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
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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。
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来源期刊
CiteScore
4.20
自引率
0.00%
发文量
145
审稿时长
19 weeks
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