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European Commission has approved Venclyxto plus Gazyvaro for adults with previously untreated chronic lymphocytic leukaemia


The European Commission has approved Venclyxto ( Venetoclax ) in combination with Gazyvaro ( Obinutuzumab ) for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia ( CLL ).

The approval is based on results from the primary analysis of the pivotal phase III CLL14 study, which evaluated the combination of 12-month, fixed-duration Venetoclax plus Obinutuzumab compared to Obinutuzumab plus Chlorambucil in adults with previously untreated CLL who had co-existing medical conditions.

Results from the primary analysis showed that the combination of Venetoclax plus Obinutuzumab led to a 65% reduction in the risk of disease worsening or death ( progression-free survival [ PFS ], as assessed by investigators ) compared to Obinutuzumab plus Chlorambucil, a current standard-of-care for CLL ( hazard ratio, HR=0.35; 95% CI 0.23-0.53; p less than 0.0001 ). When PFS survival was assessed by an independent review committee, this finding was confirmed.
Venetoclax plus Obinutuzumab also showed higher response rates ( ORR ), doubled the complete response rates ( CR/CRi ) and demonstrated higher rates of minimal residual disease ( MRD )-negativity. In peripheral blood, MRD-negativity rates were 76% for Venetoclax plus Obinutuzumab versus 35% for Obinutuzumab plus Chlorambucil, and in bone marrow MRD-negativity rates were 57% versus 17%, respectively.
Results from an updated efficacy analysis ( with a median follow-up of 40 months ) were consistent with the primary data, and showed that the combination reduced the risk of disease worsening or death by 69% compared to Obinutuzumab plus Chlorambucil ( HR=0.31; 95% CI 0.22-0.44 ).
Safety for Venetoclax plus Obinutuzumab appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.
The most commonly reported adverse events in people treated with Venetoclax plus Obinutuzumab were low white blood cell count ( neutropenia ), diarrhoea and upper respiratory tract infection.
Results from the CLL14 study has further demonstrated Venetoclax’s potential across multiple lines ( in the R/R and the frontline settings ) in CLL.

CLL14 is a randomised phase III study evaluating the combination of fixed-duration Venetoclax plus Obinutuzumab compared to Obinutuzumab plus Chlorambucil in adult patients with previously untreated chronic lymphocytic leukaemia and co-existing medical conditions.
432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venetoclax alongside six-month duration of Obinutuzumab ( Arm A ) or six-month duration of Obinutuzumab alongside 12-month duration of Chlorambucil ( Arm B ).
Arm A started with an initial dosing of Obinutuzumab followed by a five-week Venetoclax dose ramp-up to help reduce the risk of tumour lysis syndrome.
The primary endpoint of the study is investigator-assessed progression-free survival. Secondary endpoints include PFS assessed by independent review committee, minimal residual disease status, overall response rate, complete response rate ( with or without complete blood count recovery ), overall survival, duration of response, event-free survival, time to next CLL treatment, and safety.
MRD-negativity means no cancer can be detected using a specific, highly sensitive test, and was defined as less than one cancer cell in 10,000 leukocytes.

The most common adverse reactions ( greater than or equal to 20% ) with Venetoclax plus Obinutuzumab were low white blood cell count ( neutropenia ), diarrhoea and upper respiratory tract infection.
The most common serious adverse events in people treated with Venetoclax plus Obinutuzumab were febrile neutropenia, pneumonia, infusion-related infection and pyrexia.

Venetoclax is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 ( BCL-2 ) protein.
In some blood cancers and other tumours, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venetoclax blocks the BCL-2 protein and works to restore the process of apoptosis.

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B-cells, but not on stem cells or plasma cells.
Obinutuzumab is designed to attack and destroy targeted B-cells both directly and together with the body's immune system.

Chronic lymphocytic leukaemia is the most common type of leukaemia in the Western world.
CLL mainly affects men and the median age at diagnosis is about 70 years.
Worldwide, the incidence of all leukaemias is estimated to be over 400,000, with an incidence of over 100,000 in Europe.
CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia. ( Xagena )

Source: Roche, 2020

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