PO.CT01.05 · 临床试验

卡博替尼联合纳武利尤单抗治疗转移性去势抵抗性前列腺癌的一项2期研究（CANOPY）：中期分析

A phase 2 study of cabozantinib and nivolumab in metastatic castration resistant prostate cancer (CANOPY): Interim analysis

编号 CT149 展板 13 时间 4/20 02:00–05:00 区域 Section 52 主讲 Yu-Wei Chen, MD;MS

分会场 Phase II and Phase III Clinical Trials

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作者与单位 Authors & Affiliations

Justine Panian¹, Lin Liu¹, Minya Pu¹, Emily Pittman¹, Samuel Pena¹, Archana Ajmera¹, Yu-Wei Chen¹, Christos Kyriakopoulos², Qian Qin³, James Michael Randall¹, Tian Zhang³, Joshua Michael Lang², Akash Patnaik⁴, Rana R. McKay¹

¹UCSD Medical Ctr., San Diego, CA,²University of Wisconsin Carbone Cancer Center, Madison, WI,³UT Southwestern Medical Center, Dallas, TX,⁴The University of Chicago Cancer Center, Chicago, IL

摘要 Abstract

中文摘要

背景：晚期转移性去势抵抗性前列腺癌（mCRPC）仍是一种致命疾病，治疗选择有限。卡博替尼是一种靶向VEGFR、MET和AXL的多靶点酪氨酸激酶抑制剂，已在mCRPC患者中显示出活性，尤其是伴有骨和肝转移的患者。基于我们的临床前研究显示卡博替尼介导前列腺癌（PC）中固有免疫的激活，我们研究了卡博替尼联合纳武利尤单抗在mCRPC患者中的疗效（NCT05502315）。方法：这项前瞻性、多中心、单臂、两阶段开放标签II期研究入组了按PCWG3标准进展的mCRPC患者，且既往接受过雄激素受体通路抑制剂。允许既往使用紫杉烷类。患者接受卡博替尼40 mg每日口服联合纳武利尤单抗480 mg静脉注射，每4周一次。主要终点为按RECIST 1.1/PCWG3的6个月影像学无进展生存期（rPFS）。采用Simon两阶段MiniMax设计，检验效能为80%，假设6个月rPFS>30%。第1阶段要求24例患者中≥7例在6个月时无进展，方可继续进入第2阶段，第2阶段将额外入组23例患者。结果：第1阶段入组24例患者（中位年龄71岁）。基线特征：50%（12/24）为初诊转移性疾病，91.7%（n=22）有骨转移，29.2%（n=7）为仅骨转移，16.7%（n=4）为内脏转移，66.7%（n=16）接受过既往化疗，25%（n=6）接受过既往¹⁷⁷Lu-PSMA-617治疗。8例患者在6个月时保持无进展，满足进入第2阶段的继续标准。中位rPFS为5.5个月（95% CI >3.6个月）。客观缓解率为17.6%（3/17例可评估患者）。中位基线PSA为28.05 ng/mL，中位PSA进展时间为1.87（95% CI 1.81-3.78）个月。1例患者出现PSA50。≥3级治疗相关不良事件发生于52%（n=12）的患者，有5例治疗相关严重不良事件。最常见的不良事件为食欲减退58%（n=14）、腹泻58%（n=14）、疲乏54%（n=13）、恶心46%（n=11）、贫血38%（n=9）、AST升高38%（n=9）、ALT升高33%（n=8）、便秘33%（n=8）和甲状腺功能减退29%（n=7）。结论：CANOPY试验达到了其中期疗效阈值，证明卡博替尼联合纳武利尤单抗在mCRPC患者中具有活性。该联合方案显示出可控的毒性。研究继续进入第2阶段入组，以进一步评估这一有前景的联合治疗。

查看英文原文 English abstract

Background: Advanced metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with limited treatment options. Cabozantinib is a multi-tyrosine kinase inhibitor targeting VEGFR, MET, and AXL that has demonstrated activity in mCRPC patients, particularly those with bone and liver metastases. Based on our preclinical studies showing cabozantinib-mediated activation of innate immunity in PC, we investigated the efficacy of cabozantinib plus nivolumab in mCRPC patients (NCT05502315). Methods: This prospective, multi-center, single-arm, two-stage open-label phase II study enrolled patients with progressive mCRPC per PCWG3 criteria and prior androgen receptor pathway inhibitor exposure. Prior taxane was permitted. Patients received cabozantinib 40 mg daily orally plus nivolumab 480 mg IV every 4 weeks. The primary endpoint was radiographic progression-free survival (rPFS) at 6 months by RECIST 1.1/PCWG3. A Simon two-stage MiniMax design was used with 80% power, hypothesizing 6-month rPFS >30%. Stage 1 required ≥7 of 24 patients to be progression-free at 6 months to continue to Stage 2, which will enroll an additional 23 patients. Results: Twenty-four patients were enrolled in Stage 1 (median age 71 years). Baseline characteristics: 50% (12/24) had de novo metastatic disease, 91.7% (n=22) had bone metastases, 29.2% (n=7) bone-only disease, 16.7% (n=4) visceral metastases, 66.7% (n=16) received prior chemotherapy, and 25% (n=6) prior ¹⁷⁷Lu-PSMA-617 therapy. Eight patients remained progression-free at 6 months, meeting continuation criteria for Stage 2. Median rPFS was 5.5 months (95% CI >3.6 months). Objective response rate was 17.6% (3/17 evaluable patients). Median baseline PSA was 28.05 ng/mL and median time to PSA progression was 1.87 (95% CI 1.81-3.78) months. One patient experienced PSA 50 . Grade ≥3 treatment-related adverse events occurred in 52% (n=12) of patients, with 5 treatment-related serious adverse events. Most common adverse events were anorexia 58% (n=14), diarrhea 58% (n=14), fatigue 54% (n=13), nausea 46% (n=11), anemia 38% (n=9), AST increase 38% (n=9), ALT increase 33% (n=8), constipation 33% (n=8), and hypothyroidism 29% (n=7). Conclusions: The CANOPY trial met its interim efficacy threshold, demonstrating activity of cabozantinib plus nivolumab in mCRPC patients. The combination showed manageable toxicity. The study continues to Stage 2 enrollment to further evaluate this promising combination therapy.

利益披露 Disclosure

J. Panian, None.. L. Liu, None.. M. Pu, None.. E. Pittman, None.. S. Pena, None. A. Ajmera, Nexus Pharmaceuticals Inc Other, Consulting or Advisory Role. Eisai Other, Consulting or Advisory Role. Astellas Pharma Other, Consulting or Advisory Role. NCCN Other, Honoraria. Y. Chen, Amgen Other, An Immediate Family Member is employed at this company. Eisa, Johnson & Johnson/Janssen, Other, Consulting or Advisory Role. DAVA Oncology Other, Travel, Accommodations, Expenses. Amgen Other, An immediately family member owns stock. Eisai, OncLive/MJH Life Sciences, GU ONCOLOGY NOW, Bayer, Ideology Health, City of Hope, Targeted Oncology Other, Honoraria. Gilead Sciences ). C. Kyriakopoulos, Epic Systems Other, Employment. Exelixis, Sanofi, AVEO, EMD Serono, Janssen Oncology, Pfizer Other, Consulting or Advisory Role. Biogen Stock. Epic Systems Other, An immediate family member owns stock. Sanofi, Gilead Sciences, AstraZeneca, ESSA, Pionyr, Bristol Myers Squibb Foundation, Madison Vaccines, Inc., EMD Serono ). Q. Qin, Exelixis, Eisai, Janssen Other, Consulting or Advisory Role. MJH Life Sciences, GU Oncology Now Other, Honoraria. Exelixis, Janssen Research Funding. J. M. Randall, None. T. Zhang, Exelixis, Pfizer, Bristol-Myers Squibb, Eisai, Bayer, Lilly, AVEO, Merck, Novartis, Gilead Sciences, EMD Serono, AstraZeneca, Loxo/Lilly, Xencor, Johnson & Johnson/Janssen, Dendreon Other, Consulting or Advisory Role. Capio BioSciences, Archimmune Therapeutics Other, An immediate family member is in leadership. Bayer, Janux Therapeutics, Johnson & Johnson/Janssen Other, Travel, Accommodations, Expenses. Circulating tumor cell novel capture by c-MET technology, Prochelators as Targeted Prodrugs for Prostate Cancer Other, Patents, Royalties, Other Intellectual Property of this author's institution. ASCO, Kidney Cancer Association, KidneyCan, Myrovlytis Trust, Winn Foundation Other. Capio Biosciences, Archimmune Therapeutics, Nanorobotics Stock Option, Other, An immediately family member owns stock in these companies. MJH Life Sciences, Aptitude Health, Curio Science, Peerview, Clinical Care Options, Mashup Media, Dava Oncology Other, Honoraria. Loxo/Lilly, Tempus, Pfizer, ALX Oncology, Exelixis, OncoC4, Astellas Pharma, Janssen, Janux Therapeutics, Bayer, Kura Oncology, Merck ). J. Lang, Sanofi, Janssen, Pfizer/Astellas, Gilead Sciences, Arvinas, Pfizer/Myovant, 4D Pharma, AstraZeneca, Pfizer, Macrogenics, Foundation Medicine, Daiichi Sankyo/Astra Zenec Other, Consulting or Advisory Role. EOLAS Diagnostics, INC Other, Leadership. I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC though no commercial products are available. Patent. Medivation, Agensys, GlaxoSmithKline, Immunomedics, Bristol-Myers Squibb, Janssen, Gilead Sciences, Arvinas ). A. Patnaik, Exelixis, Guidepoint Pharmacy, Gerson Lehrman Group, Curio Science, Novartis, Johnson & Johnson/Janssen, AstraZeneca Other, Consulting or Advisory Role. Bristol-Myers Squibb, Prime Oncology, Exelixis Other, Travel, Accommodations, Expenses. Gilead Sciences, Merck, Infinity Pharmaceuticals Stock. Prime Oncology, Medscape, BostonGene Other, Honoraria. Bristol-Myers Squibb, Progenics, Clovis Oncology, Laekna Health Care, AstraZeneca, Xencor, Zenith Pharmaceuticals, Exelixis ). R. R. McKay, Ambrx; Ambrx; Arcus Biosciences; Astellas Medivation; AstraZeneca; AVEO; Bayer; Blue Earth Diagnostics; Bristol-Myers Squibb; Calithera Biosciences; Caris Life Sciences; Dendreon; Esiai; Exelixis; Ja Other, Consulting or Advisory Role. Artera (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol Myers Squibb (Inst); Exelixis (Inst); Oncternal Therapeutics (Inst); Tempus (Inst) ).

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