Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study

Younes, Anas; Brody, Joshua; Carpio, Cecilia; López‐Guillermo, Armando; Ben‐Yehuda, Dina; Ferhanoğlu, Burhan; Nagler, Arnon; Özcan, Muhıt; Avivi, Irit; Bosch, Francesc; Barrigón, María Dolores Caballero; Hellmann, Andrzej; Kuss, Bryone J.; David, D. F.; Demırkan, Fatih; Yağcı, Münci; Horowitz, Netanel A.; Marlton, Paula; Córdoba, Raúl; Wróbel, Tomasz; Buglio, David Lo; Streit, Marcus R.; Hodkinson, Brendan P.; Schäffer, Michael; Alvarez, John; Ceulemans, Rob; Balasubramanian, Sriram; Jong, Jan de; Wang, Shean‐Sheng; Fourneau, Nele; Jurczak, Wojciech

doi:10.1016/s2352-3026(18)30217-5

Cited by 167 publications

(125 citation statements)

References 37 publications

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“…These data evaluating somatic mutations associated with response are hypothesis generating, precluding definitive conclusion and requiring further confirmation. While the association of PD‐L1 expression with response could not be determined in this study, recent work has demonstrated an association between expression of PD‐L1 and CR in DLBCL patients treated with combination ibrutinib and nivolumab, an antibody to the PD‐1 receptor . The difference in results of the two studies could be attributed to potential differences in the mechanism of action of durvalumab and nivolumab (ie, PD‐L1 rather than PD‐1 blockade), differences in methodologies for PD‐L1 detection and definitions of elevated PD‐L1 expression, or other differences in study design.…”

Section: Discussionmentioning

confidence: 73%

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B‐cell lymphoma

et al. 2019

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This phase 1b/2, multicenter, open-label study evaluated ibrutinib plus durvalumab in relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL).Patients were treated with once-daily ibrutinib 560 mg plus durvalumab 10 mg/kg every 2 weeks in 28-day cycles in phase 1b without dose-limiting toxicities, confirming the phase 2 dosing. Sixty-one patients with FL (n = 27), germinal center B-cell (GCB) DLBCL (n = 16), non-GCB DLBCL (n = 16), and unspecified DLBCL (n = 2) were treated. Overall response rate (ORR) was 25% in all patients, 26% in patients with FL, 13% in patients with GCB DLBCL, and 38% in patients with non-GCB DLBCL. Overall, median progression-free survival was 4.6 months and median overall survival was 18.1 months; both were longer in patients with FL than in patients with DLBCL. The most frequent treatment-emergent adverse events (AEs) in patients with FL and DLBCL, respectively, were diarrhea (16 [59%]; 16 [47%]), fatigue (12 [44%]; 16 [47%]), nausea (9 [33%]; 12 [35%]), peripheral edema (7 [26%]; 13 [38%]), decreased appetite (8 [30%]; 11 [32%]), neutropenia (6 [22%]; 11 [32%]), and vomiting (5 [19%]; 12 [35%]). Investigator-definedimmune-related AEs were reported in 12/61 (20%) patients. Correlative analyses were conducted but did not identify any conclusive biomarkers of response. In FL, GCB DLBCL, and non-GCB DLBCL, ibrutinib plus durvalumab demonstrated similar activity to single-agent ibrutinib with the added toxicity of the PD-L1 blockade; the combination resulted in a safety profile generally consistent with those known for each individual agent.

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Section: Discussionmentioning

confidence: 73%

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B‐cell lymphoma

et al. 2019

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“…Despite pre-clinical evidence supporting the combination of ibrutinib and checkpoint blockade, a phase 1/2a trial of nivolumab with ibrutinib demonstrated an ORR of 61% in patients with R/R CLL, similar to the ORR previously reported with single-agent ibrutinib [87]. In contrast, the activity of PD-1/PD-L1 inhibition in Richter transformation appears to be more promising.…”

Section: Combining Btk Inhibitors With Checkpoint Inhibitorsmentioning

confidence: 83%

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

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“…Preliminary data from ongoing clinical trials suggest that anti-PD-1 monoclonal antibodies (nivolumab and pembrolizumab) have promising activity in patients with Richter's transformation. [36][37][38] In a phase I/ II study that included 20 patients with Richter's transformation, nivolumab + ibrutinib resulted in an ORR of 60% (CR, 5% and PR, 55%) 37 ; median PFS was 4 months. Diarrhea (31%), pyrexia (23%), and fatigue (23%) were the most common treatment-related grade 1/2 adverse events.…”

Section: Nccn Guidelines ® Insightsmentioning

confidence: 99%

NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019

Wierda¹,

Byrd²,

Abramson³

et al. 2019

J Natl Compr Canc Netw

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Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study

Cited by 167 publications

References 37 publications

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B‐cell lymphoma

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B‐cell lymphoma

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019

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