RESUMO
Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.
Assuntos
Antineoplásicos/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfoma de Zona Marginal Tipo Células B/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Adenina/análogos & derivados , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Anemia/patologia , Antineoplásicos/efeitos adversos , Linfócitos B/enzimologia , Linfócitos B/imunologia , Linfócitos B/patologia , Intervalo Livre de Doença , Esquema de Medicação , Fadiga/induzido quimicamente , Fadiga/patologia , Feminino , Humanos , Imunoterapia/métodos , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Piperidinas , Pneumonia/induzido quimicamente , Pneumonia/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/metabolismo , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , RecidivaRESUMO
Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Resultado do TratamentoAssuntos
Medula Óssea/patologia , Linfocitose/etiologia , Linfoma de Célula do Manto/patologia , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Medula Óssea/enzimologia , Medula Óssea/metabolismo , Humanos , Linfocitose/induzido quimicamente , Linfocitose/patologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/enzimologia , Piperidinas , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagemRESUMO
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor A2A de Adenosina/química , Terapia de Salvação , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptor A2A de Adenosina/metabolismo , Taxa de SobrevidaRESUMO
The two major subtypes of diffuse large B cell lymphoma (DLBCL)--activated B cell-like (ABC) and germinal center B cell-like (GCB)--arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a â¼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.