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1.
Clin Cancer Res ; 27(13): 3630-3640, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33820783

RESUMO

PURPOSE: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. PATIENTS AND METHODS: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. RESULTS: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. CONCLUSIONS: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.


Assuntos
Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias
2.
Clin Lymphoma Myeloma ; 7(3): 199-204, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17229335

RESUMO

BACKGROUND: Denileukin diftitox, a fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin and human interleukin, resulted in a response rate of 30% in the phase III registration trial in patients with recurrent or persistent cutaneous T-cell lymphoma (CTCL). Little is known with regard to the biologic correlates of response or the impact of denileukin diftitox on disease progression and survival. PATIENTS AND METHODS: In our single-center series of 37 patients with early- and advanced-stage disease with CTCL treated with denileukin diftitox at a dose of 9 microg/kg or 18 microg/kg per day, we observed an overall response rate of 51%. RESULTS: In 8 patients with early-stage (< IIA) CTCL, there were 5 responses (62.5%), and the median survival has not been reached, with 70% of patients still alive at 46 months. In 29 patients with advanced-stage (>/= IIB) disease, there were 14 responses (49.3%), and the median survival was 31 months. Changes in the number of CD4+ CD25+ T-cell populations were observed in 7 of 19 responders, with no overall changes in the absolute lymphocyte counts during the course of therapy. Decrease in lactate dehydrogenase was strongly correlated with clinical response (P < 0.05). CONCLUSION: Denilekin diftitox was a well-tolerated treatment in early- and advanced-stage CTCL and was not associated with detrimental immunologic efects on lymphocyte populations.


Assuntos
Antineoplásicos/uso terapêutico , Toxina Diftérica/uso terapêutico , Interleucina-2/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/mortalidade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/metabolismo , Ensaios Clínicos como Assunto , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Masculino , Pessoa de Meia-Idade , Micose Fungoide/etiologia , Micose Fungoide/patologia , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento
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