Targeting the MET Pathway in Urothelial Carcinoma

靶向尿路上皮癌的 MET 通路

• 批准号: 10702596
• 负责人: Andrea Apolo
• 金额: $ 118.93万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702596
• 关键词: Adverse event; Angiogenesis Inhibitors; Anorexia; Avidity; Binding; Bladder Adenocarcinoma; Blood; Body Weight decreased; CCR; CD8-Positive T-Lymphocytes; Cancer Patient; Cancer cell line; Carboplatin; Carcinoid Tumor; Cell surface; Cells; Cisplatin; Clear cell renal cell carcinoma; Clinical; Clinical Treatment; Data; Data Pooling; Databases; Dehydration; Diarrhea; Dose; Dose-Limiting; ENG gene; Endoglin; Endometrial Carcinoma; Enzymes; Equilibrium; Evaluable Disease; Fatigue; Flow Cytometry; Functional disorder; Goals; HGF gene; Human; Immune; Immune checkpoint inhibitor; Immunotherapeutic agent; Innate Immune Response; International; Journals; KDR gene; Literature; Liver; MAP Kinase Gene; Malignant neoplasm of penis; Malignant neoplasm of urinary bladder; Manuscripts; Mediating; Medicine; Metastatic Renal Cell Cancer; Monoclonal Antibodies; Mononuclear; Mucositis; Myelogenous; Myeloid-derived suppressor cells; Nausea and Vomiting; Neuroendocrine Tumors; New England; Nivolumab; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase II Clinical Trials; Placebos; Platinum; Population; Primary carcinoma of the liver cells; Progressive Disease; Property; Protein Tyrosine Kinase; Proteins; Randomized; Receptor Protein-Tyrosine Kinases; Recurrence; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Reporting; Risk; Running; Safety; Sarcomatoid Features; Sarcomatoid Renal Cell Carcinoma; Series; Signal Pathway; Signal Transduction; Squamous cell carcinoma; T-Lymphocyte; Testing; Therapeutic; Therapeutic Trials; Thyroid Gland; Toxic effect; Transitional Cell Carcinoma; Triplet Multiple Birth; Unresectable; Urine; Urothelium; Uterine Corpus Carcinosarcoma; adaptive immunity; advanced disease; angiogenesis; base; bevacizumab; checkpoint inhibition; chemotherapy; cohort; effector T cell; exhaust; gemcitabine; granulocyte; immunoregulation; improved; ipilimumab; lenalidomide; melanoma; monocyte; mortality risk; neoplastic cell; neuroendocrine differentiation; peripheral blood; phase 1 study; phase 2 study; phase 3 study; phase III trial; programmed cell death protein 1; rare cancer; response; small molecule inhibitor; standard care; symposium; targeted agent; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

Effect of cabozantinib on peripheral blood immune subsets in urothelial carcinoma and other GU tumors We conducted a study to assess the impact of cabozantinib on systemic innate and adaptive immune cells. TKIs against VEGFR and other receptor tyrosine kinases may have antitumor immune mediated mechanisms. MET is expressed in tumor cells and in immunosuppressive myeloid cells including human monocytes and granulocytic, MDSCs. Signaling downstream of HGF MET interaction in monocytes may shift the Th1/Th2 balance and expand MDSCs and Tregs. We hypothesized that cabozantinib can modify the tumor microenvironment by modulating immunosuppressive Tregs and MDSCs. We assessed peripheral blood mononuclear cell (PBMC) immune subsets, including effector T cells, exhausted T cells, Tregs, MDSCs, and the functional markers PD 1 and TIM 3, using flow cytometry in metastatic urothelial carcinoma patients undergoing treatment with cabozantinib at baseline and after 2 cycles of continuous cabozantinib treatment, and correlated our findings with clinical response to therapy, PFS, and OS. In summary, our study showed that cabozantinib has innate and adaptive immunomodulatory properties that provide a rationale for combining cabozantinib with immunotherapeutic strategies. Cabozantinib modulated peripheral blood myeloid populations, including decreasing classical monocytes, increasing non classical monocytes, and decreasing MDSCs. Cabozantinib also favorably impacted CD4 polarization to decrease Tregs, increase the ratio of CD8 T cells to Tregs, and upregulate PD 1 expression on Tregs. We plan to validate these findings in 155 patients treated with CaboNivo or CaboNivoIpi with a larger immune subset panel and additional functional markers with the goal to further understand the immune response of innate mononuclear cells that may serve as a targetable nexus for therapeutic engagement of adaptive immunity. Combining cabozantinib with checkpoint inhibition with nivolumab and ipilimumab Based on the immunomodulation seen with cabozantinib, I initiated a multicenter phase 1 study where I combined CaboNivo or CaboNivoIpi. The study included a phase 1 study with 8 dose levels (n = 54) and 7 expansion cohorts, including urothelial carcinoma, renal cell carcinoma, urothelial carcinoma patients previously treated with checkpoint inhibitors, adenocarcinoma of the bladder/urachal, penile cancer, squamous cell carcinoma, and other rare tumors (n = 155). The phase 1 portion is complete, but we are still running the expansion cohorts. Safety of the combination of CaboNivo and CaboNivoIpi: In a phase 1 study, I assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) with or without ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma and other GU malignances. Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase 2 dose (RP2D). Overlapping toxicities with the use of TKIs and checkpoint inhibitors included thyroid dysfunction, diarrhea, and elevated liver enzymes. Cabozantinib 60 mg/day led to higher rates of clinical treatment related adverse events of all grades, including fatigue, diarrhea, anorexia, weight loss, nausea, vomiting, mucositis, and dehydration. Although the study did not have any dose limiting toxicities, the RP2D was cabozantinib 40 mg/day plus nivolumab 3 mg/kg for the doublet and cabozantinib 40 mg/day, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for the triplet, based on better clinical tolerability and similar efficacy of cabozantinib at 40 mg/day vs. 60 mg/day. These data established the safety of the combinations and the RP2D for larger trials. Activity of CaboNivo and CaboNivoIpi: In the phase 1 study of CaboNivo and CaboNivoIpi (n = 54), we reported an ORR of 30.6% for all patients and 38.5% for urothelial carcinoma patients.23 Median duration of response was 21.0 months for all patients and not reached for metastatic urothelial carcinoma patients. Median PFS was 5.1 months for all patients and 12.8 months for urothelial carcinoma patients. Median OS was 12.6 months for all patients and 25.4 months for metastatic urothelial carcinoma patients. Based on the initial efficacy seen in the phase 1 patients, additional expansion cohorts were added to the study. Expansion cohorts of CaboNivo and CaboNivoIpi in patients naive to checkpoint inhibition: The pooled data from the phase 1 and expansion cohorts in patients naive to immune checkpoint inhibition (n = 120) are currently being analyzed. For all currently evaluable patients (n = 109), the ORR = 37.6%, CR = 9.2%, PR = 28.4%, and SD = 43.1%. The urothelial carcinoma expansion cohort included 24 patients treated with CaboNivo (n = 12) and CaboNivoIpi (n = 12). Similar to the phase 1 study where the ORR was 38.5%, in the urothelial carcinoma expansion cohort the ORR = 42.9% for the 24 urothelial carcinoma patients and for the phase 1+ expansion cohort (n = 40) the ORR = 41.2%, CR = 20.6%, PR = 20.6%, SD = 38.2%, and progressive disease = 23.5%. The clear cell renal cell carcinoma (RCC) patients included patients with sarcomatoid features. In phase 1, all 3 RCC patients had a PR, the RCC expansion cohort included 12 patients treated with CaboNivo (n = 6) and CaboNivoIpi (n = 6), and an additional RCC sarcomatoid patient from the rare tumor cohort. The phase 1 + RCC expansion cohort (n = 16) had an ORR = 62.5%, CR = 12.5%, PR = 50%, SD = 37.5%, and progressive disease = 0%. The promising activity seen in this phase 1 study has led to additional expansion cohorts within this study, including cohorts for urothelial carcinoma, RCC, and other rare GU tumors with no standard treatment options, and has also led to larger trials in GU tumors including CheckMate 9ER, a randomized phase 3 trial of CaboNivo vs. sunitinib in the first line treatment of mRCC, PDIGREE, an adaptive phase 3 trial of CaboNivoIpi in untreated mRCC, COSMIC 313, a phase 3 trial of CaboNivoIpi vs. NivoIpi plus placebo in mRCC, and the Alliance ICONIC study of CaboNivoIpi for rare GU tumors. Several other trials are testing CaboNivo in non clear cell RCC, carcinoid tumors, metastatic triple negative breast cancer, locally advanced hepatocellular carcinoma, advanced endometrial cancer, recurrent uterine carcinosarcoma, poorly differentiated neuroendocrine tumors, and non small cell lung cancer. A study of CaboNivoIpi in unresectable advanced melanoma is also underway. I am on the steering committee for CheckMate 9ER. The first results from the randomized phase 3 study, n = 651 were presented in the presidential symposium at ESMO 2020 showing first line CaboNivo vs. sunitinib improves PFS, 16.6 vs. 8.3 months, OS, 40% decrease in risk of death and ORR, 55.7 vs. 27.1%, with benefit in all International Metastatic RCC Database Consortium risk groups. CaboNivo has potential as first line therapy for metastatic RCC patients. I am an author of the manuscript which was submitted to the New England Journal of Medicine. I am currently working on a subset analysis for patients with sarcomatoid RCC within the 9ER study. For bladder cancer patients, I am working on developing a phase 3 study for the second line treatment of patients post platinum based therapy.

Cabozantinib对尿路上皮癌和其他GU肿瘤中外周血免疫亚群的影响我们进行了一项研究，以评估Cabozantinib对全身先天和适应性免疫细胞的影响。针对VEGFR和其他受体酪氨酸激酶的TKI可能具有抗肿瘤免疫介导的机制。 MET在肿瘤细胞和免疫抑制性髓样细胞中表达，包括人单核细胞和粒细胞MDSC。 HGF下游的信号传导在单核细胞中的相互作用可能会移动TH1/TH2平衡并扩大MDSC和Tregs。我们假设Cabozantinib可以通过调节免疫抑制Treg和MDSC来改变肿瘤微环境。 We assessed peripheral blood mononuclear cell (PBMC) immune subsets, including effector T cells, exhausted T cells, Tregs, MDSCs, and the functional markers PD 1 and TIM 3, using flow cytometry in metastatic urothelial carcinoma patients undergoing treatment with cabozantinib at baseline and after 2 cycles of continuous cabozantinib treatment, and correlated our findings with clinical response to治疗，PFS和OS。总而言之，我们的研究表明，卡博替尼具有先天和适应性的免疫调节特性，这为将Cabozantinib与免疫治疗策略相结合提供了理由。 Cabozantinib调节外周血髓样群体，包括减少经典单核细胞，增加非经典单核细胞和减少MDSC。 Cabozantinib还有利地影响CD4极化，以减少Treg，增加CD8 T细胞与Treg的比率，并在Tregs上上调PD 1表达。我们计划在155例接受Cabonivo或Cabonivoipi治疗的患者中验证这些发现，并具有较大的免疫子集面板和其他功能标记，其目标是进一步了解先天单核细胞的免疫反应，这些细胞可以作为适应性免疫的治疗性接合的可靶向性Nexus。基于Cabozantinib看到的免疫调节，将Cabozantinib与nivolumab和ipilimumab结合起来，并结合了Cabozantinib的免疫调节，我开始了一项多中心1期研究，在该研究中，我将Cabonivo或Cabonivoipi组合在一起。该研究包括一项具有8剂水平（n = 54）和7个扩张队列的1阶段研究，包括尿路上皮癌，肾细胞癌，先前用检查点抑制剂治疗的尿路上皮癌患者，膀胱/膀胱/胸腔癌，阴茎型细胞癌和其他罕见的tame（n = 155）（n = 155）。第1阶段部分已经完成，但是我们仍在运行扩展队列。 Cabonivo和Cabonivoipi组合的安全性：在一项第一阶段研究中，我评估了Cabozantinib和Nivolumab（Cabonivo）的安全性和功效，其中有或没有ipilimumab（cabonivoipi）（Cabonivoipi）对转移性尿道癌和其他GU的患者的安全性。患者接受了Cabonivo或Cabonivoipi的不断升级。主要目标是建立建议的2期剂量（RP2D）。使用TKI和检查点抑制剂的重叠毒性包括甲状腺功能障碍，腹泻和肝脏升高。 Cabozantinib 60 mg/天导致所有等级的临床治疗相关不良事件的率更高，包括疲劳，腹泻，厌食症，体重减轻，恶心，呕吐，粘膜炎和脱水。尽管该研究没有任何剂量的限制毒性，但RP2D为双臂40毫克/天加40毫克/千克的nivolumab和40 mg/day的nivolumab 3 mg/kg，nivolumab 3 mg/kg，iPilimumab 1 mg/kg，基于40 mg/kg，基于40 mg/kg，基于40 mg/kg，基于40 mg/kg，cap/kg cap/kg cap/kg cap/kg。毫克/天。 这些数据确定了组合和RP2D的安全性，用于更大的试验。 Cabonivo和Cabonivoipi的活性：在Cabonivo和Cabonivoipi的第一阶段研究中（n = 54），我们报告所有患者的ORR为30.6％，尿路上皮癌患者为38.5％。23患者的反应持续时间为21.0个月，所有患者均为21.0个月，未触及转移性尿毒蛋白瘤患者。所有患者的PFS中位数为5.1个月，尿路上皮癌患者为12.8个月。所有患者的中位OS为12.6个月，转移性尿路上皮癌患者为25.4个月。根据第1阶段患者中最初的功效，将额外的扩张队列添加到研究中。幼稚到检查点抑制的患者Cabonivo和Cabonivoipi的膨胀队列：目前正在分析对免疫检查点抑制天真的患者的汇总数据和膨胀队列的汇总数据（n = 120）。对于当前可评估的患者（n = 109），ORR = 37.6％，CR = 9.2％，PR = 28.4％，SD = 43.1％。尿路上皮癌的扩张队列包括24例接受Cabonivo（n = 12）和Cabonivoipi（n = 12）治疗的患者。与1阶段的研究相似，其中ORR为38.5％，在尿馆癌肿瘤的膨胀队列中，ORR = 42.9％的尿馆癌症患者和1阶段以上的1+膨胀队列（n = 40）ORR = 41.2％，CR = 20.6％，CR = 20.6％，PR = 20.6％，STD = 38.2％，且5％= 38.2％，且速度= 38.2％，且5％。透明细胞肾细胞癌（RCC）患者包括具有肉瘤性特征的患者。在第1阶段，所有3例RCC患者均具有PR，RCC扩张队列包括12例接受Cabonivo（n = 6）和Cabonivoipi治疗的患者（n = 6），以及来自稀有肿瘤队列的额外RCC肉瘤患者。阶段1 + RCC扩展队列（n = 16）的ORR = 62.5％，CR = 12.5％，PR = 50％，SD = 37.5％，进行性疾病= 0％。 The promising activity seen in this phase 1 study has led to additional expansion cohorts within this study, including cohorts for urothelial carcinoma, RCC, and other rare GU tumors with no standard treatment options, and has also led to larger trials in GU tumors including CheckMate 9ER, a randomized phase 3 trial of CaboNivo vs. sunitinib in the first line treatment of mRCC, PDIGREE, an adaptive phase 3 trial of CaboNivoIpi in未经治疗的MRCC，宇宙313，Cabonivoipi与Nivoipi Plus MRCC中的3期试验以及Cabonivoipi的联盟标志性研究针对稀有的GU肿瘤。其他几项试验是在非透明细胞RCC，类癌肿瘤，转移性三重阴性乳腺癌，局部晚期肝细胞癌，晚期子宫内膜癌，复发性子宫肉癌，神经内聚肿瘤分化较差的情况下测试Cabonivo。在无法切除的晚期黑色素瘤中对Cabonivoipi的研究也正在进行中。我是Checkmate 9ER的指导委员会。在第3阶段研究中的第一个结果，在ESMO 2020年的总统研讨会上介绍了N = 651，显示第一线Cabonivo vs. Sunitinib改善PFS，16.6 vs. 8.3个月，OS，OS，死亡风险下降40％，死亡风险和ORR的风险下降，55.7 vs. 27.1％，有55.7 vs. 27.1％受益于所有国际转移RCC Database Confum constase constase constase constase constase constase constass constass constass consort consort tarkase consortaltium consortortaltium。 Cabonivo具有转移性RCC患者的第一线治疗。我是手稿的作者，该手稿已提交新英格兰医学杂志。我目前正在为9ER研究中的肉瘤类动物RCC患者进行子集分析。对于膀胱癌患者，我正在研究基于铂基治疗后患者的第二行治疗的第三阶段研究。