Alexander M. Castellino, PhD

December 05, 2016

UPDATED December 6, 2016 // SAN DIEGO — Patients with advanced-stage symptomatic follicular lymphoma (FL) currently receive rituximab-based chemoimmunotherapy induction followed by rituximab (Rituxan, Genentech/Roche) maintenance as standard treatment.

However, the newer agent obinutuzumab (Gazyva/Gazyvaro, Genentech/Roche) may now be poised to be another option in the first-line setting. Interim data from the GALLIUM study suggest that patients with FL may be better off taking obinutuzumab, as the newer drug improved progression-free survival. However, there was no difference in overall survival, and there was concern over the higher mortality seen in the subgroup of patients who received induction therapy with these agents in addition to bendamustine. The results were presented here during the plenary session at the American Society of Hematology 58th Annual Meeting (abstract 6).

As reported by Robert E. Marcus, MD, of King's College Hospital, London, United Kingdom, data from the study indicate patients on obinutuzumab-based induction followed by obinutuzumab maintenance ha a 34% reduced risk of progression compared with rituximab-based induction followed by rituximab maintenance.

While presenting the safety data, Dr Marcus reported there were more deaths in patients who received bendamustine-based induction regimens with obinutuzumab or rituximab compared with other chemotherapy-based induction regimens in combination with obinutuzumab or rituximab

"This is another large study demonstrating the efficacy of obinutuzumab compared with rituximab in B cell malignancies, and it was reassuring that the induction regimen with obinutuzumab was equivalent to rituximab induction," Nadia Khan, MD, from the department of hematology/oncology at the Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News.

"The continuation of obinutuzumab in maintenance improved PFS over rituximab maintenance over 2 years," she added.

Dr Khan indicated that obinutuzumab is a potential replacement for rituximab in FL. "But not all patients are appropriate candidates for maintenance therapy," she said.

"PRIMA, a previous study that provided data for rituximab-chemotherapy induction followed by rituximab maintenance, helped us understand that there was no survival advantage for patients receiving rituximab maintenance," Dr Khan told Medscape Medical News.

"Therefore, in my practice I reserve maintenance therapy for patients with more aggressive disease who may not see a complete response with induction therapy. In such patients, obinutuzumab maintenance may convert a partial responder to a complete responder," she said.

However, Dr Khan noted that GALLIUM is the largest study evaluating a maintenance strategy after an induction regimen that included bendamustine, and concerningly, there was a higher mortality rate in both arms with bendamustine. "Further evaluation is warranted before moving forward with maintenance after bendamustine," she said.

When asked whether patients currently on rituximab may benefit from switching to obinutuzumab, she pointed out there are no data to support that approach. "Patients currently on rituximab should continue receiving rituximab," she said.

Currently, obinutuzumab is not approved as first-line therapy in newly diagnosed FL. It is approved for use as induction therapy in combination with bendamustine (Treanda, Teva Pharmaceuticals) followed by obinutuzumab maintenance specifically for patients with FL who have relapsed after, or are refractory to, a rituximab-containing regimen.

Given that obinutuzumab-based induction provided similar results to rituximab-based induction, Medscape Medical News asked Dr Khan if she would use obinutuzumab over rituximab when available. "I would consider using it. If I have a significant concern regarding tolerability of infusion reaction, then I may prefer rituximab," she said.

Study Details

At the meeting, Dr Marcus presented results for 1202 patients with advanced stage FL. The study involved treatment-naive patients with FL who had Stage 3/4 disease or Stage 2 disease with tumors ≥ 7 cm, were Eastern Cooperative Group Performance Status 0-2, and required treatment according to the GELF criteria.

Patients were randomized to receive induction therapy with rituximab (n = 601) or obinutuzumab (n = 601) in combination with chemotherapy, which varied with the study center, and included bendamustine (57%), CHOP (cyclosporine, doxorubicin [hydroxydaunomycin], vincristine (Oncovin), and prednisolone) (33%), or CVP (cyclophosphamide/vincristine/prednisone) (10%).

During induction, rituximab 375 mg/m2 (R) was provided on day 1 of each cycle and obinutuzumab (G) 1000 mg was given on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles.

Induction chemoimmunotherapy with CHOP or CVP was administered over 8 cycles, each of 21 days. Induction chemoimmunotherapy with bendamustine was administered over 6 cycles, each of 28 days.

Patients with a complete response (CR) or partial response (PR) further received maintenance therapy — those receiving R-chemotherapy received rituximab and those receiving G-chemotherapy received obinutuzumab every 2 months for 2 years or until disease progression.

With a projected 3-year improvement in progression-free survival (PFS) rate from 70.7% to 77.4% or median PFS from 6.0 to 8.1 years, the study was 80% powered to detect a hazard ratio (HR) of 0.74. With 370 PFS events needed for this to happen, the data monitoring safety board determined during a planned interim analysis in January 2016 that the primary endpoint had been reached and the study was unblinded.

GALLIUM Study Results

Median follow-up was 34.5 months and, at the time of data cut-off, 114 patients were still receiving maintenance therapy — 60 patients on obinutuzumab and 54 patients on rituximab. At the end of induction therapy, the objective response rate (ORR) and CR was similar in both arms. ORR was 88.5% (CR, 19.5%) for patients receiving obinutuzumab-based induction and 86.9% (CR, 23.8%) for patients receiving rituximab-based induction.

Dr Marcus reported that patients on obinutuzumab had a 34% reduced risk of progression (HR, 0.66; P = .0012). Three-year PFS was 81.9% for patients on obinutuzumab maintenance vs 77.9% for patients on rituximab maintenance. Median PFS was not reached for patients in either arm.

However, the PFS benefits did not translate to overall survival (OS). Although the estimated 3-year OS was higher for patients on obinutuzumab that rituximab (94.0% vs 92.1%), the difference was not significant (HR, 0.75; P = .21).

Time-to-next-treatment rates were higher with obinutuzumab than rituximab (87.1% vs 81.2%).

The safety data also show a higher incidence of Grade 3/5 and serious adverse events for patients in the obinutuzumab arm. Grade 3/5 adverse events were seen in 74.6% of patients in the obinutuzumab arm and 67.8% of patients in the rituximab arm.

The most common Grade 3 or higher adverse events that occurred more often in the obinutuzumab vs rituximab arm were low white blood cell count (neutropenia, 43.9% vs 37.9%; leukopenia, 8.6% vs 8.4%), febrile neutropenia (6.9% vs 4.9%), infusion-related reactions (12.4% vs 6.7%), low platelet count (thrombocytopenia, 6.1% vs 2.7%), infections (20.0% vs 15.6%), and second neoplasms (4.7% vs 2.7%).

The incidence of serious adverse events was 46.1% for patients on obinutuzumab and 39.9% for patients on rituximab. Treatment was discontinued in 16.3% of patients on obinutuzumab and 14.2% of patients on rituximab.

Fatal Grade 5 adverse events were reported in 4% of patients on obinutuzumab and 3.4% of patients on rituximab. However, when analyzed by chemotherapy used in induction, bendamustine was associated with the highest rate of deaths: 5.6% (19 patients) for obinutuzumab-bendamustine and 4.4% (15 patients) for rituximab-bendamustine. In contrast, fatal deaths occurred in nine patients across all other arms.

Death from infection was also reported for bendamustine-containing regimens — 2.7% (nine patients) for obinutuzumab-bendamustine and 0.6% (two patients) for rituximab-bendamustine. Death from infection was reported in one patient across all other arms.

PFS was significantly improved for all three chemotherapy regimens used in combination with obinutuzumab.

Each physician will have to balance the risk-benefit profile before deciding which chemotherapy to use in combination with obinutuzumab, Dr Marcus pointed out.

Obinutuzumab-chemotherapy plus maintenance is superior to rituximab-chemotherapy plus maintenance in untreated advanced FL at the interim efficacy analysis; it significantly improves outcomes and should now be offered as a first-line option for these patients, he concluded.

The study was funded by Genentech/Roche. Dr Marcus reported consulting for and receiving honoraria from Roche and travel funding from Takeda. Some coauthors are employees of Genentech or Roche.

American Society of Hematology 58th Annual Meeting. Abstract 6. Presented December 4, 2016.

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