Sistema de Salut de Catalunya
Institut Català de la Salut
[Munoz-Couselo E] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Soria Rivas S] Department of Medical Oncology, University Hospital Ramón y Cajal, Madrid, Spain. [Sandhu S] Department of Medical Oncology, Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Australia. [Long GV] Melanoma Institute Australia, The University of Sydney, Sydney, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia. [Sanmamed MF] Department of Medical Oncology, Clinica Universidad de Navarra, Pamplona, Spain. CIBERONC, Instituto de Salud Carlos III, Madrid, Spain. [Spreafico A] Division of Medical Oncology, Princess Margaret Cancer Centre University Health Network, Toronto, Canada
Vall d'Hebron Barcelona Hospital Campus
2025-03-20T12:42:22Z
2025-03-20T12:42:22Z
2025-02-24
Immunocitocina simlukafusp alfa; Pembrolizumab; Melanoma avançat
Inmunocitocina simlukafusp alfa; Pembrolizumab; Melanoma avanzado
Immunocytokine simlukafusp alfa; Pembrolizumab; Advanced melanoma
Purpose: This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma. Patients and Methods: This open-label, multicenter, phase Ib clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or CPI-experienced. Patients received 10 mg FAP-IL2v either continuously once every 3 weeks (Q3W) or in an induction/maintenance setting consisting of a 3-week induction phase with weekly (QW) dosing followed by continuous Q3W dosing. Pembrolizumab was dosed Q3W at 200 mg. Results: Eighty-three patients were treated: 16 patients in two safety run-in cohorts and 67 patients in two extension cohorts; 75 (90.4%) patients were CPI-experienced. The pharmacokinetics of FAP-IL2v in combination with pembrolizumab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded NK and CD8 T cells. The most common FAP-IL2v–related grade 3/4 adverse events were lymphopenia (23%), elevated γ-glutamyltransferase (8%), elevated alanine aminotransferase (6%), and infusion-related reaction (6%). A response was observed in 5 of 75 (6.7%) CPI-experienced patients (all partial responses) and 2 of 8 CPI-naïve patients (one complete response and one partial response). The median progression-free survival was 3.1 months. Conclusions: The safety profile of FAP-IL2v in combination with pembrolizumab was manageable and consistent with the known safety profile. However, further exploration of FAP-IL2v and pembrolizumab was precluded in patients with melanoma with prior CPI due to the lack of clinical activity. Significance: In this phase Ib study, the combination of FAP-IL2v, an immune-cytokine developed to overcome the limitations of wild-type IL2, with the CPI pembrolizumab did not show meaningful antitumor activity in patients who had progressed on prior CPI therapy, suggesting that FAP-IL2v alone cannot overcome CPI resistance or unresponsiveness.
This study was funded by F. Hoffmann-La Roche Ltd.
Article
Versió publicada
Anglès
Anticossos monoclonals - Ús terapèutic; Melanoma - Tractament; Quimioteràpia combinada; Pell - Càncer - Tractament; DISEASES::Neoplasms::Neoplasms by Site::Skin Neoplasms; DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neuroendocrine Tumors::Melanoma; Other subheadings::Other subheadings::Other subheadings::/drug therapy; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols; CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal::Antibodies, Monoclonal, Humanized; Other subheadings::Other subheadings::/therapeutic use; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias cutáneas; ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::tumores neuroendocrinos::melanoma; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada; COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales; Otros calificadores::Otros calificadores::/uso terapéutico
American Association for Cancer Research
Cancer Research Communications;5(2)
https://doi.org/10.1158/2767-9764.CRC-24-0601
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
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