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1.
Clin Cancer Res ; 27(10): 2773-2781, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33441294

RESUMO

PURPOSE: Investigate the safety and efficacy of LY3415244, a TIM-3/PD-L1 bispecific antibody that blocks TIM-3 and PD-L1 in patients with advanced solid tumors. PATIENTS AND METHODS: A phase I, multicenter, open-label study was conducted in patients with advanced solid tumors. Patients were dosed every 2 weeks intravenously with flat doses of LY3415244 escalating from 3 to 70 mg. The primary endpoints were safety, tolerability, and identification of the recommended phase II dose. RESULTS: Between November 2018 and October 2019, 12 patients were enrolled into four cohorts and received at least one dose of LY3415244. Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions and all patients developed treatment-emergent antidrug antibodies (TE-ADA). ADA titers were sometimes very high and negatively impacted soluble TIM-3 target engagement in most patients. ADA epitope specificity was against both TIM-3 and PD-L1 arms of the bispecific antibody; most TE-ADAs initially targeted the TIM-3 arm after the first dose. Preexisting ADAs against LY3415244 were also detected in normal (unexposed) human serum samples. One patient with PD-1 refractory non-small cell lung cancer had a near partial response (-29.6%). CONCLUSIONS: This TIM-3 and PD-L1 bispecific format was associated with unexpected immunogenicity targeting both arms of the bispecific antibody, resulting in early study termination. Epitope specificity analysis revealed an initial response toward the TIM-3 arm and presence of preexisting ADAs to the bispecific molecule in the general population. This experience emphasizes the importance of thorough analyses for preexisting ADAs as part of immunogenicity risk assessment of novel antibodies.See related commentary by de Spéville and Moreno, p. 2669.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Biomarcadores , Gerenciamento Clínico , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/mortalidade , Resultado do Tratamento
2.
Clin Cancer Res ; 27(8): 2168-2178, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33514524

RESUMO

PURPOSE: T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor. PATIENTS AND METHODS: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis. RESULTS: No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients. CONCLUSIONS: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Receptor Celular 2 do Vírus da Hepatite A , Inibidores de Checkpoint Imunológico , Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Antígeno B7-H1/antagonistas & inibidores , Relação Dose-Resposta a Droga , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacocinética , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/mortalidade , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos
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