Efficacy and safety of pembrolizumab in relapsed/refractory primary mediastinal large B‐cell lymphoma (rrPMBCL): interim analysis of the KEYNOTE‐170 phase 2 trial

Zinzani, Pier Luigi; Thiéblemont, Catherine; Melnichenko, Vladimir; Osmanov, Dzhelil; Bouabdallah, Kamal; Walewski, Jan; Majlis, Alejandro; Fogliatto, Laura; Barrigón, María Dolores Caballero; Christian, Beth; Gülbaş, Zafer; Özcan, Muhıt; Salles, Gilles; Shipp, Margaret A.; Balakumaran, Arun; Chlosta, Sabine; Chatterjee, Arkendu; Armand, Philippe

doi:10.1002/hon.2437_49

Cited by 26 publications

(26 citation statements)

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“…Consistent with the current indications for PD‐1/L1 inhibitor monotherapy , combination regimens were most commonly being studied for the treatment of lung cancer, genitourinary cancer, gastrointestinal cancer, and melanoma (Fig. C).…”

Section: Reports Of Pd‐1/l1 Inhibitor Combination Therapy Trials At Asupporting

confidence: 55%

“…As of November 1, 2018, the U.S. Food and Drug Administration (FDA) had approved six immune checkpoint inhibitors (ICIs) targeting the programmed death‐1 (PD‐1) pathway, including three PD‐1 inhibitors (pembrolizumab, nivolumab, and cemiplimab) and three PD‐1 ligand (PD‐L1) inhibitors (atezolizumab, avelumab, and durvalumab). With indications spanning multiple tumor types , PD‐1 and PD‐L1 inhibitors have become the standard of care for many cancers. Because of their mechanism of action, PD‐1 and PD‐L1 inhibitors can cause a distinct set of inflammatory side effects, known as immune‐related adverse events (irAEs).…”

Section: Introductionmentioning

confidence: 99%

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Immune-Related Adverse Events in the Setting of PD-1/L1 Inhibitor Combination Therapy

et al. 2019

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In 2018, a multi‐disciplinary workshop was held at the Massachusetts General Hospital to discuss challenges in defining, diagnosing, and treating immune‐related adverse events (irAE), including those that occur in patients administered PD‐1/L1 inhibitor combination therapy. In this commentary, the workshop participants present a clinical case that illustrates the complexity of irAE diagnosis and management in a patient receiving PD‐1/L1 combination therapy, summarize the current state of PD‐1/L1 combination therapy, and discuss challenges and opportunities for the evaluation of irAEs as these combinations become more widely used to treat patients with cancer.

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Section: Reports Of Pd‐1/l1 Inhibitor Combination Therapy Trials At Asupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Immune-Related Adverse Events in the Setting of PD-1/L1 Inhibitor Combination Therapy

et al. 2019

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“…Across lymphoma entities, anti-PD-1 monotherapy showed the greatest efficacy in R/R cHL. [20][21][22][23]76,[107][108][109][110][111][112][113][114][115] In a phase 1 trial of nivolumab, the objective response rate (ORR) was remarkable (87%). 20 In phase 2 trials, nivolumab and pembrolizumab had similar ORRs (68% and 69%) and OS rates (99%) at 6 months, 22,23 leading to accelerated FDA approval in 2016 for nivolumab and in 2017 for pembrolizumab.…”

Section: Pd-l1 Expression and Clinical Roles In B-cell Lymphomasmentioning

confidence: 99%

“…107 In R/R PMBCL, the ORR with pembrolizumab was 41% in a phase 1b trial 109 and 35% in a phase 2 trial (interim results). 115 Notably, a retrospective study showed that all 4 patients (100%) with PCNSL/PTL (R/R PCNSL or PTL with central nervous system relapse) treated with nivolumab had clinical and radiographic responses, and 3 patients remained free of progression at 131 to 171 months. 110 Phase 2 trials for nivolumab or pembrolizumab monotherapy in FL, DLBCL, PMBCL, and PCNSL/PTL are ongoing (CheckMate 140, CheckMate 139, NCT02362997, KEYNOTE-170, 115 NCT02779101, NCT03255018, and CheckMate 647), and results informing ORRs, OS, and PFS are awaited.…”

Section: Pd-l1 Expression and Clinical Roles In B-cell Lymphomasmentioning

confidence: 99%

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

Xu-Monette

Zhou

Young

2018

Blood

327

306

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Programmed cell death protein 1 (PD-1) blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/programmed death-ligand 1 (PD-L1) expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD-1 tumor-infiltrating T cells, 9p24.1 genetic alteration, and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORRs) of 65% to 87% and durable disease control in phase 1/2 clinical trials. The median duration of response was 16 months in a phase 2 trial. PD-1 blockade has also shown promise in a phase 1 trial of nivolumab in relapsed/refractory B-cell non-Hodgkin lymphomas, including follicular lymphoma, which often displays abundant PD-1 expression on intratumoral T cells, and diffuse large B-cell lymphoma, which variably expresses PD-1 and PD-L1. In primary mediastinal large B-cell lymphoma, which frequently has 9p24.1 alterations, the ORR was 35% in a phase 2 trial of pembrolizumab. In contrast, the ORR with pembrolizumab was 0% in relapsed chronic lymphocytic leukemia (CLL) and 44% in CLL with Richter transformation in a phase 2 trial. T cells from CLL patients have elevated PD-1 expression; CLL PD-1 T cells can exhibit a pseudo-exhaustion or a replicative senescence phenotype. PD-1 expression was also found in marginal zone lymphoma but not in mantle cell lymphoma, although currently anti-PD-1 clinical trial data are not available. Mechanisms and predictive biomarkers for PD-1 blockade immunotherapy, treatment-related adverse events, hyperprogression, and combination therapies are discussed in the context of B-cell lymphomas.

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“…Optimal therapy for patients with this disease remains to be defined. Active areas of investigation include the role for immunotherapy with agents such as checkpoint inhibitors (Zinzani et al , ,b). Given that those diagnosed with this unique rare B‐NHL are largely adolescent and young adults, design of intergroup trials including paediatric and adult patients is appealing (Giulino‐Roth, ).…”

Section: Primary Mediastinal B Cell Lymphoma (Pmbcl)mentioning

confidence: 99%

Mature B‐NHL in children, adolescents and young adults: current therapeutic approach and emerging treatment strategies

2019

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Mature B cell lymphomas account for approximately 60% of all cases of non-Hodgkin lymphoma (NHL) in children and adolescents and includes Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL) and other less common histologies. The outcome for patients treated with modern regimens in resource-intensive settings is excellent. Improvements in care have been accomplished through enhanced supportive therapy, including tumour lysis management and incremental refinement of chemotherapy backbones via cooperative group clinical trials in which patients receive risk group-specific intensive chemotherapy. More recent trials have established the safety and efficacy of immunotherapy. Ongoing work is required to address the substantial burden of acute therapy-related toxicity, as well as the identification of effective therapies for those patients with relapsed and refractory disease, for whom outcomes remain very poor. In this review we will summarize the results from recent therapeutic clinical trials, describe the evidence to support the inclusion of rituximab and review the rationale for the investigation of several new categories of novel agents for mature B cell lymphomas in children and adolescents.

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Efficacy and safety of pembrolizumab in relapsed/refractory primary mediastinal large B‐cell lymphoma (rrPMBCL): interim analysis of the KEYNOTE‐170 phase 2 trial

Cited by 26 publications

References 0 publications

Immune-Related Adverse Events in the Setting of PD-1/L1 Inhibitor Combination Therapy

Immune-Related Adverse Events in the Setting of PD-1/L1 Inhibitor Combination Therapy

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

Mature B‐NHL in children, adolescents and young adults: current therapeutic approach and emerging treatment strategies

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