In the phase III GALLIUM trial reported in The New England Journal of Medicine by Robert Marcus, MBBS, of University College London, and colleagues, obinutuzumab (Gazyva)-based therapy significantly prolonged progression-free survival vs rituximab (Rituxan)-based therapy in patients with previously untreated advanced follicular lymphoma.1 Obinutuzumab is currently indicated for treatment in combination with bendamustine followed by obinutuzumab monotherapy in patients with follicular lymphoma who have relapsed after or are refractory to a rituximab-containing regimen.
In the open-label international trial, 1,202 patients from sites in Asia (n = 185), Eastern Europe (n = 157), North America (n = 152), Western Europe (n = 580), and elsewhere (n = 128) were randomized between July 2011 and February 2014 to receive obinutuzu-mab at 1,000 mg (n = 601) on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles or rituximab at 375 mg/m2 (n = 601) on day 1 of each cycle for 6 or 8 cycles, depending on the chemotherapy regimen. Chemotherapy regimens consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine, as stipulated at each study site; all patients at each site received the same regimen using standard doses.Error loading Partial View script (file: ~/Views/MacroPartials/TAP Article Portrait and Quote.cshtml)
Baseline characteristics were similar in the obinutuzumab and rituximab groups. Randomization was stratified by chemotherapy regimen, Follicular Lymphoma International Prognostic Index (FLIPI) risk group, and geographic region. Patients with a response to induction treatment received maintenance obinutuzumab or rituximab according to randomized group for up to 2 years. The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population.
At a planned interim analysis performed at a median follow-up of 34.5 months, the estimated 3-year progression-free survival rate was 80.0% in the obinutuzumab group vs 73.3% in the rituximab group (hazard ratio [HR] = 0.66, P = .001). Results were similar for progression-free survival assessed by an independent review committee (81.9% vs 77.9, HR = 0.71, P = .01).
Post hoc subgroup analyses according to baseline and stratification factors showed results similar to the primary analysis, including by chemotherapy regimen. However, the treatment benefit appeared to be stronger in women (HR = 0.49, 95% confidence interval [CI] = 0.33– 0.74) vs men (HR = 0.82, 95% CI = 0.59–1.15), with P = .06 for interaction.
Response rates at the end of induction were 88.5% in the obinutuzumab group vs 86.9% in the rituximab group (P = .33), including a complete response in 19.5% vs 23.8% (P = .07). New antilymphoma treatments were begun in 13% vs 18% of patients. At the time of the analysis, the estimated 3-year overall survival rate was 94.0% vs 92.1% (HR = 0.75, P = .21).
Grade ≥ 3 adverse events occurred in 74.6% of the obinutuzumab group vs 67.8% of the rituximab group. The most common events in both the obinutuzumab group and rituximab group were neutropenia (45.9% vs 39.5%), infection (20.0% vs 15.6%), and infusion-related events (12.4% vs 6.7%). Any grade infusion-related reaction occurred in 68.2% vs 58.5%; they were considered due to obinutuzumab vs rituximab in 59.3% vs 48.9% (P < .001).
Serious adverse events occurred in 46.1% vs 39.9%; the most common side effects in both groups were infection (18.2% vs 14.4%) and neutropenia (8.4% vs 7.4%). Adverse events led to discontinuation of at least one treatment in 16.3% vs 14.2%. Adverse events resulted in death in 4.0% vs 3.4% of patients.
The investigators concluded: “[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. The frequency of high-grade adverse events was higher with obinutuzumab than with rituximab.” ■
DISCLOSURE: The study was funded by F. Hoffmann–La Roche. For full disclosures of the study authors, visit www.nejm.org.
1. Marcus R, Davies A, Ando K, et al: Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:1331-1344, 2017.
The roadside along the path to curing follicular lymphoma is riddled with the debris of failed cytotoxic regimens. For decades, clinical trials unsuccessfully pitted various chemotherapy combinations against each other. It took but a single, noncytotoxic molecule, rituximab (Rituxan), to forever...