medwireNews: First-in-human study findings suggest an antibody–drug conjugate may offer a novel treatment for tumors that overexpress the transmembrane tumor differentiation antigen mesothelin.
The investigators explain that anetumab ravtansine comprises an immunoglobulin G1 antibody targeting mesothelin conjugated to the maytansinoid tubulin inhibitor DM4, and was previously demonstrated as cytotoxic in several mesothelin-expressing cell lines.
Raffit Hassan (National Cancer Institute, Bethesda, Maryland, USA) and co-workers recruited 148 adult patients with advanced, metastatic or recurrent malignant mesothelioma, ovarian cancer, and other solid tumors to the phase 1 open-label trial.
Forty-five participants were assigned to receive anetumab ravtansine as a 1-hour intravenous infusion at a dose of 0.15–7.5 mg/kg every 3 weeks within one of 10 dose-escalation cohorts.
The maximum tolerated dose was determined to be 6.5 mg/kg given every 3 weeks, with one dose-limiting toxicity of grade 3 increase in aspartate aminotransferase (AST) occurring at this dose.
Three cohorts of patients with mesothelioma or advanced epithelial ovarian cancer were assigned to receive the maximum tolerated dose (n=32), a weekly 1.8 mg/kg dose (n=35) or a weekly 2.2 mg/kg dose (n=36).
Writing in the Journal of Clinical Oncology, the team reports no treatment-related deaths among these three cohorts.
Drug-related treatment-emergent adverse events (TEAEs) at grade 3 and worse occurred in 29% of patients in the 6.5 mg/kg every 3 weeks cohort; TEAEs at this severity included fatigue (16%) and nausea (8%), with 5% of patients experiencing elevated AST, keratitis, or dyspnea.
For the 1.8 mg/kg weekly group, 23% experienced grade 3 or more severe drug-related TEAEs, with 6% experiencing abdominal pain and 3% reporting nausea, diarrhea, vomiting, AST elevation, keratitis, or dyspnea. And 19% of patients given the 2.2 mg/kg weekly dose experienced grade 3 and more severe drug-related TEAEs, with the most common TEAEs being dyspnea (11%), keratitis (8%), and hypoalbuminemia (6%).
The researchers describe anetumab ravtansine as “well tolerated,” noting that the “drug-related TEAEs either were reversible and resolved within 2–4 weeks of study drug cessation or showed a clear trend toward recovery at the last follow-up.”
Tumor response was assessed in 138 of the patients and showed “encouraging preliminary clinical activity,” the investigators say, with a complete response in one, a partial response in 11, and stable disease in 66 patients. The objective response rates in mesothelioma and ovarian cancer patients given the 6.5 mg/kg dose were 31% and 5%, respectively. The corresponding rates were 6% and 11% for the 1.8 mg/kg dose, and 0% and 10% for the 2.2 mg/kg dose.
“On the basis of all the findings from the phase I study of anetumab ravtansine, several additional clinical trials are underway (ClinicalTrials.gov identifiers: NCT02751918, NCT03455556, NCT03126630, and NCT03102320) to evaluate the safety, tolerability, and activity of anetumab ravtansine as monotherapy or in combination with standard of care in a variety of mesothelin-expressing solid tumors,” conclude Hassan and co-authors.
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