Fiche publication
Date publication
janvier 2025
Journal
Signal transduction and targeted therapy
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BERTAUT Aurélie
,
Pr GHIRINGHELLI François
,
Mme TRUNTZER Caroline
,
Dr VINCENT Julie
,
Dr BENGRINE-LEFEVRE Leila
,
Pr SCHMITT Antonin
,
Dr DERANGERE Valentin
,
Dr FUMET Jean-David
,
Dr THIBAUDIN Marion
,
Dr BELLIO Hélène
Tous les auteurs :
Thibaudin M, Roussot N, Burlot C, Schmitt A, Vincent J, Tharin Z, Bengrine L, Bellio H, Bertaut A, Hampe L, Daumoine S, Rederstorff E, Peroz M, Huppe T, Derangère V, Rageot D, Simard J, Truntzer C, Fumet JD, Ghiringhelli F
Lien Pubmed
Résumé
In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1-5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC.
Mots clés
Humans, Male, Female, Aged, Trifluridine, therapeutic use, Middle Aged, Bevacizumab, administration & dosage, Pyrrolidines, therapeutic use, Thymine, Antineoplastic Combined Chemotherapy Protocols, therapeutic use, Interleukin-1alpha, genetics, Colorectal Neoplasms, drug therapy, Adult, Drug Combinations
Référence
Signal Transduct Target Ther. 2025 01 17;10(1):22
