SAN DIEGO — Obinutuzumab-based induction and maintenance therapy significantly improved PFS compared with rituximab-based therapy in patients with untreated follicular lymphoma, according to results of the phase 3 GALLIUM study presented during the plenary session of the ASH Annual Meeting and Exposition.
“We’ve seen significant benefit with the inclusion of rituximab [Rituxan; Genentech, Biogen] plus maintenance therapy as part of first-line treatment of patients with previously untreated follicular lymphoma,” Robert E. Marcus, MBBS, FRCP, FRCPath, consultant hematologist at Kings College Hospital in London, United Kingdom, said during his presentation. “The median PFS is over 6 years, but the majority of patients will still relapse, and it is a challenge treating those patients, especially those who relapse early after first-line therapy.”
Obinutuzumab (Gazyva, Genentech) — a glycoengineered type II anti-CD20 monoclonal antibody with enhanced direct cell killing — has demonstrated promising activity and tolerability when combined with chemotherapy for relapsed indolent non-Hodgkin lymphoma.
Marcus and colleagues compared the safety and efficacy of rituximab or obinutuzumab with chemotherapy followed by maintenance for first-line treatment of indolent NHL.
The analysis included 1,202 patients (median age, 59 years; 53.2% women) with grade 1 to grade 3a previously untreated follicular lymphoma; an additional 195 patients with chemotherapy-naive marginal zone lymphoma also were treated and will be analyzed separately. Over 40% of patients had high FLIPI index, suggesting poor prognosis, Marcus said. The median time from diagnosis to treatment was under 3 months.
“This was not a population that could have been subjected to watch-and-wait policy,” Marcus said.
Patients received CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1%), CVP (cyclophosphamide, vincristine and prednisone; 9.8%) or bendamustine (Treanda, Teva Oncology; 57.1%) chemotherapy.
“Because there was and still is no international consensus on the appropriate first-line therapy for follicular lymphoma, individual centers were free to choose one of three therapeutic options,” Marcus said.
Researchers randomly assigned patients 1:1 to 375 mg/m2 rituximab (day 1 of each cycle) or 1,000 mg obinutuzumab (days 1, 8 and 15 of cycle 1; day 1 of subsequent cycles). Patients who received CVP or CHOP chemotherapy underwent eight 21-day cycles of their assigned therapy, and those who received bendamustine underwent six 28-day cycles.
Patients who achieved a complete or partial response at the end of induction continued to receive rituximab or obinutuzumab as maintenance therapy every 2 months for 2 years or until disease progression. At the end of induction, the overall response rate was 86.9% (95% CI, 83.9-89.5) in the rituximab arm and 88.5% (95% CI, 85.7-91) in the obinutuzumab arm.
PFS served as the investigator-assessed primary endpoint.
Marcus and colleagues conducted an interim efficacy analysis after 67% of 370 PFS events had occurred. At that time, the study was unblinded based on a recommendation from the independent data monitoring committee.
Median follow-up was 34.5 months (range, 0-54.5). At the time of the analysis, maintenance was ongoing in 114 patients.
Significantly fewer patients in the obinutuzumab arm experienced a PFS event (16.8% vs. 24%), equating to a 34% reduction in risk for progression (HR = 0.66; 95% CI, 0.51-0.85).
Estimated 3-year PFS was 80% (95% CI, 75.9-83.6) in the obinutuzumab arm and 73.3% (95% CI, 68.8-77.2) in the rituximab arm. Median PFS had not yet been reached for either arm.
At the time of the analysis, 5.5% of patients treated with obinutuzumab and 8.7% of patients treated with rituximab had died (HR = 0.75; 95% CI, 0.49-1.17).
Patients demonstrated a PFS benefit with obinutuzumab regardless of the induction chemotherapy regimen they had received, Marcus said. However, fatal adverse events were more common among patients receiving bendamustine in both treatment arms.
“Individual clinicians will have to make a decision as to whether any benefits in PFS associated with more intensive regimens outweigh any safety concerns,” he added.
More patients treated with obinutuzumab experienced grade 3 to grade 5 adverse events (74.6% vs. 67.8%) and serious adverse events (46.1% vs. 39.9%). A similar proportion of patients experienced fatal adverse events (4% vs. 3.4%).
Treatment discontinuation due to adverse events occurred in 16.3% of patients on the obinutuzumab arm and 14.2% of patients on the rituximab arm.
“What this may translate to, subject to the survival curves remaining stable, will be an improvement in PFS in first remission to over 8 years,” Marcus said. “Obinutuzumab-based therapy improves the outcomes compared with rituximab-based therapy and should now be considered one of the options for patients for first-line therapy of follicular lymphoma.” – by Alexandra Todak
Marcus RE, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Marcus reports consultant roles with and honoraria from Roche, as well as travel support from Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures.