A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors

IF 3 Q2 ONCOLOGY
Kathryn E. Beckermann MD, PhD , Christine M. Bestvina MD , Badi El Osta MD , Rachel E. Sanborn MD , Hossein Borghaei MD , Philip Edward Lammers MD, MSCI , Giovanni Selvaggi MD , Jennifer G. Whisenant PhD , Ellen Heimann-Nichols MBA , Lynne Berry PhD , Chih-Yuan Hsu PhD , Yu Shyr PhD , Leora Horn MD, MSc, MHPE , Heather Wakelee MD, FASCO
{"title":"A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors","authors":"Kathryn E. Beckermann MD, PhD ,&nbsp;Christine M. Bestvina MD ,&nbsp;Badi El Osta MD ,&nbsp;Rachel E. Sanborn MD ,&nbsp;Hossein Borghaei MD ,&nbsp;Philip Edward Lammers MD, MSCI ,&nbsp;Giovanni Selvaggi MD ,&nbsp;Jennifer G. Whisenant PhD ,&nbsp;Ellen Heimann-Nichols MBA ,&nbsp;Lynne Berry PhD ,&nbsp;Chih-Yuan Hsu PhD ,&nbsp;Yu Shyr PhD ,&nbsp;Leora Horn MD, MSc, MHPE ,&nbsp;Heather Wakelee MD, FASCO","doi":"10.1016/j.jtocrr.2023.100619","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies.</p></div><div><h3>Methods</h3><p>This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate.</p></div><div><h3>Results</h3><p>A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%–60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%–17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%–27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%–33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%–27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%–100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors.</p></div><div><h3>Conclusions</h3><p>Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 2","pages":"Article 100619"},"PeriodicalIF":3.0000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364323001625/pdfft?md5=dccb3d4c2096d1c8b2f2221d50859b62&pid=1-s2.0-S2666364323001625-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JTO Clinical and Research Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666364323001625","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction

Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies.

Methods

This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate.

Results

A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%–60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%–17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%–27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%–33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%–27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%–100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors.

Conclusions

Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

评估Nivolumab与血管内皮生长因子酪氨酸激酶抑制剂Vorolanib联合治疗难治性胸部肿瘤患者的安全性和活性的1/2期研究
导言针对肿瘤微环境可增强对免疫疗法(免疫检查点抑制剂)的反应并改善患者的预后。本研究测试了血管内皮生长因子、血小板衍生生长因子和c-KIT的新型酪氨酸激酶抑制剂vorolanib联合程序性细胞死亡蛋白1阻断剂nivolumab治疗难治性胸部恶性肿瘤的安全性和有效性。方法这项单臂多中心研究招募了广泛期SCLC、胸腺癌和NSCLC患者,这些患者要么是对化疗或免疫检查点抑制剂(原发性或获得性耐药)持怀疑态度,要么已经取得进展。第一阶段的主要目标是确定最大耐受剂量,每个剂量扩展队列的主要终点是客观反应率。结果 第一阶段(11 例)和剂量扩展队列(77 例)共招募了 88 例患者。转氨酶是剂量限制因素,因此扩增组采用每日口服沃罗来尼200毫克、每2周静脉注射尼伐单抗240毫克的治疗方案。每个队列的客观反应率如下:NSCLC天真患者为33%(15例中有5例,95%置信区间[CI]:13%-60%),NSCLC原发性难治患者为5.9%(17例中有1例,95%CI:0%-17.6%),NSCLC获得性耐药患者为11.1%(18例中有2例,95%CI:0%-27.8%);SCLC为0%(18例中有0例),胸腺癌为11%(9例中有1例,95%CI:0%-33%)。疾病控制率从SCLC的11.1%(18例中的2例,0%-27.8%)到胸腺癌的66.7%(9例中的6例,95% CI:33.3%-100%)不等。最常见的不良反应是疲劳(32%)、天冬氨酸转氨酶(27%)和丙氨酸转氨酶升高(25%)以及腹泻(19%)。结论Vorolanib联合nivolumab具有可控的安全性,可能对各种胸部恶性肿瘤有临床疗效。胸腺恶性肿瘤的疾病控制率值得进一步评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
4.20
自引率
0.00%
发文量
145
审稿时长
19 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信