On June 24, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending approval of a new treatment option with IMBRUVICA (ibrutinib) in an oral fixed-duration combination with venetoclax (I+V) for adults with previously untreated chronic lymphocytic leukaemia (CLL) (Press release, Johnson & Johnson, JUN 24, 2022, View Source [SID1234616251]).
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Outcomes for patients with CLL have improved in the last decade with the advent of oral therapies that target the underlying disease biology.3 This provides the opportunity to combine these novel treatments for an effective and convenient approach that results in deep responses with time-limited therapy.1 If approved, I+V will be the first all-oral, once daily, fixed-duration combination treatment with a Bruton’s tyrosine kinase (BTK) inhibitor for first-line treatment of patients with CLL.
"With this innovative treatment regimen, healthcare professionals would have the flexibility to use ibrutinib either in a fixed-duration combination or as a continuous therapy, helping them to better tailor frontline CLL therapy based on patients’ individual needs," said Edmond Chan, MBChB, M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "This recommendation brings us one step closer to European Commission (EC) approval and to providing patients with an all-oral, once daily, fixed-duration regimen, which until this point has not been available with the BTK inhibitor class of treatments."
The CHMP positive opinion is supported by data from the pivotal Phase 3 GLOW study (NCT03462719), which demonstrated that I+V was superior to chlorambucil-obinutuzumab with respect to the primary endpoint, progression-free survival (PFS), 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 It is also supported by the fixed-duration cohort of the Phase 2 CAPTIVATE study (NCT02910583) which evaluated I+V in 159 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, and Blood, respectively,1,4 and featured as oral presentations at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Congress. Secondary analyses from GLOW, with additional study follow-up, were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting, and additional data from the CAPTIVATE study including clinical outcomes at three years and evidence of immune restoration post-treatment were recently presented at the EHA (Free EHA Whitepaper) 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.1,4 In the GLOW study, the most common treatment-emergent adverse events (TEAEs) were diarrhoea (50.9 percent) and neutropenia (41.5 percent) in the ibrutinib-venetoclax arm, and neutropenia (58.1 percent) and infusion-related reactions (29.5 percent) in the chlorambucil-obinutuzumab arm.1 TEAEs of Grade 3 or greater occurred in 80 (75.5 percent) and 73 (69.5 percent) of patients in the ibrutinib-venetoclax and chlorambucil-obinutuzumab arms, respectively.1 In the CAPTIVATE fixed-duration cohort, the most common TEAEs were diarrhoea (62 percent), nausea (43 percent), neutropenia (42 percent), and arthralgia (33 percent) and primarily were Grade 1 or 2 in severity.4 The most common Grade 3/4 AEs were neutropenia (33 percent), hypertension (6 percent), and decreased neutrophil count (5 percent).4
"The promising data from GLOW and CAPTIVATE reinforce the distinct and complementary modes of action between ibrutinib and venetoclax, and the potential of this combination regimen to provide treatment-free remissions for patients," said Craig Tendler, M.D., Global Head of Late Development, Diagnostics & Medical Affairs, Hematology & Oncology, Janssen Research & Development, LLC. "The positive CHMP opinion for I+V is testament to our commitment and continued leadership in developing innovative and convenient treatment regimens that may help improve outcomes for people living with complex blood cancers like CLL."
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About Ibrutinib
Ibrutinib is a once-daily oral medication that is jointly developed and commercialised by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.5 Ibrutinib blocks the Bruton’s tyrosine kinase (BTK) protein, which is needed by normal and abnormal B-cells, including specific cancer cells, to multiply and spread.6 By blocking BTK, ibrutinib may help move abnormal B-cells out of their nourishing environments and inhibits their proliferation.7
Ibrutinib is approved in more than 100 countries and has been used to treat more than 250,000 patients worldwide.8 There are more than 50 company-sponsored clinical trials, including 18 Phase 3 studies, over 11 years evaluating the efficacy and safety of ibrutinib.1,9 In October 2021, ibrutinib was added to the World Health Organization’s Model Lists of Essential Medicines (EML), which refer to medicines that address global health priorities and which should be available and affordable for all.10
Ibrutinib was first approved by the European Commission (EC) in 2014, and approved indications to date include:1
As a single agent or in combination with rituximab or obinutuzumab for the treatment of adult patients with previously untreated CLL
As a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy
As a single agent for the treatment of adult patients with relapsed or refractory (RR) mantle cell lymphoma (MCL)
As a single agent for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients with WM
For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.
About the CAPTIVATE study
The Phase 2 CAPTIVATE study evaluated previously untreated adult patients with CLL who were 70 years or younger, including patients with high-risk disease, in two cohorts: an MRD-guided cohort (N=164; median age, 58 years) and a fixed-duration cohort (N=159; median age, 60 years).4 Patients in the fixed-duration cohort received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]) and the primary endpoint was complete response (CR) rate.4
About the GLOW study
The Phase 3 GLOW study (N=211; median age, 71 years) is a randomised, open-label trial which evaluated the efficacy and safety of first-line, fixed-duration I+V vs. Clb+O in elderly patients (≥65 years of age) with CLL/SLL, or patients ages 18-64 with a cumulative illness rating scale (CIRS) score of greater than six or creatinine clearance less than 70 mL/min, without del(17p) or known TP53 mutations.1 Patients in the study were randomised to receive either I+V (n= 106) or Clb+O (n=105).1
About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.11 The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.12 CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.13
While patient outcomes have dramatically improved in the last few decades, the disease is still characterised by consecutive episodes of disease progression and the need for therapy.3 Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.14