Approval marks the first all-oral, once-daily, fixed-duration Bruton’s tyrosine kinase (BTK) inhibitor-based regimen for first-line treatment of CLL
BEERSE, BELGIUM, – The Janssen Pharmaceutical Companies of Johnson & Johnson announced today that the European Commission granted marketing authorisation for the expanded use of IMBRUVICA® (ibrutinib) in an all-oral, fixed-duration (FD) treatment combination with venetoclax (I+V) for adults with previously untreated chronic lymphocytic leukaemia (CLL). The approval is based on the pivotal Phase 3 GLOW study that demonstrated superior progression-free survival (PFS) in patients treated with I+V versus chlorambucil-obinutuzumab (Clb+O), and the FD cohort of the Phase 2 CAPTIVATE study, which showed deep and durable responses in patients treated with I+V, including those with high-risk features.[1],[2]
“Developing innovative therapies remains vitally important in CLL, to ensure we have the option and ability to best tailor treatment to meet individual patient needs and preferences,” said Edmond Chan, MBChB, M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. “Over the past 11 years, the efficacy and safety profile of ibrutinib has been established in clinical trials and real-world settings. With this approval, healthcare professionals will now have the flexibility to use ibrutinib either in a fixed-duration combination with venetoclax or as a continuous monotherapy in first-line CLL.”
In Europe, ibrutinib is already approved as a continuous therapy in several indications across three blood cancers (CLL, mantle cell lymphoma and Waldenström’s macroglobulinaemia).[3] In CLL, patient outcomes have improved over the last decade.[4] A wave of innovation, including the advent of novel oral therapies that target the underlying disease biology, has shifted the standard of care from chemoimmunotherapy to targeted agents and combination therapies.[4] Unmet needs remain, including time-limited combinations of targeted therapies that provide durable remissions and the flexibility to better tailor first-line therapy.[1]
“The distinct and complementary mechanisms of action of ibrutinib and venetoclax, and the potential of this combination regimen to provide treatment-free remissions, mark important progress for how we approach first-line CLL therapy,” said Arnon Kater†, M.D., Ph.D., Deputy Head of Haematology, Amsterdam University Medical Centres, University of Amsterdam and Chairman of the HOVON CLL Working Group, the Netherlands and GLOW principal study investigator. “These highly active blood cancer treatments not only combine to deliver superior progression-free survival versus chlorambucil plus obinutuzumab, but also demonstrate robust disease clearance in lymphoid tissue, blood and bone marrow, and early sustainability of those responses after stopping treatment.”
The EC approval is supported by data from the pivotal Phase 3 GLOW study (NCT03462719), which demonstrated that I+V was superior to Clb+O with respect to the primary endpoint, PFS assessed by an independent review committee, in elderly or unfit patients with CLL (PFS hazard ratio [HR]: 0.216; 95 percent confidence interval [CI], 0.131 to 0.357; P<0.001).[1] The improvement in PFS with I+V was consistent across predefined subgroups, including older patients and those with comorbidities and high-risk features.[1k] It is also supported by the FD cohort of the Phase 2 CAPTIVATE study (NCT02910583) which evaluated I+V in patients with previously untreated CLL who were 70 years or younger, including patients with high-risk CLL disease.[2]
Data from these studies were recently published in NEJM Evidence[1] and Blood,[2] respectively, and primary analyses were originally featured as oral presentations at the European Hematology Association (EHA) 2021 Congress. Secondary analyses from GLOW were presented at the American Society of Hematology (ASH) 2021 Annual Meeting, and additional data from the CAPTIVATE study including clinical outcomes at three years and evidence of immune restoration post-treatment were presented at the EHA 2022 Congress.
Updated data for both studies showed the safety profile of the I+V regimen was consistent with known safety profiles of ibrutinib and venetoclax.[1],[2] In GLOW, the most common adverse events (AEs) were diarrhoea (50.9 percent) and neutropenia (41.5 percent) in the I+V arm and neutropenia (58.1 percent) and infusion-related reactions (29.5 percent) in the Clb+O arm.[1] AEs of Grade 3 or greater occurred in 75.5 percent and 69.5 percent of patients in the I+V and Clb+O arms, respectively.[1] Any-grade atrial fibrillation occurred in 15 patients (14.2 percent) receiving I+V and two patients (1.9 percent) receiving Clb+O, however, only two patients (1.9 percent) discontinued ibrutinib due to atrial fibrillation while continuing venetoclax.[1] Although overall survival data is not mature, with a median follow-up of 34 months, there were 11 deaths in the I+V arm and 16 deaths in the Clb+O arm (HR: 0.760; 95 percent CI, 0.352 to 1.642).[1] In the CAPTIVATE FD cohort, the most common AEs were diarrhoea (62 percent), nausea (43 percent), neutropenia (42 percent), and arthralgia (33 percent) and were primarily Grade 1 or 2 in severity.[2] The most common Grade 3/4 AEs were neutropenia (33 percent), hypertension (6 percent), and neutrophil count decreased (5 percent). Serious AEs occurred in 36 patients (23 percent) and one fatal AE occured.[2]
“Ibrutinib is the first approved BTK inhibitor globally, which has helped transform outcomes and quality of life for patients living with blood cancers, such as CLL,” said Craig Tendler, M.D., Global Head of Late Development, Diagnostics & Medical Affairs, Hematology & Oncology, Janssen Research & Development, LLC. “This approval reinforces our relentless ambition to advance and optimise treatment regimens, including this all-oral, once-daily, fixed-duration combination of ibrutinib-venetoclax, delivering deep and durable remissions for patients with previously untreated CLL.”
