McGahan , L (2018): Ibrutinib (Imbruvica®) in combination with rituximab for the treatment of Waldenström’s macroglobulinaemia. DSD: Horizon Scanning in Oncology 85.
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Constitutive Bruton tyrosine kinase (BTK) activation is associated with B-cell proliferation and lymphoma progression. Ibrutinib, a first-generation BTK inhibitor, selectively and irreversibly binds BTK, blocking B-cell receptor signalling and inducing apoptosis in WM cells. To date, ibrutinib is approved in the US in combination with rituximab, for previously untreated Waldenström's macroglobulinemia (WM) and for those with rituximab-sensitive disease recurrence. Currently, ibrutinib has not received marketing authorisation for this indication in Europe.
In the phase III, iNNOVATE trial, 150 symptomatic treatment naïve or relapsed/refractory WM patients were randomised 1:1 to 420 mg oral ibrutinib or placebo daily, in combination with 375 mg/m2 rituximab IV once weekly for four weeks, followed by another four-week course after a three-month interval. Adding ibrutinib prolonged progression-free survival (PFS) by 54%, conferring a longer PFS than rituximab alone (not reached versus 20.3 months, respectively) and reducing the relative risk of progression or death by 80%. The PFS benefit was observed regardless of previous treatment, MYD88 or C-X-C chemokine receptor type 4 (CXCR4) genotype, or prognostic score. At 30 months, the overall survival (OS) rates were 94% versus 92% for ibrutinib- and placebo combination, respectively, with permitted crossover for patients in the placebo arm to ibrutinib single in case of progression; median OS was not reached in either group. Adding ibrutinib increased the overall response rate (ORR) by 45% compared with rituximab alone, largely independent of the genotype. Adding ibrutinib to rituximab therapy increased the number of patients with sustained haemoglobin (Hb) by 32% and resulted in fewer immunoglobulin M (IgM) flares (8% versus 47%, respectively). Atrial fibrillation and bleeding events were 12% and 30% more common in patients receiving ibrutinib combination versus rituximab alone, respectively.
Overall, adding ibrutinib to rituximab therapy increases PFS and ORR, and reduces the risk of death and progression for symptomatic WM patients with untreated or recurrent disease. Consistent PFS and ORR benefit were observed regardless of line, genotype or prognostic score. Further evaluation is needed to identify the role of ibrutinib as first-line versus salvage therapy; monotherapy versus in combination with biologic agents, other small molecules or chemoimmunotherapy; optimal duration of treatment; management of ibrutinib intolerant or resistant patients; and the comparative safety and effectiveness with new BTK inhibitors.
|Item Type:||DSD: Horizon Scanning in Oncology|
|Keywords:||Ibrutinib, Imbruvica®, Rituximab, MabThera®, Waldenström’s macroglobulinemia|
|Subjects:||WB Practice of medicine > WB 300-962 Therapeutics|
QZ Pathology > QZ 200-380 Neoplasms.Cysts
WH Hemic and lymphatic systems
QV Pharmacology, toxicology, pharmacy > QV 60-370 Pharmacology
|Series Name:||DSD: Horizon Scanning in Oncology 85|
|Deposited on:||20 Dec 2018 13:28|
|Last Modified:||22 Feb 2019 12:40|
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