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

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, 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

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.

Keywords: Advanced solid tumors; Checkpoint inhibitors; Immunotherapy; Nivolumab; Pembrolizumab; Vorolanib.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. Saiama N. Waqar reports funding from SWOG-Clinical Trials Partnership for oversight of the Lung-MAP master protocol and sub-study activities as co-Principal Investigator, and serves as Chair of Data Safety Monitoring Board for a Hoosier Cancer Research Network study. On behalf of all authors, the corresponding author states that there is no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Patient flow diagram
Fig. 2
Fig. 2
Radiographic tumor response and duration of therapy. Spider plot of best overall response. Radiographic response evaluated on the basis of Response Evaluation in Solid Tumors version 1.1 (RECIST v1.1). Each line represents one patient. The dotted lines at + 20% represent cutoffs for progressive disease and at − 30% represent cutoffs for partial response. X82 300 mg: Vorolanib 300 mg. X82 400 mg: Vorolanib 400 mg. Pembro: Pembrolizumab. Nivo: Nivolumab. HCC: Hepatocellular cancer. SCLC: Small cell lung cancer

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