Abstract A017-PR013: Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: An update from the iMATRIX alectinib phase I/II open-label, multi-center study

IF 16.6 1区 医学 Q1 ONCOLOGY
Francois Doz, Michela Casanova, Kyung-Nam Koh, Karsten Nysom, Adela Canete, Hyoung Jin Kang, Matthias Karajannis, Darren Hargrave, Nadege Corradini, Yeming Wu, Huanmin Wang, David Ziegler, Nicolas Prud'homme, Carla Manzitti, Quentin Campbell-Hewson, Carolina Sturm-Pellanda, Tao Xu, Dhruvitkumar S. Sutaria, Livingstone Fultang, Clare Devlin, Francis Mussai, Amar J Gajjar
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Methods: Patients, less than 18 years of age, with ALK fusion-positive CNS and non-CNS tumors for whom prior treatment had proven to be ineffective or for whom there was no satisfactory treatment available were eligible. Patients were recruited to Part 1 to confirm the recommended phase 2 dose (RP2D) and to study drug pharmacokinetics. Alectinib was administered as an oral tablet or suspension twice a day according to initial weight. Investigators reported Best Overall Response according to RANO (CNS tumors) or RECIST v1.1 (solid tumors) criteria (data cut off February 2025). Results: In total 25 patients with a median age of 7.5 years (range 0-17 years) were enrolled. Fifteen patients were diagnosed with solid tumors: inflammatory myofibroblastic tumor (n = 10), renal cell carcinoma (n = 2), mesothelioma (n = 1), nephroblastoma (n = 1), and atypical melanocytic tumor (n = 1). Eight patients were diagnosed with CNS tumors: high grade glioma (n = 7) and pleomorphic xanthoastrocytoma (n = 1). Two patients had ineligible conditions: histiocytosis (n = 1) and anaplastic large cell lymphoma (n = 1). Ten of 25 patients had received prior systemic therapy. ALK fusion partners were EML4 and CLTC in 3 patients, TPM3, KIF5C, PPP1CB and FN1 in 2 patients, and DCTN1, KIF5B, NPM, STRN, CLIP1, RANBP2, ZEB2, PLEKHA7, CDC42BPB, HNRNPA3, and ZNF397 in 1 patient each. In the 24 safety evaluable patients, only 1 Dose Limiting Toxicity (DLT) of Grade 3 increased alanine aminotransferase, during multiple viral infections, was reported. The DLT resolved after treatment interruption and Alectinib was successfully tolerated at a reduced dose level. Twenty patients (83%) experienced at least one Adverse Event (AE) reported as related to Alectinib, mostly Grade 1 or 2. Grade ≥ 3 AEs assessed as related to alectinib by the investigator were reported for 6 patients (25%) and consisted of increases in CPK,AST, ALT, bilirubin; neutropenia, optic neuropathy, encephalopathy and weight gain. Of these the increased ALT (DLT) and optic neuropathy/ encephalopathy in 2 patients were serious AEs. No new safety signals were detected. Investigator reported Best Overall Response rate in 19 patients was 89.5%; (3 CRs, 14 PRs) and 2 patients were reported to have confirmed stable disease. One complete response and 5 partial responses were observed in 6/6 evaluable patients with CNS tumors. Two complete responses and 9 partial responses were seen in 11 evaluable patients with solid tumours. Four patients were excluded from the efficacy analysis due to ineligible tumor type (n = 2), not dosed (n = 1), no measurable disease according to RANO criteria (n = 1). Conclusions: Alectinib continues to have a favourable safety profile in pediatric patients. Clinical efficacy results are highly encouraging with most patients experiencing a tumor response. Citation Format: Francois Doz, Michela Casanova, Kyung-Nam Koh, Karsten Nysom, Adela Canete, Hyoung Jin Kang, Matthias Karajannis, Darren Hargrave, Nadege Corradini, Yeming Wu, Huanmin Wang, David Ziegler, Nicolas Prud'homme, Carla Manzitti, Quentin Campbell-Hewson, Carolina Sturm-Pellanda, Tao Xu, Dhruvitkumar S. Sutaria, Livingstone Fultang, Clare Devlin, Francis Mussai, Amar J Gajjar. Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: An update from the iMATRIX alectinib phase I/II open-label, multi-center study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A017-PR013.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"69 1","pages":""},"PeriodicalIF":16.6000,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1538-7445.pediatric25-a017-pr013","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Alectinib is a next generation, oral, ALK inhibitor being investigated in children and adolescents with ALK-fusion bearing tumors. Here we present updated safety and efficacy data from iMATRIX Alectinib phase I-II study (NCT04774718). Methods: Patients, less than 18 years of age, with ALK fusion-positive CNS and non-CNS tumors for whom prior treatment had proven to be ineffective or for whom there was no satisfactory treatment available were eligible. Patients were recruited to Part 1 to confirm the recommended phase 2 dose (RP2D) and to study drug pharmacokinetics. Alectinib was administered as an oral tablet or suspension twice a day according to initial weight. Investigators reported Best Overall Response according to RANO (CNS tumors) or RECIST v1.1 (solid tumors) criteria (data cut off February 2025). Results: In total 25 patients with a median age of 7.5 years (range 0-17 years) were enrolled. Fifteen patients were diagnosed with solid tumors: inflammatory myofibroblastic tumor (n = 10), renal cell carcinoma (n = 2), mesothelioma (n = 1), nephroblastoma (n = 1), and atypical melanocytic tumor (n = 1). Eight patients were diagnosed with CNS tumors: high grade glioma (n = 7) and pleomorphic xanthoastrocytoma (n = 1). Two patients had ineligible conditions: histiocytosis (n = 1) and anaplastic large cell lymphoma (n = 1). Ten of 25 patients had received prior systemic therapy. ALK fusion partners were EML4 and CLTC in 3 patients, TPM3, KIF5C, PPP1CB and FN1 in 2 patients, and DCTN1, KIF5B, NPM, STRN, CLIP1, RANBP2, ZEB2, PLEKHA7, CDC42BPB, HNRNPA3, and ZNF397 in 1 patient each. In the 24 safety evaluable patients, only 1 Dose Limiting Toxicity (DLT) of Grade 3 increased alanine aminotransferase, during multiple viral infections, was reported. The DLT resolved after treatment interruption and Alectinib was successfully tolerated at a reduced dose level. Twenty patients (83%) experienced at least one Adverse Event (AE) reported as related to Alectinib, mostly Grade 1 or 2. Grade ≥ 3 AEs assessed as related to alectinib by the investigator were reported for 6 patients (25%) and consisted of increases in CPK,AST, ALT, bilirubin; neutropenia, optic neuropathy, encephalopathy and weight gain. Of these the increased ALT (DLT) and optic neuropathy/ encephalopathy in 2 patients were serious AEs. No new safety signals were detected. Investigator reported Best Overall Response rate in 19 patients was 89.5%; (3 CRs, 14 PRs) and 2 patients were reported to have confirmed stable disease. One complete response and 5 partial responses were observed in 6/6 evaluable patients with CNS tumors. Two complete responses and 9 partial responses were seen in 11 evaluable patients with solid tumours. Four patients were excluded from the efficacy analysis due to ineligible tumor type (n = 2), not dosed (n = 1), no measurable disease according to RANO criteria (n = 1). Conclusions: Alectinib continues to have a favourable safety profile in pediatric patients. Clinical efficacy results are highly encouraging with most patients experiencing a tumor response. Citation Format: Francois Doz, Michela Casanova, Kyung-Nam Koh, Karsten Nysom, Adela Canete, Hyoung Jin Kang, Matthias Karajannis, Darren Hargrave, Nadege Corradini, Yeming Wu, Huanmin Wang, David Ziegler, Nicolas Prud'homme, Carla Manzitti, Quentin Campbell-Hewson, Carolina Sturm-Pellanda, Tao Xu, Dhruvitkumar S. Sutaria, Livingstone Fultang, Clare Devlin, Francis Mussai, Amar J Gajjar. Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: An update from the iMATRIX alectinib phase I/II open-label, multi-center study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A017-PR013.
a17 - pr013: Alectinib治疗含有alk融合的儿童和青少年实体或中枢神经系统肿瘤:iMATRIX Alectinib I/II期开放标签、多中心研究的最新进展
背景:Alectinib是下一代口服ALK抑制剂,正在研究用于儿童和青少年ALK融合肿瘤。在此,我们提供iMATRIX Alectinib I-II期研究(NCT04774718)的最新安全性和有效性数据。方法:年龄小于18岁的ALK融合阳性中枢神经系统和非中枢神经系统肿瘤患者,先前的治疗被证明无效或没有令人满意的治疗。第一部分招募患者以确认推荐的2期剂量(RP2D)并研究药物药代动力学。根据初始体重给予阿勒替尼口服片剂或混悬剂,每天两次。研究者根据RANO(中枢神经系统肿瘤)或RECIST v1.1(实体肿瘤)标准报告了最佳总体缓解(数据截止到2025年2月)。结果:共纳入25例患者,中位年龄为7.5岁(范围0-17岁)。确诊实体瘤15例:炎性肌纤维母细胞瘤(n = 10)、肾细胞癌(n = 2)、间皮瘤(n = 1)、肾母细胞瘤(n = 1)、非典型黑素细胞瘤(n = 1)。8例患者被诊断为中枢神经系统肿瘤:高级别胶质瘤(n = 7)和多形性黄色星形细胞瘤(n = 1)。2例患者有不符合条件的情况:组织细胞增多症(n = 1)和间变性大细胞淋巴瘤(n = 1)。25例患者中有10例既往接受过全身治疗。ALK融合伙伴为EML4、CLTC 3例,TPM3、KIF5C、PPP1CB、FN1 2例,DCTN1、KIF5B、NPM、STRN、CLIP1、RANBP2、ZEB2、PLEKHA7、CDC42BPB、HNRNPA3、ZNF397各1例。在24例可安全性评估的患者中,只有1例在多重病毒感染期间丙氨酸转氨酶3级升高的剂量限制性毒性(DLT)被报道。DLT在治疗中断后消退,Alectinib在降低剂量水平下成功耐受。20名患者(83%)经历了至少一次与Alectinib相关的不良事件(AE),主要是1级或2级。6例患者(25%)报告了研究者评估的与alectinib相关的≥3级ae,包括CPK、AST、ALT、胆红素升高;中性粒细胞减少,视神经病变,脑病和体重增加。其中ALT (DLT)升高和视神经病变/脑病2例为严重ae。没有检测到新的安全信号。研究者报告19例患者的最佳总有效率为89.5%;报告3例CRs, 14例PRs, 2例确诊病情稳定。在6/6可评估的中枢神经系统肿瘤患者中观察到1例完全缓解和5例部分缓解。在11例可评估的实体瘤患者中观察到2例完全缓解和9例部分缓解。4例患者因肿瘤类型不符合要求(n = 2)、未给药(n = 1)、根据RANO标准无可测量疾病(n = 1)而被排除在疗效分析之外。结论:Alectinib在儿科患者中仍然具有良好的安全性。临床疗效结果是非常令人鼓舞的,大多数患者经历肿瘤反应。引文格式:Francois Doz, Michela Casanova, Kyung-Nam Koh, Karsten Nysom, Adela Canete, hyyoung Jin Kang, Matthias Karajannis, Darren Hargrave, Nadege Corradini, Yeming Wu, Huanmin Wang, David Ziegler, Nicolas Prud'homme, Carla Manzitti, Quentin Campbell-Hewson, Carolina Sturm-Pellanda, Tao Xu, Dhruvitkumar S. Sutaria, Livingstone Fultang, Clare Devlin, Francis Mussai, Amar J Gajjar。阿勒替尼治疗含有alk融合的儿童和青少年实体或中枢神经系统肿瘤:iMATRIX阿勒替尼I/II期开放标签多中心研究的最新进展[摘要]。AACR癌症研究特别会议论文集:儿童癌症的发现和创新-从生物学到突破性疗法;2025年9月25日至28日;波士顿,MA。费城(PA): AACR;癌症研究2025;85(18_Suppl_2): nr A017-PR013。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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