1. Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study
- Author
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Alessandro D Santin, Ignace Vergote, Antonio González-Martín, Kathleen Moore, Ana Oaknin, Ignacio Romero, Sami Diab, Larry J Copeland, Bradley J Monk, Robert L Coleman, Thomas J Herzog, Jonathan Siegel, Linda Kasten, Andreas Schlicker, Anke Schulz, Karl Köchert, Annette O Walter, Barrett H Childs, Cem Elbi, Iurie Bulat, Institut Català de la Salut, [Santin AD] Yale School of Medicine, New Haven, CT, USA. [Vergote I] University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. [González-Martín A] Clinica Universidad de Navarra, Madrid, Spain. [Moore K] University of Oklahoma Health Sciences Center, Oklahoma, OK, USA. [Oaknin A] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Romero I] Instituto Valenciano de Oncología, Valencia, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Science & Technology ,Anticossos monoclonals - Ús terapèutic ,Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES] ,BEVACIZUMAB ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Medicaments antineoplàstics - Ús terapèutic ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Obstetrics & Gynecology ,Obstetrics and Gynecology ,aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::globulinas séricas::inmunoglobulinas::anticuerpos::inmunoconjugados [COMPUESTOS QUÍMICOS Y DROGAS] ,Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Serum Globulins::Immunoglobulins::Antibodies::Immunoconjugates [CHEMICALS AND DRUGS] ,Ovaris - Càncer - Tractament ,neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES] ,CHEMOTHERAPY ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,ovarian cancer ,Oncology ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,TRIAL ,WEEKLY PACLITAXEL ,TOPOTECAN ,Life Sciences & Biomedicine - Abstract
ObjectivesAnetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer.MethodsAnetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing.ResultsIn dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months.ConclusionsAnetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.Trial registration numberNCT02751918.
- Published
- 2022