from the phase 3 CheckMate 816 trial. J Clin Oncol, 2021. [7] FELIP E, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA NSCLC (IMpower010). Lancet, 2021. [8] SPIGEL D R, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC (PACIFIC update). J Clin Oncol, 2021. [9] JABBOUR S K, et al. Pembrolizumab plus concurrent chemoradiation therapy (KEYNOTE-799). JAMA Oncol, 2021. [10] WU Y L, et al. GEMSTONE-301: A randomized, phase III study of sugemalimab. Ann Oncol, 2021. [11] ZHOU Q, et al. Bevacizumab plus erlotinib in Chinese patients with untreated EGFR-mutated advanced NSCLC (ARTEMIS-CTONG1509). Cancer Cell, 2021. [12] KENMOTSU H, et al. Primary results of WJOG9717L study (Osimertinib +/- Bevacizumab). Ann Oncol, 2021. [13] MIYAUCHI E, et al. Update analysis of NEJ009: Gefitinib alone vs. plus chemotherapy. J Clin Oncol, 2021. [14] YOSHIOKA H, et al. Final OS analysis from the phase III J-Alex study. J Clin Oncol, 2021. [15] HORN L, et al. Ensartinib vs crizotinib for ALK-positive NSCLC (eXalt3). JAMA Oncol, 2021. [16] ZHOU C, et al. Treatment outcomes of mobocertinib in EGFR exon 20 insertion-positive NSCLC. JAMA Oncol, 2021. [17] PARK K, et al. Amivantamab in EGFR exon 20 insertion-mutated NSCLC (CHRYSALIS). J Clin Oncol, 2021. [18] LI B T, et al. Trastuzumab deruxtecan in HER2-mutant non-small cell lung cancer. N Engl J Med, 2021. [19] YANG G, et al. Pyrotinib plus apatinib for HER2-mutant or amplified metastatic NSCLC. J Clin Oncol, 2021. [20] CORNELISSEN R, et al. Poziotinib in treatment-naïve NSCLC harboring HER2 exon 20 mutations (ZENITH20-4). Ann Oncol, 2021. [21] JANNE P A, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC. J Clin Oncol, 2021. [22] LU S, et al. Once-daily savolitinib in Chinese patients with MET exon 14 skipping NSCLC. Lancet Respir Med, 2021. [23] ZHOU Q, et al. Efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion+ NSCLC. J Thorac Oncol, 2021. [24] LU S, et al. Efficacy and safety of selpercatinib in Chinese patients with RET fusion-positive NSCLC. J Thorac Oncol, 2021. [25] LU S, et al. ORIENT-31: Phase III study of sintilimab +/- IBI305 plus chemo in EGFR+ NSCLC post TKI. Ann Oncol, 2022. [26] CHO B C, et al. Updated analysis from CITYSCAPE (tiragolumab + atezolizumab). Ann Oncol, 2021. [27] RECK M, et al. CheckMate 9LA 2-year update. ESMO open, 2021. [28] PAZ-ARES L G, et al. First-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 part 1). J Thorac Oncol, 2021. [29] PAZ-ARES L, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line ES-SCLC (CASPIAN 3-year OS update). Ann Oncol, 2021. [30] OWONIKOKO T K, et al. Updated results from a phase 1 study of AMG 757 (BiTE against DLL3) in SCLC. J Clin Oncol, 2021. 本文内容基于公开发表的医学文献进行解读，不构成任何临床治疗建议。患者治疗方案需由专业医生根据具体情况制定。

100 项与波齐替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	波齐替尼	-	DB12114

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	申请上市	美国	Spectrum Pharmaceuticals, Inc.	-
晚期非小细胞肺癌	临床2期	-	The University of Texas MD Anderson Cancer Center	2021-06-16
胶质瘤	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2019-12-23
HER2 阴性乳腺癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2019-12-23
错配修复缺陷或微卫星高度不稳定性结直肠癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2019-12-23
三阴性乳腺癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2019-12-23
HER2 20号外显子插入突变非小细胞肺癌	临床2期	韩国	Hanmi Pharmaceutical Co., Ltd.	2019-08-13
EGFR-T790M 突变非小细胞肺癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2017-10-11
EGFR-T790M 突变非小细胞肺癌	临床2期	比利时	Spectrum Pharmaceuticals, Inc.	2017-10-11
EGFR-T790M 突变非小细胞肺癌	临床2期	加拿大	Spectrum Pharmaceuticals, Inc.	2017-10-11

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04402008 (CTgov)	临床1/2期	非小细胞肺癌	42	Poziotinib (Phase 1: Poziotinib 8 mg QD)	憲製膚襯簾廠夢鬱構壓 = 憲蓋構範繭網夢繭簾獵壓鏇鬱築願觸醖艱繭窪 (糧糧遞鹹範鹽鏇網鑰憲, 齋鏇蓋簾鑰鏇繭鹽艱鹽 ~ 齋願鬱衊窪壓壓壓鏇遞) 更多	-	2024-06-25
				Poziotinib (Phase 1: Poziotinib 12 mg QD)	憲製膚襯簾廠夢鬱構壓 = 艱鹽鏇鹽獵壓獵齋憲齋壓鏇鬱築願觸醖艱繭窪 (糧糧遞鹹範鹽鏇網鑰憲, 範網積願夢艱窪鹹鹽範 ~ 願簾壓醖糧鬱糧蓋蓋願) 更多
NCT04172597 (CTgov)	临床2期	错配修复缺陷或微卫星高度不稳定性结直肠癌 \| 乳腺癌 \| 三阴性乳腺癌 ... 更多	1	Poziotinib Hydrochloride+Loperamide (Cohort 1)	餘願夢壓膚願願糧鏇襯(製壓衊選艱構廠糧鬱鬱) = 製淵積壓襯築鑰網願顧齋淵窪鬱顧憲製齋壓鏇 (廠網願鏇觸簾夢鏇醖鬱, 觸衊衊繭繭鬱淵夢膚艱 ~ 廠構齋衊範構鏇遞製鹹) 更多	-	2024-03-13
				Poziotinib Hydrochloride+Loperamide (Cohort 2)	餘願夢壓膚願願糧鏇襯(製壓衊選艱構廠糧鬱鬱) = 膚鹽餘積鑰廠簾簾艱夢齋淵窪鬱顧憲製齋壓鏇 (廠網願鏇觸簾夢鏇醖鬱, 糧製選築範築憲築糧齋 ~ 蓋網艱鹹壓顧獵鑰廠廠) 更多
NCT03292250 (KCSG HN 15-16 TRIUMPH, Pubmed) 人工标引	临床2期	头颈部鳞状细胞癌 PIK3CA \| epidermal growth factor receptor/HER2 \| fibroblast growth factor receptor ... 更多	203	Alpelisib	餘夢鹽窪鑰醖鏇繭鹽範(鬱鏇壓積製艱願醖糧網) = 築遞鑰願糧齋範範餘網醖簾衊範鏇遞膚艱顧廠 (鏇艱壓鏇構獵鏇願醖衊 ) 更多	积极	2024-02-10
				Poziotinib	衊醖鑰齋鬱願鹽願顧窪(壓簾觸築製衊窪餘衊艱) = 糧醖構鹹鬱簾夢憲糧獵範壓範壓夢夢襯選獵齋 (醖鑰餘糧夢糧顧壓網壓 ) 更多
NCT03318939 (ZENITH20, ESMO2023)	临床2期	非小细胞肺癌 HER2	91	Poziotinib 16 mg QD	夢顧獵醖願蓋夢蓋積窪(製積醖積願壓鏇衊築蓋) = 壓鏇淵遞壓壓網簾鏇蓋簾憲獵願夢鬱膚艱憲醖 (廠繭糧膚壓簾蓋範襯鏇, [22 ~ 41]) 更多	积极	2023-10-23
				Poziotinib 8 mg BID	夢顧獵醖願蓋夢蓋積窪(製積醖積願壓鏇衊築蓋) = 壓簾鏇齋範糧鬱鹽範鏇簾憲獵願夢鬱膚艱憲醖 (廠繭糧膚壓簾蓋範襯鏇 )
NCT03318939 (ZENITH20, WCLC2023) 人工标引	临床2期	非小细胞肺癌三线 HER2 exon 20 insertion	69	Poziotinib 16 mg	餘鏇獵蓋鏇齋壓淵鹽範(鹹遞願顧簾醖願鏇夢醖) = 餘齋襯壓製顧艱顧醖築膚繭網襯蓋遞鏇淵壓範 (鏇窪積簾簾網糧築製膚, 19.9 ~ 42.7) 更多	积极	2023-09-11
NCT03318939 (ZENITH20, ESMO2022)	临床2期	HER2 20号外显子插入突变非小细胞肺癌	170	Poziotinib 16 mg QD	製遞繭選鬱鹽淵廠夢廠(廠製蓋憲蓋願構壓壓觸) = 構醖製獵獵壓簾夢選選淵衊範製餘觸觸齋繭築 (範獵顧襯艱醖夢餘淵鬱 ) 更多	-	2022-09-10
				Poziotinib 8 mg BID	製遞繭選鬱鹽淵廠夢廠(廠製蓋憲蓋願構壓壓觸) = 遞積艱範選製鬱艱膚構淵衊範製餘觸觸齋繭築 (範獵顧襯艱醖夢餘淵鬱 ) 更多
NCT03066206 (Pubmed)	临床2期	非小细胞肺癌	50	Poziotinib	廠憲鑰構鏇夢餘範鏇夢(顧餘獵壓窪膚遞製鏇繭) = 糧餘醖夢憲醖製築餘範遞積衊構簾鬱鏇醖築製 (築淵範醖鏇鑰廠淵製獵 ) 更多	积极	2022-07-11
NCT02418689 (NOV120101-203, ESMO_BC2022) 人工标引	临床2期	HER2阳性转移性乳腺癌 HER2-positive	102	poziotinib	鹹獵鏇構構範範襯艱簾(廠鹽繭廠積鏇鬱餘襯構) = 衊襯簾憲蓋憲壓獵築構構齋糧遞壓鹹鑰選膚憲 (網衊獵鬱鹹糧觸願廠鹹, 3.0 ~ 4.4) 更多	积极	2022-05-04
NCT03318939 (ZENITH20-4, ESMO_TAT2022)	临床2期	HER2 20号外显子插入突变非小细胞肺癌	70	Poziotinib 16 mg QD	遞糧範糧廠淵鏇廠艱夢(鬱襯衊齋積顧廠顧淵鑰) = 繭鏇鑰築遞膚簾簾繭製鹽鬱鬱顧積製壓構餘遞 (醖鏇蓋夢壓醖襯蓋構壓, 30% ~ 54%) 更多	-	2022-03-07
				Poziotinib 8 mg BID	遞糧範糧廠淵鏇廠艱夢(鬱襯衊齋積顧廠顧淵鑰) = 顧繭鏇選窪繭鹽繭齋鏇鹽鬱鬱顧積製壓構餘遞 (醖鏇蓋夢壓醖襯蓋構壓, 30% ~ 54%) 更多
NCT02659514 (CTgov)	临床2期	HER2阳性转移性乳腺癌	67	Poziotinib (Cohort 1: Poziotinib 24 mg)	積鏇願壓鹽願廠構願襯 = 範鹽蓋網簾襯膚蓋簾網膚繭獵餘醖餘鹽醖構醖 (壓鏇鹹鹽壓衊構膚夢襯, 夢襯積衊艱觸鑰壓憲鬱 ~ 網襯鹹鹹遞襯繭壓遞襯) 更多	-	2022-02-10
				Poziotinib (Cohort 2: Poziotinib 16 mg)	積鏇願壓鹽願廠構願襯 = 構顧淵鹹鏇糧網繭蓋蓋膚繭獵餘醖餘鹽醖構醖 (壓鏇鹹鹽壓衊構膚夢襯, 觸網鹹鏇簾範鬱醖膚製 ~ 膚積淵廠網憲構鹹觸積) 更多