Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors.

Abstract

PURPOSE:

Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors.

METHODS:

We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).

RESULTS:

Sixteen patients (9 in pembrolizumab arm, 7 in nivolumab arm) with gastrointestinal or lung cancers were enrolled. All patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all cohorts were lymphopenia (n = 7), leukopenia (n = 5), fatigue (n = 5), and alanine aminotransferase elevation (n = 5); most toxicities were grade (G) 1-2. DLTs were reported in 3 patients at vorolanib 400 mg dose level, with G3 aspartate aminotransferase elevation, G3 rectal hemorrhage, and G3 rash. Of 13 total response-evaluable patients, 2 patients had confirmed partial responses (1 rectal squamous cell cancer and 1 small cell lung cancer). Two patients achieved prolonged stable disease. Vorolanib 300 mg daily was determined to be the RP2D for either pembrolizumab or nivolumab.

CONCLUSION:

Combination vorolanib 300 mg orally once daily plus CPI appears to be a feasible regimen with manageable toxicity and promising efficacy in select tumor types. NCT03511222. Date of Registration: April 18, 2018.

• Authors: Nusayba A Bagegni, Haeseong Park, Katlyn Kraft, Maura O-Toole, Feng Gao, Saiama N Waqar, Lee Ratner, Daniel Morgensztern, Siddhartha Devarakonda, Manik Amin, Maria Q Baggstrom, Chris Liang, Giovanni Selvaggi, Andrea Wang-Gillam
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 89 Issue 4 Pg. 487-497 (04 2022) ISSN: 1432-0843 [Electronic] Germany
• PMID: 35247086 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Immune Checkpoint Inhibitors
• Indoles
• Pyrroles
• Pyrrolidines
• Nivolumab
• vorolanib

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Humans
• Immune Checkpoint Inhibitors (adverse effects)
• Indoles
• Lung Neoplasms (etiology)
• Neoplasms (pathology)
• Nivolumab (therapeutic use)
• Pyrroles
• Pyrrolidines