Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With or Without the IL-15 Super-Agonist N-803 as Adjuvant Therapy for PD-L1 Negative Non-Small Cell Lung Cancer

Background:
Surgery is the primary treatment for non-small cell lung cancer (NSCLC) that is diagnosed in its earlier stages. But the tumors often return. Radiation and chemotherapy can improve survival in some people who have had surgery for NSCLC, but these treatments also cause serious side effects. A new approach, called immunotherapy, may be a better way to stop NSCLC tumors from coming back.
Objective:
To test a new treatment (H1299 lung cancer cell vaccine combined with the drug N-803) in people who received surgery for NSCLC.
Eligibility:
Adults aged 18 years or older with no sign of disease after surgery for NSCLC.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart and lung function. They will have imaging scans.
Study treatment will be given in 28-day cycles. Participants will visit the clinic on the first day of each cycle. They will receive 2 treatments at each visit:
The study vaccine is given as 2-4 small shots under the skin of the thigh or arm.
N-803 is given as a shot under the skin of the abdomen.
Treatment will continue for 6 cycles. Blood tests and imaging scans will be repeated throughout the study.
Participants will have a blood test 1 month after receiving the 6th vaccine. Some participants may then resume taking N-803; they may also receive 2 more vaccinations at 3 and 6 months after their previous treatment.
Follow-up visits will continue for up to 5 years.

开始日期2025-05-07

申办/合作机构

National Cancer Institute

NCT05840770

/ Recruiting临床2期IIT

A Phase II Trial of Cemiplimab Alone for Untreated Brain Metastases From PD-L1 ≥ 50% Non-Small Cell Lung Cancer

This phase II trial tests how well cemiplimab works in treating patients with PD-L1 >= 50% non-small cell lung cancer (NSCLC) that has spread from where it first started (primary site) to the brain (metastases). Approximately 10% of patients diagnosed with metastatic NSCLC present with brain metastases and another 30% develop brain metastases during the illness. Currently, the management of brain metastases relies on stereotactic radiosurgery (SRS), which has high rates of local control, but in combination with systemic therapy, can cause certain toxicities, including central nervous system (CNS) necrosis or potential cognitive changes or memory deficits. Additionally, in patients with numerous brain metastases, whole brain radiation (WBRT) is recommended, leading to significant neurocognitive deficits. Immunotherapy with monoclonal antibodies, such as cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. However, there is little data on the effectiveness of newer systemic therapies, such as immunotherapy, in penetrating and treating previously untreated brain metastases. Cemiplimab without upfront SRS or WBRT for asymptomatic brain metastases may help delay the need for radiation in patients with untreated brain metastases from PD-L1 >= 50% NSCLC.

开始日期2025-04-15

申办/合作机构

City of Hope National Medical Center

[+1]

NCT06868277

/ Not yet recruiting临床3期

A Phase III, Randomized, Double-blind, Multicenter, Global Study of Rilvegostomig or Pembrolizumab Monotherapy for the First-line Treatment of Patients With PD-L1-high Metastatic Non-small Cell Lung Cancer (ARTEMIDE-Lung04)

The purpose of ARTEMIDE-Lung04 is to assess the efficacy and safety of rilvegostomig compared with pembrolizumab monotherapy as 1L treatment in participants with mNSCLC and whose tumors express PD-L1.

开始日期2025-04-15

申办/合作机构

AstraZeneca PLC

100 项与 PD-L1阳性非小细胞肺癌相关的临床结果

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100 项与 PD-L1阳性非小细胞肺癌相关的转化医学

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0 项与 PD-L1阳性非小细胞肺癌相关的专利（医药）

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项与 PD-L1阳性非小细胞肺癌相关的文献（医药）

2025-10-01·Talanta

Diagnosis of PD-L1 related non-small cell lung cancer from micro-liters blood

Article

作者: Wang, Lei ; Gao, Jianzhi ; Liu, Tianqing ; Yin, Feiyang ; Liang, Xiao ; Li, Xiaoxiao ; Liu, Fei ; Pan, Minghu ; Zhang, Lu ; Wang, Yuanzhang ; Guo, Quanmin ; Huang, Rou ; Qu, Danyao ; Zhang, Guangjian ; Wu, Weiwei ; Wang, Qi ; Jing, Minxuan ; Su, Chen

Early diagnosis of cancer can significantly decrease the mortality rate, and improve the effectiveness of treatment. However, early diagnosis leads to an increased and additional burden of medical resources. Lung cancer with the highest incidence and mortality rate of cancer presents a great challenge to the health of human beings. Non-small cell lung cancer (NSCLC), accounting for approximately 85 % of all lung cancer, desires a diagnostics method with low-cost, high accuracy, easy-operation, and fast speed. Recent research highlights the diagnostic potential of exosomes, particularly programmed death-ligand 1 (PD-L1) exosomes, which play a critical role in NSCLC by facilitating tumor cell immune evasion. This study introduces an organic electrochemical transistor (OECT)-based biosensor equipped with a carbon nanofibers-gold nanoparticles (CNFs-GNPs) gate electrode with super high surface area for detecting PD-L1 exosomes from micro-liters blood samples. The optimal stability, biocompatibility, and detection accuracy are systematically studied. The OECTs realize high sensitivity and selectivity, characterized by a transconductance of 66.7 mS, a rapid response time of about 42 ms, and less than 6 % current change after 2000 s of cycling. By immobilizing the PD-L1 aptamer on CNFs-GNPs via gold-sulfur bonding, the biosensor detects PD-L1 exosomes with a sensitivity as low as 10 pg/mL. Clinical trials using micro-liters blood has shown distinct differences between NSCLC patients and healthy individuals, suggesting this technology could significantly enhance early NSCLC detection and expand to other cancer diagnostics.

2025-03-01·The Lancet

Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China

Article

作者: Hu, Mingxiu ; Li, Gaofeng ; Lu, Dongmei ; Mei, Xiaodong ; Zhou, Caicun ; Chen, Jianhua ; Wang, Jinliang ; Zhong, Hua ; Li, Xingya ; Xiong, Anwen ; Cheng, Ying ; Liu, Xuewen ; Zhou, Chengzhi ; Wu, Lin ; Shi, Qin ; Hao, Jiqing ; Yao, Jifang ; Ai, Xiaohong ; Zhao, Yanqiu ; Yang, Jie ; Sun, Daqiang ; Ge, Hui ; Xia, Michelle ; Shan, Jinlu ; Chu, Qian ; Lin, Yu ; Chen, Bolin ; Yao, Jun ; Zhou, Ming ; Chen, Junqiang ; Wang, Jing ; Huang, Dingzhi ; Wang, Lei ; Li, Baiyong ; Liu, Baogang ; Sun, Yulan ; Wang, Zhongmin Maxwell ; Yang, Hongzhong ; Han, Zhengxiang ; Nie, Ligong ; Yu, Xinmin ; Li, Jie ; Ji, Yinghua ; Shang, Yanhong ; Bu, Qing

BACKGROUNDIvonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer.METHODSHARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later.FINDINGSBetween Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38-0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1-49% (HR 0·54 [95% CI 0·37-0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29-0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups.INTERPRETATIONIvonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer.FUNDINGAkeso Biopharma.

2025-03-01·Journal of Thoracic Oncology

Cemiplimab Monotherapy for First-Line Treatment of Patients with Advanced NSCLC With PD-L1 Expression of 50% or Higher: Five-Year Outcomes of EMPOWER-Lung 1

Article

作者: Kaul, Manika ; Magnan, Heather ; Schenker, Michael ; Bondarenko, Igor ; Gogishvili, Miranda ; Zyuhal, Kasimova ; Perez, Javier ; Scheusan, Roxana-Ioana ; Li, Yuntong ; Zhu, Cong ; Kim, Eric ; Seebach, Frank ; Garassino, Marina Chiara ; Kilickap, Saadettin ; Gumus, Mahmut ; Baramidze, Ana ; Özgüroğlu, Mustafa ; Sezer, Ahmet ; Fuang, Ho Gwo ; Lowy, Israel ; Kulyaba, Yaroslav ; Cicin, Irfan ; Nechaeva, Marina ; Pouliot, Jean-Francois

INTRODUCTIONEarlier results from the phase 3 EMPOWER-Lung 1 trial indicated significant survival benefits and a generally acceptable safety profile of first-line cemiplimab monotherapy versus chemotherapy for patients with advanced NSCLC with programmed cell death-ligand 1 (PD-L1) expression in 50% or more tumor cells and no EGFR, ALK, or ROS1 aberrations. Here, we report the five-year outcomes.METHODSPatients were randomized 1:1 to cemiplimab 350 mg intravenously every three weeks for two years or the investigator's choice of chemotherapy. The primary endpoints were overall survival (OS) and progression-free survival.RESULTSA total of 712 patients were randomized to cemiplimab (n = 357) or chemotherapy (n = 355). The median duration of follow-up was 59.6 months (interquartile range: 55.1-66.7 months) at the data cutoff (January 16, 2024). In patients with verified 50% or higher PD-L1 (n = 565), median OS was 26.1 months for cemiplimab versus 13.3 months for chemotherapy (hazard ratio = 0.59, 95% confidence interval [CI]: 0.48-0.72); the median progression-free survival was 8.1 months versus 5.3 months (hazard ratio = 0.50, 95% confidence interval: 0.41-0.61); and the objective response rate was 46.5% versus 20.6%. The five-year OS probability was 29.0% for cemiplimab and 15.0% for chemotherapy. Improved survival outcomes were observed with both squamous and nonsquamous histology, and increasing activity of cemiplimab was correlated with higher PD-L1 expression, with the highest PD-L1 expression having the best outcome. The safety profile remains consistent with previous results. Grade 3 or higher treatment-related adverse events occurred in 18.3% of patients for cemiplimab and 39.9% for chemotherapy.CONCLUSIONSAt five-year follow-up, first-line cemiplimab monotherapy continued to show durable clinical benefits versus chemotherapy in patients with advanced NSCLC with 50% or higher PD-L1. Patients with 90% or higher PD-L1 derived the largest clinical benefits.

325

项与 PD-L1阳性非小细胞肺癌相关的新闻（医药）

2025-05-04

·CPHI制药在线

康方生物：一个冉冉升起的“小而美”Biopharma

关注并星标CPHI制药在线处于舆论中心的康方生物，最近有点忙。重磅产品——派安普利单抗获FDA批准，成为首个由中国公司全过程独立主导（研发，临床，生产供药和申报注册）且成功获得FDA批准上市的创新生物药。同时，核心产品依沃西单抗头对头战胜了百济神州的替雷利珠单抗联合疗法。接着，依沃西单抗（AK-112）与K药头对头的总生存期（OS）的期中分析结果读出。在一系列利好消息加持下，康方生物股价大涨，市值已高达800多亿港元。康方生物正在长成Biopharma的模样。被高盛背书的核心大单品依沃西单抗是康方生物基于Tetrabody 技术，自主研发的一款PD-1/VEGF（血管内皮生长因子）双特异性抗体，其可阻断 PD-1 与 PD-L1 和 PD-L2 的结合，并同时阻断VEGF与VEGF受体的结合，达到抑制肿瘤免疫逃逸和血管新生的目的。2022 年 12 月，康方与Summit Therapeutics达成协议，以 50 亿美元总额实现 License out 交易，罕见高额引起行业震动。2024年5月，依沃西单抗获NMPA批准上市，用于 EGFR-TKI 治疗进展的局部晚期或转移性 nsq-NSCLC（非鳞状非小细胞肺癌），同年 11 月被纳入 2024 年国家医保目录。依沃西的上市标志着“肿瘤免疫+抗血管生成”协同抗肿瘤机制的双特异性抗体新药正式进入临床应用。要说依沃西的一战成名，还是在与“药王”K药（帕博利珠单抗）的头对头战役中。2024年世界肺癌大会上，康方公布了依沃西（AK-112）单药对比K药单药一线治疗PD-L1表达阳性（PD-L1 TPS≥1%）的局部晚期或转移性NSCLC 的注册性III期临床研究(HARMONi-2）数据。在意向治疗人群（ITT）中，依沃西单药相较K药单药显著延长了患者PFS（无进展生存期），mPFS（中位无进展生存期）近乎是K药组两倍（11.14个月vs 5.82个月），且显著降低患者疾病进展/死亡风险达49%。依沃西单药对比帕博利珠获得决定性胜出阳性结果，这是全球首个击败药王的产品。不过由于金标准OS数据未出，且康方生物未能透露更多详细数据，人们对依沃西的含金量依然存疑。直到4月25日，依沃西头对头K药的OS终于出来了。结果显示，在ITT人群中，在39%成熟度时进行的OS的期中分析（本次分析α分配值仅为0.0001），依沃西单抗对比帕博利珠单抗具有显著的临床生存获益，HR=0.777，降低死亡风险22.3%。尽管合作方Summit在这一消息公布后，股价暴跌近37%，但这次发布的数据，大家要关注的核心是，39% OS成熟度的时候，分配的α值是0.0001。据花旗分析师Yigal Nochomovitz博士称这一初始总生存数据是一个“极好的结果”，并指出0.0001的统计学门槛“异常高”。这是因为，统计学上常用的显著性水平，总单边α值是0.025。而这次期中分析只用了0.0001，剩下的0.024留给最终OS分析。在α值仅0.0001的情况下，HR还能达到0.777，显示依沃西的OS潜力极强。未来随着数据成熟（更多患者事件发生），HR可能进一步缩小，最终分析达到统计学显著性的概率高达99.99%。基于此结果，依沃西单抗的新适应症获NMPA批准，用于一线治疗PD-L1阳性NSCLC。值得一提的是，K药作为肿瘤免疫治疗的标杆，2024年销售额高达294.82亿美元。过去，无论是单药还是联合疗法，尚没有在头对头试验中击败K药的先例。依沃西单抗是全球首例在与K药头对头比较中，同时在PFS（HR=0.51）和OS（HR=0.777）上都胜出的疗法。依沃西若成为NSCLC一线治疗新标准，将冲击K药的300亿美元市场。目前，Summit公司还在开展名为HARMONi-3的临床试验，旨在比较依沃西单抗联合化疗与K药联合化疗在一线转移性鳞状非小细胞癌中的疗效，开展美国和欧洲在内的海外临床研究部分。预计在2028年初，这一临床试验将会公布最终结果。届时，依沃西单抗与K药谁更胜一筹，将更有说服力。除了与K药头对头外，康方生物于4月23日还公布了在一线治疗晚期sq-NSCLC的III期临床研究中，依沃西单抗联合化疗与百济的PD-1替雷利珠单抗联合化疗的头对头结果。经独立数据监察委员会(IDMC)评估，期中分析显示强阳性结果：达到PFS的主要研究终点，具有统计学显著意义和重大临床获益。依沃西单抗面对实力强劲的对手，再次以硬核的临床数据，取得第二次头对头胜利，证实了其突破性临床价值和创新竞争力。全球顶级投行高盛曾在一份报告中预测，到2041年，依沃西单抗的销售峰值将达到530亿美元，近乎是K药2024年销售额的2倍。而辉瑞与Summit的联合，无疑将为依沃西单抗的适用范围再添一砖。两家公司于今年2月达成合作，将共同推进依沃西单抗与ADCs药物在多种实体瘤中的联合治疗应用。备受瞩目的明星双抗联合目前备受行业追捧的ADC，两者将会擦出什么样的火花，值得期待。聚焦肿瘤和慢病赛道打造“小而美”Biopharma与传统Biopharma广泛布局不同，康方目前管线主要聚焦肿瘤和慢病赛道，试图打造“小而美”Biopharma。肿瘤领域除了依沃西单抗外，康方生物还有自主研发的PD-1单抗药物派安普利单抗（商品名：安尼可），它是全球首个采用IgG1亚型并进行Fc段改造的PD-1单抗。其Fc段改造通过消除与FcγR的结合，避免了抗体依赖性细胞吞噬（ADCP）和细胞因子释放（ADCR），从而提升抗肿瘤活性并降低全身免疫毒性。近日，派安普利单抗获FDA批准，用于治疗复发或转移性鼻咽癌（NPC）的一线治疗和用于以铂类为基础的化疗治疗失败的转移性鼻咽癌的两项适应症。这是首个由中国公司全过程独立主导（研发，临床，生产供药和申报注册）且成功获得FDA批准上市的创新生物药，也是中国第三个成功获FDA批准上市的PD-1单抗。另外，早在2022年6月，康方生物的PD-1/CTLA-4双抗卡度尼利获NMPA批准上市，成为全球首个获批的肿瘤免疫治疗双抗新药，也是中国第一个双特异性抗体新药。卡度尼利单抗目前已拿下二线宫颈癌适应症，且于2024年12月，和依沃西单抗一起，通过医保谈判被纳入国家新版医保目录。今年初，这两款药已完成所有挂网工作（西藏除外），纳入30+省份的双通道目录，实现1000余家医院准入，预计2025年底实现2000+医院覆盖。除了双抗产品外，康方生物还积极布局ADC，已有两款ADC新药推进到临床阶段，其中第二款ADC新药AK146D1首次披露为Trop2/Nectin-4 ADC，未来康方生物将推进多款ADC候选产品到临床阶段。除此以外，康方生物还布局了mRNA肿瘤疫苗，并且将目标瞄准“癌王”胰腺癌。4月6日，康方生物在Clinicaltrials.gov网站上注册了个体化mRNA疫苗单药或联合PD-1/CTLA-4双抗、PD-1/VEGF双抗辅助治疗胰腺癌的IIT临床试验。在慢病领域，康方生物自主研发的PCSK9抑制剂伊努西单抗于2024年10月获NMPA批准，用于治疗原发性高胆固醇血症和混合型高脂血症，以及杂合子型家族性高胆固醇血症，是康方生物在非肿瘤领域的首个获批产品，今年4月，康方生物的依若奇单抗在国内上市，用于对环孢素、甲氨蝶呤（MTX）等其他系统性治疗或PUVA（补骨脂素和紫外线A）不应答、有禁忌或无法耐受的中度至重度斑块状银屑病的成年患者的治疗。依若奇单抗是中国首个且唯一获批上市的IL-12/IL-23“双靶向”单克隆抗体，其上市为数百万银屑病患者带来了新的治疗药物选择。很明显，无论是心血管疾病还是银屑病，都是容易出重磅炸弹的领域。康方生物的野心可见一斑。过去一年，康方生物由于没有了高额的授权收入导致营收和净利润锐减并由盈转亏，总收入下滑53.08%至约21.24亿元，但同期的产品商业销售收入实现了同比24.88%的涨幅，达20.02亿元，同时经营性亏损持续收窄。接下来随着两款核心产品卡度尼利单抗、依沃西单抗被纳入2024年医保目录，2025年将进一步放量，加之不断解锁新的适应症，未来无疑将为康方生物贡献更多的收入。而康方生物也在从一个名不见经传的Biotech历变为一个冉冉升起的全球性Biopharma。参考来源： 1.康方官网，CDE官网 2.国际金融报，《康方生物再传喜讯！PD-1在美拿下两项适应症》END领取CPHI & PMEC China 2025展会门票来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床3期上市批准引进/卖出临床结果医药出海

2025-05-04

·康方生物Akeso

逐梦康方放飞梦想

往期推荐产品动态依沃西一线治疗NSCLC获批上市（全球首个对比帕博利珠单抗获显著阳性结果的III期研究）产品动态美国重磅上市！派安普利单抗2个适应症获FDA批准上市，用于晚期鼻咽癌治疗产品动态康方生物爱达罗®（依若奇,IL-12/IL-23）治疗中重度斑块状银屑病适应症获批上市临床进展首个自研ADC澳洲临床入组！康方生物IO 2.0+ADC战略再进一步临床进展非肿瘤首个双抗|康方生物全球首创IL-4Rα/ST2（AK139）IND获受理，剑指呼吸系统及皮肤疾病领域临床进展依沃西方案对比替雷利珠方案1L治疗sq-NSCLC的Ⅲ期临床完成患者入组临床进展康方生物古莫奇（IL-17）单抗新药上市申请获NMPA受理数据发布荣登Nature Medicine！卡度尼利方案1L治疗胃癌Ⅲ期研究结果全文发表产品动态康方生物卡度尼利、依沃西纳入2024年国家医保目录临床进展头对头度伐利尤单抗方案，依沃西方案一线治疗胆道肿瘤III期临床完成首例患者入组临床进展全球首个CD47单抗实体瘤III期临床首例入组：依沃西联合莱法利一线治疗HNSCC（对比帕博利珠单抗）数据发布卡度尼利一线宫颈癌III期研究成果荣登《Nature Reviews Clinical Oncology》（影响因子高81.1）数据发布IGCS 2024 LBA & 《柳叶刀》主刊，卡度尼利1L宫颈癌III期研究PFS和OS双阳性结果重磅发布产品动态一线胃癌全人群获批！康方生物卡度尼利获批第二个适应症产品动态获FDA快速通道资格！依沃西国际多中心III期研究HARMONi完成入组，2L+EGFRm NSCLC数据发布全球首个对比帕博利珠单抗取得显著阳性结果的随机对照大III期研究——依沃西HARMONi-2重磅研究成果在WCLC发表临床进展康方生物卡度尼利联合方案治疗uHCC的III期临床研究完成首例患者入组临床进展针对PD-1/L1治疗进展晚期胃癌，卡度尼利+普络西（VEGFR-2）联合疗法Ⅲ期临床完成首例入组数据发布ASCO Oral & JAMA主刊丨Ⅲ期HARMONi-A研究重磅公布，依沃西疗法有望改变EGFR-TKI进展肺癌全球治疗标准临床进展史无前例！康方依沃西单药对比帕博利珠1L治疗PD-L1阳性NSCLC的III期临床获决定性胜出阳性结果产品动态康方生物双抗卡度尼利一线治疗晚期宫颈癌全人群的sNDA获CDE受理临床进展国际多中心注册性III期研究HARMONi-3中国启动：依沃西单抗联合化疗对比帕博利珠单抗联合化疗1L治疗sq-NSCLC产品动态高达50亿美金！康方生物与Summit就PD-1/VEGF双抗依沃西达成合作和许可协议产品动态全球首个肿瘤免疫治疗双抗——开坦尼®（PD-1/CTLA-4双抗，卡度尼利）获批上市

临床3期ASCO会议抗体药物偶联物上市批准临床结果

2025-04-30

·VIP说

0.777意味什么| 从HR值看OS显著获益的意义

横看成岭侧成峰，远近高低各不同不识庐山真面目，只缘身在此山中2025年4月25日，在PD-L1表达阳性(TPS≥1%) NSCLC中，依沃西单抗（PD-1/VEGF双抗，AK112)对比帕博利珠单抗的HARMONI-2 研究公布了期中分析的结果，在39%数据成熟度的OS分析显示HR为0.777[1]，结果一经公布Summit股价暴跌36%。而就在两天前，康方生物刚刚宣布，依沃西单抗联合化疗对比替雷利珠单抗联合化疗一线治疗晚期鳞状非小细胞肺癌的III期头对头临床试验(HARMONi-6)，期中分析取得强阳性结果：达到无进展生存期(PFS)的主要研究终点，具有显著统计学意义[2]。为何如此卓越的结果，资本市场会不买单呢？为什么选择在PD-L1≥1%人群中头对头K药HARMONI-2在2024WCLC上公布PFS结果时，不少专家提出疑问，为什么选择PD-L1≥1%人群，为什么没选择PD-L1≥50%人群？从KEYNOTE-042研究的结果可以略见端倪。KEYNOTE-042研究结果结果显示，帕博利珠单抗单药在PD-L1≥1%人群中的HR值最高，OS的HR值为0.79（0.70-0.89），PFS的HR值为1.03（0.91-1.16）,帕博利珠单抗相比化疗PFS未取得获益，死亡风险下降21%[3]。主要原因是PD-L1表达在1-49%的人群使用帕博利珠单抗单药的获益有限。而选择相较于化疗HR值越差的人群越有可能做出显著差异。我们做一个简单的数学计算，依沃西单抗相较K药，死亡风险下降了23.3%，而K药相较化疗，死亡风险下降了21%。因此两者相加，可以推断出，在PD-L1阳性人群中，依沃西单抗相较化疗死亡风险下降了44.3%，也就是OS HR值在0.557。这个结果是否足以撼动临床实践？我们知道，虽然K药单药治疗获批了适应症，但在临床实践中，对于PD-L1阳性人群，临床专家常用的治疗策略仍然是免疫联合化疗。KEYNOTE-189研究中， OS HR值为0.60[4]。KEYNOTE-189研究OS结果在国产PD-1卡瑞利珠单抗的CameL-sq研究中，PD-L1阳性人群的OS HR值为0.60[7] CameL-sq研究OS结果可见依沃西单抗如果想要在PD-L1阳性人群中单药战胜PD-1联合化疗，生机有限。对比替雷利珠+化疗也是如此HARMONi-6研究选择了依沃西单抗+化疗头对头替雷利珠单抗+化疗。替雷利珠单抗联合化疗一线治疗非鳞NSCLC的RATIONALE-304研究结果显示，替雷利珠单抗联合化疗mOS 为21.4个月（vs化疗组20.1个月），相较化疗组仅延长1.3个月，HR 0.87（CI: 0.65, 1.17），OS置信区间上限超过了1[5]。从OS曲线也可以看出，替雷利珠单抗组和化疗组的曲线交织在一起，4年OS率提升仅3.1%。RATIONALE-307研究中，替雷利珠单抗联合化疗(白紫+卡铂)的mOS为23.3个月（对照组为19.4个月），HR 0.82（CI: 0.60, 1.11），OS置信区间上线也超过1[6], 说明mOS获益未达显著临床意义。因此，HARMONI-6研究依沃西单抗+化疗头对头替雷利珠+化疗，选择相较于化疗HR值越差的人群越有可能做出显著差异。RATIONALE-304研究非鳞癌OS曲线 RATIONALE-307研究鳞癌OS曲线(替雷利珠联合白蛋白紫杉醇/卡铂组) 相较化疗HR值达到多少能立于不败之地？HARMONI-2研究结果说明，依沃西单抗相比K药单药治疗PD-L1阳性NSCLC的死亡风险降低22.3%（HR 0.777），而KEYNOTE-042研究中K药对比化疗治疗PD-L1阳性NSCLC的OS HR为0.79，死亡风险降低21%。即K药相比化疗降低了21%，依沃西单抗相比K药又降低了23.3%。是否说明依沃西单抗相较于化疗死亡风险降低在40%的数量级（非头对头比较），那么相较于化疗OS的HR值高于0.60的都危险了？可见依沃西单抗单药要战胜免疫联合化疗，还是非常有挑战的。依沃西单抗+化疗有没有机会战胜免疫联合化疗？替雷利珠单抗RATIONALE-304和RATIONALE-307（卡铂+白紫）OS的HR分别为0.87和0.82，这么看确实危险了。但说依沃西单抗+化疗取代免疫联合化疗的地位还言之尚早。替雷利珠输了，还有卡瑞利珠CameL-sq研究是卡瑞利珠单抗联合化疗一线治疗鳞状NSCLC III期研究。在2025ELCC会上更新的5年随访数据显示，卡瑞利珠单抗联合化疗的5年生存率高达27.8%（vs对照组12.5%），近1/3晚期鳞癌患者生存超过5年[7]。OS的HR值为0.57，死亡风险降低43%。PFS的HR值为0.32，疾病进展风险降低68%。CameL-sq研究鳞癌OS、PFS曲线是非成败转头空，0.777意味着什么在中国患者中头对头比较PD-1在晚期NSCLC的疗效，选择相较于化疗HR值越差的人群越有可能做出显著差异。但选择显著延长生存，显著提升5年生存率的方案作为对照，才能进一步提升晚期NSCLC的临床治愈率，从而让更多患者从创新的治疗方案中获益。还要注意的是，这次HARMONI-2期中分析是仅在39%数据成熟度下进行的，α值仅仅分配了0.0001 ！(总的α值0.025) 最终OS分析的结果仍未可知。尽管如此，HR 0.777已经具有里程碑意义。参考文献[1] https://www.akesobio.com/cn/media/akeso-news/20250426/[2] https://www.akesobio.com/cn/media/akeso-news/20250423/[3] J Clin Oncol 2023 Apr 10;41(11):1986-1991[4] M.C. Garassino, 2022 ESMO abstract 973MO[5] Wang J. 2024 ESMO.1323P[6] Ma ZY, et al. 2024 ESMO ASIA. 632P.[7] Zhou C. 2025 ELCC. 12P

临床结果CSCO会议临床3期