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

Kathryn E Beckermann; Christine M Bestvina; Badi El Osta; Rachel E Sanborn; Hossein Borghaei; Philip Edward Lammers; Giovanni Selvaggi; Jennifer G Whisenant; Ellen Heimann-Nichols; Lynne Berry; Chih-Yuan Hsu; Yu Shyr; Leora Horn; Heather Wakelee

doi:10.1016/j.jtocrr.2023.100619

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

JTO Clin Res Rep. 2023 Dec 15;5(2):100619. doi: 10.1016/j.jtocrr.2023.100619. eCollection 2024 Feb.

Affiliations

¹ Department of Internal Medicine. Vanderbilt University Medical Center, Nashville, Tennessee.
² Department of Internal Medicine. University of Chicago. Chicago, Illinois.
³ Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, Georgia.
⁴ Providence Cancer Institute, Earle E. Chiles Research Institute, Portland, Oregon.
⁵ Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
⁶ Baptist Cancer Center, Memphis, Tennessee.
⁷ Xcovery Holding, Inc., Palm Beach Gardens, Florida.
⁸ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
⁹ Division of Oncology, Department of Internal Medicine, Stanford University School of Medicine. Stanford, California.

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.

Keywords: Anti-angiogenic; Lung cancer; Nivolumab; PD-1; Small cell; Thymic.