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":"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","authors":"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","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":null,"pages":null},"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":"{\"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 , 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\",\"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. 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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
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.
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