First-in-Class T-Cell Stimulator Varlilumab in Advanced Solid Tumors
A phase I study reported by Burris et al in the Journal of Clinical Oncology has shown that the first-in-class agonist anti-CD27 antibody varlilumab is well tolerated and active in patients with advanced solid tumors. CD27 is a co-stimulatory molecule on T cells that induces intracellular signaling for cellular activation, proliferation, effector function, and survival upon binding with its ligand CD70 (normally transiently expressed on antigen-presenting cells).
Study Details
In a dose-escalation phase, 25 patients with solid tumors (primarily colorectal cancer and melanoma) received a single intravenous dose of varlilumab at 0.1, 0.3, 1.0, 3.0, or 10 mg/kg with a 28-day observation period, followed by up to five multidose cycles (one dose per week for 4 weeks) depending on tumor response. In expansion cohorts, 16 patients with melanoma and 15 patients with renal cell carcinoma were started at a dose of 3.0 mg/kg. All patients had stage IV disease, and most were heavily pretreated.
Toxicities
Only one dose-limiting toxicity was observed, consisting of grade 3 transient asymptomatic hyponatremia at a dose of 1.0 mg/kg. No maximum tolerated dose was identified. Overall, patients received a median of four doses (range = 1–21), with 10 patients receiving at least one treatment cycle. Among all 56 patients, treatment-related toxicities were generally grade 1 or 2 and included fatigue, rash, nausea, and diarrhea; grade ≥ 3 treatment-related adverse events consisted of one case each of grade 3 hyponatremia, decreased appetite, and decreased lymphocyte count and one case of grade 4 asthma and bronchospasm.
Activity
Evidence of biologic activity, including chemokine induction, T-cell stimulation, and regulatory T-cell depletion, was observed across dose levels. One patient with metastatic renal cell carcinoma had a partial response, with progression-free survival of 2.3 years. Eight patients experienced stable disease for > 3 months, including four with renal cell carcinoma (5.3, 5.6, 9.3, and ≥ 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one with colorectal adenocarcinoma (5.7 months).
The investigators concluded: “Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.”
The study was supported by Celldex Therapeutics.
Howard A. Burris, MD, of Sarah Cannon Research Institute, Tennessee Oncology, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
