Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study
Year: 2021
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies. RESULTS: Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling. CONCLUSIONS: The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors.
Source: ESMO Open
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,140
Funders: American Association for Cancer Research, American Cancer Society, Mayo Clinic, Boehringer Ingelheim, T.J. Martell Foundation, Jeffrey Modell Foundation, Amgen, Bristol-Myers Squibb, Immune Deficiency Foundation, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Roche, American Society of Clinical Oncology, Spectrum Pharmaceuticals, AbbVie, F. Hoffmann-La Roche, Takeda Pharmaceuticals U.S.A., CSL Behring, Exelixis, Jazz Pharmaceuticals, Society for Immunotherapy of Cancer, Horizon Pharma, National Comprehensive Cancer Network, Bayer Fund, Arrien Pharmaceuticals, Incyte, Calithera Biosciences, Cytori Therapeutics, Heron Therapeutics, eFFECTOR Therapeutics, Aileron Therapeutics, Puma Biotechnology, Fujifilm Corporation, Daiichi-Sankyo, Eisai, MedImmune, European Society for Medical Oncology, Symphogen, National Institutes of Health, Genentech, EMD Serono, University of Texas MD Anderson Cancer Center, National Cancer Institute, Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
OpenAlex ID: W3137082226