In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
“[T]he results of this large collaborative trial show that the replacement of rituximab with obinutuzumab in the context of immunochemotherapy and maintenance therapy in patients with previously untreated follicular lymphoma resulted in significantly longer progression-free survival,” wrote Dr. Marcus and his colleagues (N Engl J Med. 2017 Oct 5;377;14:1331-44).They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
