Phase III GALLIUM study shows superiority of obinutuzumab over rituximab in untreated patients with follicular lymphoma
The plenary session of the 2016 annual meeting of the American Society of Hematology featured the presentation of the primary results of the randomized phase III GALLIUM study, which compared the efficacy of the two anti-CD20 monoclonal antibodies rituximab and obinutuzumab in untreated patients with follicular lymphoma (FL). In this trial, obinutuzumab-based immunotherapy and maintenance resulted in a clinically meaningful improvement in the progression-free survival (PFS), with a 34% reduction in the risk of a PFS event relative to rituximab-based therapy. This benefit did come at the cost of a higher frequency of some adverse events (infusion-related reactions (IRRs), cytopenias, and infections). Based on these data obinutuzumab-chemo has the potential to become a new standard of care in previously untreated FL patients.
Immunochemotherapy induction followed by maintenance with rituximab is the current standard of care for patients with advanced-stage symptomatic follicular lymphoma (FL). With this approach a median PFS of 6–8 year is achieved, with a median overall survival (OS) of 12–15 years. FL does remain an incurable disease and eventually most patients relapse. In approximately one third of patients this relapse occurs in the first three years and this group of patients has a poor prognosis. Obinutuzumab is a glycol-engineered type II anti-CD20 monoclonal antibody with enhanced direct cell killing and antibody-dependent cellular cytotoxicity that has promising activity and manageable toxicity when combined with chemotherapy in relapsed indolent non-Hodgkin lymphoma (iNHL).
In the open-label phase III GALLIUM trial patients were randomized 1:1 to rituximab (375mg/m2 on Day (D) 1 of each cycle) or obinutuzumab (1000mg on D1, 8 and 15 of cycle 1 and D1 of subsequent cycles) both in combination with either eight 21-day cycles of CHOP or CVP, or six 28-day cycles of bendamustine. Patients with a complete or partial response (CR or PR) at the end of induction received maintenance rituximab or obinutuzumab every 2 months for 2 years, or until disease progression. The primary endpoint of the trial was investigator assessed PFS. In order to be eligible for the study, patients should have been 18 years of age or older with previously untreated FL (grades 1–3a) or chemotherapy-naïve marginal zone lymphoma (MZL), stage III/IV disease or stage II with tumor diameter ≥7cm. They needed to have an ECOG performance score of 0–2 and should have required treatment according to GELF criteria.
During ASH 2016, results were reported for the 1,202 FL patients enrolled in the study (N=601 in each treatment arm). In the majority of patients, the chemotherapy regimen consisted of bendamustine (57.1%). In addition to this, 33.1% of patients received CHOP and 9.8% were treated with CVP. The rate of CR and the objective response rate (ORR) at the end of the induction therapy were similar for the two arms (23.8% and 86.9%, respectively, with rituximab and 19.5% and 88.5% with obinutuzumab). After a median follow-up of 34.5 months, the investigators observed a 34% reduction in the risk of disease progression or death in favor of the obinutuzumab-based therapy (HR[95%CI]: 0.66[0.51-0.85]; p=0.001). Although the median PFS was not reached in either of the arms, the observed HR of 0.66 would translate to a 1.5x longer median PFS for obinutuzumab-chemotherapy than what is seen with rituximab-chemotherapy. This corresponds to an estimated 3-year improvement in the obinutuzumab arm if a median PFS of 6 years was assumed for rituximab-chemotherapy. At the 3-year time point, the rate of PFS was 80% with obinutuzumab-chemotherapy as compared to 73.3% with rituximab-chemotherapy.
Looking at the secondary endpoints of the study, the PFS assessed by independent review was similar to what was reported by investigators (HR[95%CI]: 0.71[0.54-0.93]; p= 0.0138). Also the time to the next treatment (TTNT) was significantly delayed with obinutuzumab with a 3-year TTNT rate of 81.2% with rituximab and 87.2% with obinutuzumab (HR[95%CI]: 0.51-0.91], p= 0.0094). At the time of the analysis, 35 patients on obinutuzumab-chemo (5.5%) and 46 patients on rituximab-chemotherapy (8.7%) had died (HR[95%CI]: 0.75[0.49-1.17]; p= 0.210).
With respect to safety, obinutuzumab-chemotherapy patients had a higher frequency of grade 3–5 adverse events (AEs) (74.6%) and serious AEs (SAEs) (46.1%) than rituximab-chemotherapy patients (67.8% and 39.9%, respectively). However, the frequency of fatal AEs was similar (4.0% with obinutuzumab and 3.4% with rituximab). AEs led to treatment discontinuation in 16.3% patients on obinutuzumab and in 14.2% of the patients treated with rituximab. There was a higher rate of non-lymphoma-related mortality in the obinutuzumab group. This was predominantly the case in patients receiving the treatment in combination with bendamustine (non-lymphoma-related mortality of 5% with bendamustine versus less than 2% with CVP and CHOP). An overview of the safety results is depicted in slide 3.
In summary, in this study, obinutuzumab-based immunochemotherapy and maintenance resulted in a clinically meaningful improvement in PFS, with a 34% reduction in the risk of a PFS event relative to rituximab-based therapy. This benefit did come at the cost of a higher frequency of AEs, including infusion-related reactions (IRRs), cytopenias, and infections. Overall, these findings indicate that obinutuzumab-chemotherapy is a better approach than rituximab-chemotherapy in the first-line treatment of patients with FL.
Referentie
Marcus R, Davies A, Ando K et al. Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study. Presented at ASH 2016; Abstract 6
