Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059

Walter, Harriet S.; Jayne, Sandrine; Rule, Simon; Cartron, Guillaume; Morschhauser, Franck; Macip, Salvador; Karlin, Lionel; Jones, Ceri; Herbaux, Charles; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V.; Fegan, Christopher; Yang, Yinchuang; Mitra, Siddhartha; Salles, Gilles; Dyer, Martin J. S.

doi:10.1182/blood-2017-02-765115

Cited by 51 publications

(43 citation statements)

References 19 publications

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“…As novel agents continue to be developed for CLL, longterm data are crucial to inform practice. Additional BTK inhibitors in development for CLL have shown encouraging efficacy, but results of randomized comparative studies are not yet available and these agents lack long-term safety and efficacy data [37,38]. Here, we demonstrated that with a median of 5 years of follow-up, over half of patients with CLL/SLL were able to receive long-term continuous firstline treatment with single-agent ibrutinib and had sustained efficacy benefits (70% of ibrutinib-treated patients estimated progression-free), including-importantly-in patients with high-risk prognostic features, such as del(11q) or unmutated IGHV.…”

Section: Discussionmentioning

confidence: 99%

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

et al. 2019

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RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95%

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Section: Discussionmentioning

confidence: 99%

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

et al. 2019

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“…Ibrutinib can also lead to clinically significant toxicities in some patients, including bleeding and atrial fibrillation. It is likely that these adverse events (AEs) are partly due to the low selectivity of ibrutinib . Thus, an unmet need remains for novel, more specific BTK inhibitors that might improve efficacy, with less toxicity and shorter therapy duration.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of tirabrutinib (ONO‐4059/GS‐4059) in patients with relapsed or refractory B‐cell malignancies in Japan

et al. 2019

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We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second‐generation, enhanced‐selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B‐cell non−Hodgkin lymphoma (B‐cell NHL ) and chronic lymphocytic leukemia ( CLL ). This was an open‐label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose‐limiting toxicity for 300 mg twice daily. Common adverse events ( AE s) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AE s: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥ PR ) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD 79A/B or MYD 88 mutations, and 1 CLL patient with a TP 53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/ mL on Day 1 and 484, 971 1940, and 961 ng/ mL on Day 28 for Cohorts 1‐4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B‐cell NHL /CLL.

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“…approval for the treatment of MCL based on a complete response (CR) rate of 40% and an overall response rate (ORR) of 81% at a median follow-up of 15.2 months in a phase 2 study [7]. Tirabrutinib has demonstrated significant activity without major drug-related toxicities in a phase 1 study in R/R B-cell malignancies [8] and on extended, 3-year follow-up of patients with chronic lymphocytic leukemia [9]. Here, we provide 3-year follow-up data from patients with MCL in the phase 1 tirabrutinib extension study (NCT02457559).…”

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confidence: 99%

Long-term follow-up of patients with mantle cell lymphoma (MCL) treated with the selective Bruton’s tyrosine kinase inhibitor tirabrutinib (GS/ONO-4059)

et al. 2019

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Recent therapeutic advances for mantle cell lymphoma (MCL) include inhibitors of Bruton's tyrosine kinase (BTK), a critical component in the B-cell receptor signaling pathway [1, 2]. Remarkably, approximately two thirds of patients with relapsed/refractory (R/R) MCL treated with ibrutinib, the first-in-class BTK inhibitor, achieve a durable response [3-5]. However, ibrutinib treatment also commonly produces off-target adverse events (AEs) such as bleeding, atrial fibrillation, diarrhea, and infection. Second-generation BTK inhibitors with greater selectivity include tirabrutinib (GS/ONO-4059), acalabrutinib, and BGB-3111 [6]. In 2017, acalabrutinib received FDA * Simon A.

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Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059

Cited by 51 publications

References 19 publications

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

Phase I study of tirabrutinib (ONO‐4059/GS‐4059) in patients with relapsed or refractory B‐cell malignancies in Japan

Long-term follow-up of patients with mantle cell lymphoma (MCL) treated with the selective Bruton’s tyrosine kinase inhibitor tirabrutinib (GS/ONO-4059)

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