Roche is pleased to announce that Gazyvaro (obinutuzumab) is now available in Ireland for people with previously untreated chronic lymphocytic leukaemia (CLL).
Gazyvaro, in combination with chlorambucil chemotherapy, is indicated for the treatment of adult patients with previously untreated CLL who have comorbidities making them unsuitable for an intensive therapy (full-dose fludarabine based therapy).1
CLL, which is characterised by a neoplastic accumulation of B lymphocytes, is the most common type of leukaemia in Ireland, accounting for about 40% of cases.2 The majority of patients with CLL are older than 70 years of age, and many present with coexisting medical conditions.
Gazyvaro is a type II, glycoengineered, humanised monoclonal antibody designed to target CD20, a protein found on the surface of B lymphocytes. It induces direct cell death and mediates antibody-dependent cellular cytotoxicity, with a low degree of complement-dependent cytotoxicity.
Gazyvaro received European approval based on the outcomes of the CLL11 study, which investigated the benefit of obinutuzumab combined with chlorambucil as compared with that of chlorambucil alone or rituximab combined with chlorambucil, in patients with previously untreated CLL and comorbidities.3
Study design
CLL11 is a phase III, multicentre, open-label, randomised three-arm study which investigated the efficacy and safety of obinutuzumab plus chlorambucil compared to rituximab plus chlorambucil, or chlorambucil alone, in 781 patients with previously untreated CLL and coexisting medical conditions.
Patients received six 28-day cycles of either obinutuzumab (1000mg intravenous [IV] infusion, on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2 through 6) plus chlorambucil (0.5mg/kg orally, days 1 and 15 of each cycle), or rituximab (IV infusion, 375mg/m2 on day 1 of cycle 1, 500mg/m2 on day 1 of cycles 2 through 6) plus chlorambucil, or chlorambucil alone. In the obinutuzumab arm, in order to reduce the rate of infusion reactions, an amendment of the study protocol was implemented and the first infusion of obinutuzumab was administered over a period of 2 days.
The primary endpoint of the study was progression-free survival (PFS), as assessed by the site investigators. Secondary endpoints included response rates (RR), minimal residual disease (MRD), overall survival (OS), and adverse events.
Significant prolongation of PFS with Gazyvaro
Obinutuzumab-chlorambucil met its primary endpoint by significantly reducing the risk of disease worsening or death by 61% compared to rituximab-chlorambucil (median PFS, 26.7 vs 15.2 months; hazard ratio [HR], 0.39; p<0.001).
Figure 1. PFS with Obinutuzumab plus Chlorambucil vs Rituximab plus Chlorambucil
Click on image to enlarge
Significant benefits in RR, MRD and OS with Gazyvaro
Treatment with obinutuzumab showed higher complete response rates (20.7% vs 7%) and a ten-fold increase in the percentage of people achieving MRD negativity in blood (37.7% vs 3.3%) compared to the rituximab arm of the study. MRD negativity in bone marrow was also significantly higher after obinutuzumab-chlorambucil treatment (19.5% vs 2.6%).
Treatment with obinutuzumab-chlorambucil provided a significant benefit in OS compared with chlorambucil monotherapy (HR, 0.41; p=0.002). No significant benefit in OS was noted for obinutuzumab-chlorambucil over rituximab-chlorambucil (HR, 0.66; p=0.08), the rates of death being 8% and 12%, respectively. OS medians were not reached.
Safety profile
The most common severe adverse events (grade ≥ 3) for obinutuzumab were infusion-related reactions (IRRs), infections, thrombocytopenia and neutropenia. IRRs and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the rates of infection did not differ significantly. The incidence and severity of IRRs decreased dramatically after the first infusion and no severe IRRs were reported beyond the first infusion.
Conclusion
This study showed that Gazyvaro plus chlorambucil chemotherapy improves the outcomes in patients with previously untreated CLL and comorbidities. Treatment with Gazyvaro plus chlorambucil resulted in longer PFS, more complete responses and higher negative testing for MRD than with rituximab plus chlorambucil, and provided an OS advantage over chlorambucil alone.3
References
1. Gazyvaro SPC (revised 21st May 2015)
2. National Cancer Registry Ireland. Accessed 28th September 2015 at http://www.ncri.ie/atlas/2129-21218-other-cancers
3. Goede V. et al. N Engl J Med 2014;370:1101-10.
Full prescribing information and references available from Roche Products (Ireland) Ltd. Telephone: (01) 4690700. IE/GA101/1015/0001
