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Benefit of first-line obinutuzumab over rituximab for follicular lymphoma may be ‘too close to call’
Obinutuzumab-based chemoimmunotherapy and maintenance therapy conferred longer PFS than rituximab-based therapy for the first-line treatment of follicular lymphoma, according to the randomized phase 3 GALLIUM study published in The New England Journal of Medicine.
However, patients who received obinutuzumab (Gazyva, Genentech) plus chemotherapy achieved a similar response rate and experienced more high-grade adverse events compared with patients who received rituximab (Rituxan; Genentech, Biogen).
“The GALLIUM trial showed that PFS was longer with obinutuzumab than with rituximab, but no significant difference was observed in the rate of response,” Robert Marcus, MB, BS, consultant hematologist at King’s College Hospital in London, told HemOnc Today. “We tried to see if obinutuzumab prolongs first remission, and it does.”
Rituximab plus chemotherapy has significantly improved outcomes in patients with newly diagnosed follicular lymphoma. The combination confers a median PFS of 6 to 8 years, and an estimated 6-year OS rate of 87.4%. However, the majority of patients on rituximab eventually relapse, and early progression following first-line treatment is associated with shorter survival.
Obinutuzumab — granted FDA priority review for this indication in August, and approved for use in combination with bendamustine in previously treated patients — is a glycoengineered type II anti-CD20 monoclonal antibody that has lower complement-dependent cytotoxicity than rituximab, but greater antibody-dependent cellular cytotoxicity and phagocytosis. It also has demonstrated greater direct B-cell killing effects.
Researchers randomly assigned 601 patients (median age, 60 years; 52.9% women; 91% Ann Arbor stage III-IV) to 1,000 mg obinutuzumab (days 1, 8, and 15 of cycle 1; day 1 of subsequent cycles) and 601 patients (median age, 58 years; 53.4% women; 90.7% Ann Arbor stage III-IV) to 375 mg/m2 rituximab (day 1 of each cycle).
Chemotherapy regimens varied and included bendamustine (57.1%); CHOP (33.1%) or cyclophosphamide, vincristine and prednisone (9.8%).
Those who responded received maintenance treatment for up to 2 years with the same antibody they received at induction.
PFS served as the primary endpoint. Median follow-up was 34.5 months (range, 0-54.5 months).
A total of 35 patients (5.5%) in the obinutuzumab group and 46% (7.7%) in the rituximab group died.
Interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk for progression, relapse or death than rituximab-based chemotherapy (estimated 3-year PFS, 80% vs. 73.3%; HR for progression, relapse or death = 0.66; 95% CI, 0.51-0.85).
Response rates appeared similar in the two groups (obinutuzumab, 88.5% vs. rituximab, 86.9%).
Grade 3 to grade 5 adverse events occurred more frequently with obinutuzumab than rituximab (74.6% vs. 67.8%), as did serious adverse events (46.1% vs. 39.9%). The groups demonstrated similar occurrences of adverse events resulting in death (4% vs. 3.4%).
The most common adverse events included infusion-related reaction (59.3% vs. 48.9%; P < .001), nausea (46.9% vs. 46.6%) and neutropenia (48.6% vs. 43.6%).
Among the three chemotherapy regimens, treatment with bendamustine increased the rates of grade 3 to grade 5 infection and second neoplasms during the maintenance and follow-up phases of the study, a fact that complicated data, Marcus said.
“Because the deaths were relatively the same in both arms, the superior PFS of obinutuzumab makes it worth having,” Marcus said. “Clinicians also have the option to use a number of chemotherapy regimens with obinutuzumab and achieve superior PFS compared with rituximab-based chemotherapy.”
Additional research on biomarkers, 24-month posttreatment endpoint progression and gene expression profiles are ongoing and will be released in future publications, Marcus said.
Because data from the GALLIUM trial showed no major differences in responses to the initial chemoimmunotherapy regimen regardless of the antibody used, the advantage of obinutuzumab in prolonging remission appears to be related to maintenance treatment, James O. Armitage, MD, professor of hematology and oncology at University of Nebraska Medical Center, and Dan L. Longo, MD, professor of medicine at Harvard Medical School, wrote in an accompanying editorial.
Armitage and Longo also noted that the study data do not include relative treatment outcomes of the three chemotherapy regimens.
“Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned,” they wrote. “Even with maintenance therapy, there is no evidence from this trial of an OS benefit with obinutuzumab. These findings, combined with the higher rates of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use.”
Increasing the dosage of rituximab from 350 mg to 1,000 mg might also reduce or eliminate any difference in PFS, Armitage and Longo wrote, adding that more data on minimal residual disease might help support the use of obinutuzumab over rituximab.
“At the moment,” Armitage and Longo wrote, “the competition between these agents looks too close to call.” – by Chuck Gormley
For more information:
Robert Marcus, MB, BS , can be reached at marcus.re@googlemail.com.
Disclosures: F. Hoffmann-LaRoche funded this study. Marcus reports consultant roles with Roche and Takeda Pharmaceuticals. Please see the full study for a list of all other authors’ relevant financial disclosures. Armitage reports personal fees from Conatus, Samus Therapeutics and Tesaro. Longo reports employment with The New England Journal of Medicine.
Perspective
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These findings clearly demonstrate a moderate PFS advantage of obinutuzumab-chemotherapy followed by obinutuzumab maintenance compared with rituximab-chemotherapy and rituximab maintenance in the first-line treatment of follicular lymphoma. Interestingly, Marcus and colleagues also observed a stronger PFS benefit for obinutuzumab in women than in men (HR = 0.49 vs. 0.82).
However, several questions remain.
First, is the superior efficacy of obinutuzumab limited to indolent B-cell malignancy subtypes?
Similar to the GALLIUM study, Goede and colleagues showed obinutuzumab in combination with chlorambucil chemotherapy resulted in superior PFS compared with rituximab plus chlorambucil among older or frail patients with chronic lymphocytic leukemia. On the other hand, Vitolo and colleagues of the GOYA trial found no difference in survival or response rates when comparing obinutuzumab-CHOP and rituximab-CHOP for the upfront treatment of diffuse large B-cell lymphoma.
Another question is whether the prolonged PFS related to more intense dosing of obinutuzumab compared with rituximab rather than increased activity. Although rituximab has been available for nearly 2 decades now, its optimal dosing remains unclear, especially in elderly male patients or patients with a high metabolic tumor volume.
Third, is the benefit limited to patients who undergo maintenance therapy? Response rates after induction therapy appeared comparable between both groups, and not every patient will undergo maintenance therapy after induction for follicular lymphoma. An OS benefit did not occur; however, this might be an elusive endpoint in follicular lymphoma given its natural history and availability of effective salvage regimens.
Lastly, does the choice of the chemotherapy backbone matter? Although this trial was not designed to compare chemotherapy backbones, it was notable that a high rate of infections occurred in the bendamustine group compared with CHOP and cyclophosphamide, vincristine and prednisone, mainly during the maintenance (16.7% vs. 12.8%) and follow-up (9.3% vs. 2.3%) phases. Similarly, a 5.2% incidence of second malignancies occurred in the follow-up phase for patients treated with obinutuzumab-bendamustine vs. 0.8% with rituximab-bendamustine.
Obinutuzumab-chemotherapy followed by maintenance offers a 7% PFS benefit at 3 years compared with rituximab-chemotherapy plus maintenance. Although the study supports the use of obinutuzumab-chemotherapy plus maintenance for the front-line therapy of follicular lymphoma, the regimen is also associated with more toxicities. These can be seen even after the treatment has been completed, especially if bendamustine is the chemotherapy backbone.
References:
Goede V, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1313984.
Pfreundschuh M, et al. Blood. 2014;doi:10.1182/blood-2013-07-517037.
Tout M, et al. Blood. 2017;doi:10.1182/blood-2016-10-744292.
Vitolo U, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.73.3402.
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