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EMA: Ibrutinib in a fixed-duration combination with Venetoclax for adult patients with previously untreated chronic lymphocytic leukaemia

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 Ibrutinib ( Imbruvica ) in an oral fixed-duration combination with Venetoclax ( Venclyxto ) [ I+V ] for adults with previously untreated chronic lymphocytic leukaemia ( CLL ).

Ibrutinib + Venetoclax is 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 chronic lymphocytic leukaemia.

The CHMP positive opinion is supported by data from the pivotal phase 3 GLOW study, which has 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 chronic lymphocytic leukaemia ( PFS hazard ratio [ HR ]: 0.216; 95% confidence interval [ CI ], 0.131 to 0.357; P less than 0.001 ).
It is also supported by the fixed-duration cohort of the phase 2 CAPTIVATE study which has evaluated I+V in 159 patients with previously untreated chronic lymphocytic leukaemia who were 70 years or younger, including patients with high-risk CLL disease.

Updated data for both studies have shown the safety profile of the I+V regimen was consistent with known safety profiles of Ibrutinib and Venetoclax.

In the GLOW study, the most common treatment-emergent adverse events ( TEAEs ) were diarrhoea ( 50.9% ) and neutropenia ( 41.5% ) in the Ibrutinib - Venetoclax arm, and neutropenia ( 58.1% ) and infusion-related reactions ( 29.5% ) in the Chlorambucil - Obinutuzumab arm.
TEAEs of grade 3 or greater occurred in 80 ( 75.5% ) and 73 ( 69.5% ) of patients in the Ibrutinib-Venetoclax and Chlorambucil-Obinutuzumab arms, respectively.

In the CAPTIVATE fixed-duration cohort, the most common TEAEs were diarrhoea ( 62% ), nausea ( 43% ), neutropenia ( 42% ), and arthralgia ( 33% ) and primarily were grade 1 or 2 in severity.
The most common grade 3/4 adverse effects were neutropenia ( 33% ), hypertension ( 6% ), and decreased neutrophil count ( 5% ).

Chronic lymphocytic leukaemia is typically a slow-growing blood cancer of the white blood cells.
The overall incidence of chronic lymphocytic leukaemia 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.
Chronic lymphocytic leukaemia is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.
While patient outcomes have dramatically improved in the last few decades, the disease is still characterised by consecutive episodes of progression and the need for therapy. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.

Clinical trials

The phase 2 CAPTIVATE study has evaluated previously untreated adult patients with chronic lymphocytic leukaemia 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 ).
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 rate.

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 versus Clb+O in elderly patients ( 65 or more years of age ) with chronic lymphocytic leukaemia / small lymphocytic lymphoma ( CLL/SLL ), or patients ages 18-64 with a cumulative illness rating scale ( CIRS ) score of greater than 6 or creatinine clearance less than 70 mL/min, without del(17p) or known TP53 mutations. Patients in the study were randomised to receive either I+V ( n= 106 ) or Clb+O ( n=105 ). ( Xagena )

Source: Janssen, 2022