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Venetoclax FDA label updated to include Minimal Residual Disease negativity data
By: News Feed | Last updated: 12th September 2018 | In: Haematology, Targeted Therapies, US FDA Onc\Haem Approvals
AbbVie, CLL, leukaemia, MabThera, rituximab, Roche, Venclexta, venetoclax
On the 11th of September 2018, the FDA updated the label of venetoclax tablets (VENCLEXTA®, AbbVie) in combination with rituximab (MabThera®, Roche) to include information about pre-treated patients with chronic lymphocytic leukaemia (CLL) in the Phase III MURANO trial who had achieved Minimal Residual Disease (MRD)-negativity.
The Phase III international, multicenter, open-label, MURANO trial (NCT02005471) randomised 389 patients with relapsed or refractory (R/R) CLL 1:1 to either receive venetoclax plus rituximab (N=194) vs bendamustine plus rituximab (N=195). All participants were pretreated with at least one line of therapy for R/R CLL before the study. The median age was 65 years (range: 22-85).
The composite primary endpoint consisted of the percentage of patients with progression disease (PD) and the progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). At median follow-up of 23.4 months (range: 0.0–37.4+) the median PFS with venetoclax plus rituximab was not reached and measured 18.1 months in the bendamustine plus rituximab group (HR=0.19; 95% CI, 0.13–0.28; P<0.0001).
The secondary endpoints included the overall response rate (ORR), and included MRD evaluation by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) in patients who achieved a partial response (PR), a complete response (CR), or a CR with incomplete marrow recovery (CRi). The trial defined MRD negative status as less than one CLL cell per 10,000 lymphocytes.
The MRD-negativity rate in the peripheral blood at nine months was 53% (103/194) in the venetoclax plus rituximab group vs 12% (23/195) in the bendamustine plus rituximab group. At the same time point, the MRD-negativity rate in patients with a CR or CRi was 3% (6/194) for venetoclax plus rituximab and 2% (3/195) for bendamustine plus rituximab.
The most common (in ≥20% of patients) any-grade adverse reactions (AR) for venetoclax plus rituximab were neutropenia (65%), diarrhoea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%) and nausea (21%). Sixteen per cent of patients discontinued the combination venetoclax plus rituximab for ARs. Dose reduction and dose interruptions were reported in 15% and 71% of patients, respectively. Neutropenia was a major cause (46% of patients) for dose interruptions in the venetoclax plus rituximab arm; neutropenia and thrombocytopenia both led to discontinuation of 3% of patients.
Serious ARs in ≥5% of patients with the combination venetoclax plus rituximab were reported in 46% of patients, the most frequent being pneumonia (9%). Grade 5 ARs occurring in the absence of PD and within 30 days of the last venetoclax dosing and/or 90 days of the last rituximab dosing were reported in 2% (4/194) of patients.
In the bendamustine plus rituximab group, 10% of patients discontinued for ARs. Dose reduction and dose interruptions were reported in 15% and 40% of patients, respectively.
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