Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I
T Cascone1, R L Sacks2, I M Subbiah3
1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
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.
Insights
The combination of vandetanib (VAN) and everolimus (EV) is safe and effective for treating advanced solid tumors. This VAN + EV therapy demonstrated clinical benefit in patients with refractory cancers.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Preclinical data suggest combining vandetanib (VAN), a multi-tyrosine kinase inhibitor (targeting RET, VEGFR, EGFR), with everolimus (EV), an mTOR inhibitor, may enhance antitumor effects.
- The study aimed to assess the safety, tolerability, and preliminary efficacy of this combination in patients with advanced solid tumors.
Purpose of the Study:
- Determine the safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of vandetanib plus everolimus.
- Evaluate the efficacy of the combination therapy in patients with advanced solid tumors.
- Investigate the effect of combination therapy on cancer cell proliferation and intracellular pathways.
Main Methods:
- A phase I dose-escalation trial enrolled patients with refractory solid tumors.
- Vandetanib (100-300 mg daily) and everolimus (2.5-10 mg daily) were administered orally.
- Objective responses were assessed using RECIST v1.1, and cell-based studies utilized RET mutant cancer cell lines.
Main Results:
- Of 80 enrolled patients, 72 were evaluable; 10% achieved partial response and 51% had stable disease.
- Clinical benefit (≥ 6 months stable disease or partial response) was observed in 36% of evaluable patients.
- The MTD for VAN + EV was 300 mg + 10 mg, respectively. Combination therapy showed superior inhibition of cancer cell proliferation and signaling in vitro.
Conclusions:
- Vandetanib plus everolimus (300 mg and 10 mg, respectively) is a safe and active combination for patients with refractory solid tumors.
- The combination demonstrated promising clinical activity and manageable toxicity.
- Further research is warranted, particularly in tumors with RET pathway aberrations.
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