PO.CL05.06 · 临床研究
STA551(STA)——一种肿瘤选择性CD137激动剂作为单药及与atezolizumab(atezo)联合应用并采用CD8 PET成像评估药效学效应的I期研究
Phase I study of STA551 (STA) a tumor-selective CD137 agonist, as monotherapy and in combination with atezolizumab (atezo) using CD8 PET imaging to assess pharmacodynamic effects
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：CD137是癌症免疫治疗中一个有前景的共刺激受体。已开发出若干CD137激动剂抗体生物制剂，但由于严重毒性，均未显示出明确有前景的临床潜力。STA是一种ATP依赖性开关抗体，旨在选择性地在肿瘤内激活CD137，并最大限度地减少全身毒性。我们开展了一项STA单药或STA与atezo联合应用的I期研究，在晚期实体瘤患者中采用CD8 PET成像评估耐受性、PK和药效学。
方法：该1期研究包括剂量递增和CD8 PET队列。对于剂量递增队列，患者接受STA单药每3周静脉给药一次，或STA与atezo(1200 mg)每3周联合给药一次。对于CD8 PET队列，患者作为单药每3周接受STA治疗，共两个周期，随后从第3周期起与atezo 1200 mg联合治疗。Zr-89 crefmirlimab berdoxam(一种靶向CD8并用Zr-89标记的微型抗体)用作CD8 PET扫描的示踪剂。CD8 PET扫描在基线、两次STA给药后(第2周期第9天)以及两次联合给药后(第4周期第9天)进行。
结果：剂量递增队列(单药41例，联合41例)和CD8 PET队列(12例)共治疗94例患者。最常见的治疗相关不良事件(≥10%)在单药队列中为AST升高(17.1%)、疲乏(14.6%)和ALT升高(12.2%)；在联合和CD8 PET队列中为ALT升高(22.6%)、AST升高(18.9%)、输注相关反应(IRR)(15.1%)、恶心(13.2%)、腹泻(11.3%)和疲乏(11.3%)。未报告与Zr-89 crefmirlimab berdoxam相关的严重不良事件。在单用STA达1200 mg之前未观察到剂量限制性毒性。最大耐受剂量为STA 450 mg与atezo 1200 mg每3周联合给药。PK分析显示STA呈剂量比例性增加。在CD8 PET队列中，10例患者可评估疗效和CD8 PET分析。在一例经过大量既往治疗的三阴性乳腺癌患者中观察到一例部分缓解(PR)。5例患者疾病稳定。在一部分患者中显示肿瘤病灶的示踪剂蓄积增加。值得注意的是，在达到PR的患者中，所有可评估病灶均观察到明显的蓄积增加。在脾脏中未观察到示踪剂蓄积的明显增加，而其他全身性CD137激动剂曾报告脾脏蓄积增加。
结论：STA无论作为单药还是与atezo联合应用均表现出可控的安全性特征。CD8 PET分析提示STA在一部分患者中增加了肿瘤内CD8+ T细胞水平，对正常器官的影响有限。这些发现可能支持STA作为CD137激动剂的肿瘤选择性作用机制。
查看英文原文 English abstract
Background: CD137 is a promising costimulatory receptor for cancer immunotherapy. Several CD137 agonist antibody biologics have been developed, but none show clear promising clinical potential due to severe toxicity. STA, an ATP-dependent switch antibody, is designed to selectively activate CD137 within tumors, and minimize systemic toxicity. We conducted a phase I study of STA alone or the combination of STA and atezo to evaluate tolerability, PK and pharmacodynamics using CD8 PET imaging, in patients with advanced solid tumors.
Methods: The Phase 1 study includes dose escalation and CD8 PET cohorts. For the dose escalation cohorts, patients were treated with either STA monotherapy IV q3 weekly or STA in combination with atezo (1200 mg) q3 weekly. For the CD8 PET cohort, patients received STA q3 weekly for two cycles as monotherapy, followed by combination therapy with atezo 1200 mg from cycle 3 onwards. Zr-89 crefmirlimab berdoxam (a minibody targeting CD8, labeled with Zr-89) was used as the tracer of CD8 PET scan. CD8 PET scans were done at baseline, after two STA doses (Cycle 2 Day 9), and after two combination doses (Cycle 4 Day 9).
Results: A total of 94 patients were treated in the dose escalation cohorts (41 patients in monotherapy and 41 patients in the combination) and in the CD8 PET cohort (12 patients). The most common treatment related adverse events (≥10%) were AST increased (17.1%), fatigue (14.6%), and ALT increased (12.2%) in mono cohorts; ALT increased (22.6%), AST increased (18.9%), infusion related reaction (IRR) (15.1%), nausea (13.2%), diarrhoea (11.3%) and fatigue (11.3%) in combination and CD8 PET cohorts. No severe adverse events related to Zr-89 crefmirlimab berdoxam were reported. No dose limiting toxicities were observed up to STA 1200 mg alone. The maximum tolerated dose was 450 mg of STA in combination with 1200 mg of atezo administered q3 weekly. The PK analysis showed STA increased in a dose proportional manner. In the CD8 PET cohort, 10 patients were evaluable for efficacy and CD8 PET analyses. One partial response (PR) was observed in a heavily pretreated patient with triple negative breast cancer. Five patients had stable disease. Increased tracer accumulation in tumor lesions was indicated in a subset of patients. Notably, in the patient who achieved a PR, clear increased accumulation was observed in all evaluable lesions. No clear increase in the tracer accumulation was observed in the spleen which has been reported with other systemic CD137 agonists.
Conclusions: STA demonstrated a manageable safety profile both as monotherapy and in combination with atezo. CD8 PET analysis suggested STA increased intratumoral CD8 + T cell levels in a subset of patients, with limited effects in normal organs. These findings potentially support the tumor-selective mechanism of action of STA as a CD137 agonist.
利益披露 Disclosure
U. Banerji,
Pegasy Therapeutics Other, Advisory Board.
Carrick Therapeutics Other, Advisory Board.
PharmEnable Therapeutics Other, Advisory Board.
Ellipses Pharma Other, Advisory Board.
Dania Therapeutics Other, Advisory Board.
Amalus Therapeutics Other, Advisory Board.
Verastem Oncology ).
Avacta Therapeutics ).
The Institute of Cancer Research Employment.
Deter Oncology Other, Advisory Board.
ICR Employment.
D. Silva, None..
J. Ting, None..
Z. Zair, None.
P. Manoharan,
Novartis Other, Speaker and consultancy.
Alliance Medical Other, Speaker and consultancy.
T. Doi,
Rakuten Medical Other, Consulting or Advisory Role.
SHIONOGI ), Other, Consulting or Advisory Role.
Kaken Pharmaceutical Other, Consulting or Advisory Role.
Boehringer Ingelheim ), Consulting or Advisory Role.
Chugai Pharma ), Other, Consulting or Advisory Role.
A2 Healthcare Other, Consulting or Advisory Role.
Taiho Pharmaceutical ), Other, Consulting or Advisory Role.
IQVIA Other, Consulting or Advisory Role.
Avencell Other, Consulting or Advisory Role.
Meiji Seika Pharma Other, Consulting or Advisory Role.
Daiichi Sankyo ), Other, Honoraria.
MSD ).
Pfizer ).
Ono Pharmaceutical ).
PRA Health Sciences ).
Amgen ).
GlaxoSmithKline ).
RIN Institute ).
Abbvie ).
Bayer ).
S. Koganemaru,
Amgen ).
Daiichi-Sankyo ).
Bristol-Myers Squibb ).
Abbvie ).
Incyte ).
Ono Pharmaceutical ).
GlaxoSmithKline ).
BeiGene ).
MSD ).
N. Yamamoto,
Chugai Other, Invited Speaker, Advisory Board, Local PI, Principal Investigator.
Daiichi-Sankyo ), Other, Invited Speaker.
Eisai Other, Invited Speaker, Advisory Board, Local PI, Principal Investigator.
Healios Other, Advisory Board.
Boehringer Ingelheim Other, Advisory Board, Local PI, Principal Investigator.
Cmic Other, Advisory Board.
Merck Other, Advisory Board.
Mitsubishi Tanabe Other, Advisory Board.
Rakuten Medical ), Other, Advisory Board, Local PI, Principal investigator.
IQVIA Other, Advisory Board.
Noile-Immune Biotech Other, Advisory Board.
Janssen Pharma Other, Advisory Board, Local PI, Principal Investigator.
Astellas Other, Local PI, Principal Investigator.
Taiho Local PI, Principal Investigator.
BMS Other, Local PI, Principal Investigator.
Pfizer Other, Local PI, Principal Investigator.
Novartis Other, Local PI, Principal Investigator.
Eli Lilly Other, Local PI, Principal Investigator.
AbbVie Other, Local PI, Principal Investigator.
Bayer Other, Local PI, Principal Investigator.
T. Koyama,
Astrazeneca ), Other, Honoraria.
Novartis ).
Chugai ), Other, Honoraria.
Lilly ).
Daiichi-Sankyo ).
Zymworks ).
Takeda ).
Boehringer Ingelheim ).
Janssen ).
MSD ).
Noile ).
Sysmex Other, Honoraria.
S. Ikeda,
Chugai Pharmaceutical Co., Ltd. Employment, Stock.
ONO PHARMACEUTICAL CO., LTD. Stock.
Y. Kanai,
Chugai Pharmaceutical Co., Ltd. Employment, Stock.
Sumitomo Pharma Co., Ltd. Stock.
M. Inatani,
Chugai Pharmaceutical Co., Ltd. Employment, Stock.
H. Takeshita,
Chugai Pharmaceutical Co., Ltd. Employment.
A. Hashimoto,
Chugai Pharma Europe Ltd. Employment.
Y. Ogita,
Chugai Pharmaceutical Co., Ltd. Employment, Stock.
Y. Takano,
Chugai Pharmaceutical Co. Ltd Employment, Stock.
K. Higashikawa,
Chugai Pharmaceutical Co., Ltd. Employment, Stock.
Pfizer Inc. Stock.
F. Thistlethwaite,
T-Knife Therapeutics ), Other, Advisory Board /consultancy.
Immatics Other, Advisory Board.
Grey Wolf Therapeutics Other, Advisory Board.
AstraZeneca ), Other, Advisory Board/Consulting.
Oncobayes Other, Advisory Board.
Waypoint Other, Consulting.
GlaxoSmithKline ).
GenMab ).
Incyte ).
Janssen ).
Adaptimmune ).
Bristol-Myers Squibb ).
Immunocore ).
Achilles Therapeutics ).
Crescendo Bioscience ).
Oxford VacMedix Ltd ).
RS Oncology LLC ).
Roche ).
Sanofi ).
Chugai ).