Patients with advanced-stage symptomatic follicular lymphoma (FL) currently undergo induction therapy with rituximab (Rituxan, Genentech/Roche) plus chemotherapy, followed by rituximab maintenance as standard first-line treatment. The GALLIUM study shows that using the newer drug obintuzumab (Gazyva/Gazyvaro, Genentech/Roche) in place of rituximab results in significantly longer progression-free survival (PFS).
These data, first reported at the 2016 annual meeting of the American Society of Hematology (ASH 2016) and reported at the time by Medscape Medical News, were published October 5 in the New England Journal of Medicine. Robert E. Marcus, MBBS, of King’s College Hospital, London, is the corresponding author.
“The GALLIUM trial showed that progression-free survival was longer with obinutuzumab than with rituximab, but no significant difference was observed in the rate of response according to CT-based assessment. Overall survival [OS] was similar between the two groups,” the GALLIUM investigators write. They also note that the trial was fully analyzed early after an interim analysis showed a 34% reduced risk for progression with obinutuzumab-based therapy.
In an accompanying editorial, James O. Armitage, MD, the Joe Shapiro Professor of Medicine from the University of Nebraska, Omaha, and Dan L. Longo, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, highlight the fact that OS and overall response rates were similar with the two drugs and that there was more toxicity with obintuzumab than with rituximab. Hence, they question whether the newer drug is better.
Obinutuzumab and rituximab are both CD-20 antibodies directed against CD20. Rituximab has been available since 2000 (biosimilars are currently available). Obinutuzumab was developed as a second-generation CD-20 antibody with a lower complement-mediated cytotoxicity but greater antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing. Obinutuzumab was approved for previously treated FL in 2016, but data from the GALLIUM study will be used to relegate it to first-line use.
Question Over Doses Used
Given the similarities overall response rates (ORRs) and OS, an accompanying editorial raises questions about the higher PFS seen with obinutuzumab. The editorialists note that patients in the obinutuzumab arm received a higher dose, 1000 mg/m2. Patients in the rituximab arm received the approved dose of 375 mg/m2. In the absence of data suggesting a difference in target affinity, the editorialists ask whether “there might have been a difference in outcome if rituximab had been administered at the same dose as obinutuzumab.”
“[There] is no evidence from this trial of an overall survival benefit with obinutuzumab,” Dr Armitage and Dr Longo write. This, along with the higher rate of toxic effects and presumably higher drug costs, raise questions about the advantage of using obinutuzumab, they note.
“[The] issue is complicated further because it is possible that giving rituximab at a dose of 1000 mg might reduce or eliminate any difference in progression-free survival ― that is, if the difference is primarily a dose effect,” they write.
“The issue about dosing is always a sticking point,” hematologist Nadia Khan, MD, from the Department of Hematology/Oncology at the Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News. “Is obinutuzumab really better, or are we just giving higher and more intense dosing? No one knows, since the study hasn’t been done and won’t be done ever,” she added. “We have to settle on the data we have,” Dr Khan said.
The editorialists also note that the advantage of obinutuzumab in prolonging remission appears to be related to the maintenance treatment.
“This conclusion is undermined a bit by the allusion…to data not included in the article that patients who received obinutuzumab were more likely to have negative minimal residual disease [MRD] status than were those who received rituximab,” they write.
Dr Armitage and Dr Longo cite data, also presented at ASH 2016, showing that in patients with MRD, obinutuzumab was associated with higher rates for negative MRD status following induction (94% vs 89% for rituximab). They note that no data were provided for MRD levels after maintenance therapy or about relapse rates in patients with negative MRD during treatment compared with those who did not.
They contend that when data on MRD become available, the case favoring onituzumab may be “more compelling if a higher proportion of patients who received obinutuzumab have MRD status at some point in treatment and remain in remission longer than those who received rituximab.
At the moment, the competition between these two agents looks too close to call
“At the moment, the competition between these two agents looks too close to call,” they conclude.
Study Details
Treatment-naive patients (n = 1202) with advanced FL were randomly allocated to receive induction therapy with rituximab (n = 601) or obinutuzumab (n = 601) in combination with chemotherapy, which was varied with the study center. The chemotherapy was bendamustine (Treanda, Teva Pharmaceuticals, 57%) or CHOP (cyclosporine, doxorubin [Hydroxydaunomycin], vincristine [Oncovin], and prednisolone, 33%), or CVP (cyclophosphamide/vincristine/prednisone, 10%).
During induction, rituximab 375 mg/m2 was given on day 1 of each cycle, and obinutuzumab 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 eight cycles, each of 21 days. Induction chemoimmunotherapy with bendamustine was administered over six cycles, each of 28 days.
Patients with a complete response (CR) or partial response (PR) further received maintenance therapy ― those who were given rituximab chemotherapy received rituximab, and those who were given obinutuzumab chemotherapy received obinutuzumab every 2 months for 2 years or until disease progression.
GALLIUM Study Results
Of 1202 patients (601 in each group), 557 and 551 patients completed induction treatment with obinutuzumab chemotherapy and rituximab chemotherapy, respectively; 361 and 341 patients, respectively, completed maintenance therapy.
During the induction phase, 37 patients in the obinutuzumab group and 47 in the rituximab group withdrew from therapy, mainly because of adverse events. Likewise, withdrawals of patients receiving maintenance therapy (118 and 132 patients on obinutuzumab and rituximab, respectively) were due to progression (in 37 and 64 patients on obinutuzumab and rituximab, respectively).
Most patients received more than 90% of the planned doses; median duration of exposure to induction therapy was 25.1 weeks.
With a median follow-up was 34.5 months, at the end of induction therapy, ORR and CR were similar for both arms of the study. 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.
Investigator-assessed estimated 3-year PFS was 80.0% for patients receiving obinutuzumab-based therapy vs 73.3% for patients on rituximab-based therapy (hazard ratio [HR], 0.66; P = .001) ― similar to independent review committee assessment (81.9% vs 77.9%, respectively). Median PFS was not reached for patients on either arm of the study. Although the estimated 3-year OS was higher for patients receiving obinutuzumab (94.0% vs 92.1% for rituximab), the difference was not significant (HR, 0.75; P = .21).
The safety data showed a higher incidence of grade 3/5 and serious adverse events for patients in the obinutuzumab arm of the study. 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 the rituximab arm were low white blood cell counts (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 receiving obinutuzumab and 39.9% for patients receiving rituximab. Treatment was discontinued in 16.3% of patients receiving obinutuzumab and 14.2% for patients receiving rituximab.
Fatal grade 5 adverse events were reported for 4% of patients receiving obinutuzumab and 3.4% for patients receiving rituximab.
Bendamustine Toxicity a Concern
GALLIUM showed that patients receiving bendamustine in combination with either obinutuzumab or rituximab experiened higher rates of grade 3/5 neutropenia, infection, and second neoplasm. The rates were higher when bendamustine was used with obinutuzumab.
These details, when presented at ASH 2016, caused shock waves in the audience, because bendamustine plus rituximab has become a widely used treatment in the United States. The editorialists write: “[The] increased death rate and second cancers that were associated with the bendamustine-containing groups in this trial raise concern.” It was also worrisome, they note, that second malignancies were all reported in patients treated with obinutuzumab.
This is in line with the thinking of several hematologists interviewed by Medscape Medical News when the bendamustine-associated toxicity was reported at ASH 2016.
Will GALLIUM Have an Impact on Clinical Practice?
Notwithstanding the toxicity issue, Medscape Medical News wanted to know whether GALLIUM will have an impact on clinical care. “This is another large study demonstrating the efficacy of obinutuzumab compared with rituxmab in B-cell malignancies, and it was reassuring that the induction regimen with obinutuzumab was equivalent to rituximab induction,” Dr Khan 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 to evaluate a maintenance strategy after an induction regimen that included bendamustine, and it is concerning that the mortality rate was higher in both arms with bendamustine. “Further evaluation is warranted before moving forward with maintenance after bendamustine,” she said.
When asked whether patients currently receiving rituximab may benefit from a switch to obinutuzumab, she pointed out that here are no data to support that approach. “Patients currently on rituximab should continue receiving rituximab,” she said.
Currently, obinutuzumab is not approved as frontline therapy in newly diagnosed FL. It is approved for use as induction therapy with obinutuzumab in combination with bendamustine followed by obinutuzumab maintenance specifically for patients with FL who experience relapse after or who are 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 whether she would use obinutuzumab over rituximab when available. “I would consider using it, but if I have a significant concern regarding tolerability of infusion reaction, then I may prefer rituximab,” she said.
GALLIUM was funded by F. Hoffman-La Roche. Dr Marcus receives consulting and lecture fees from Takeda Pharmaceuticals, and travel support and consulting and lecture fees from Roche. Some of the authors are employees of F. Hoffman-La Roche. A complete list of relevant financial relationships for the GALLIUM investigators is included in the published article . Dr Armitage consults with Ziopharm Oncology, GlaxoSmithKline, IDMC, Spectrum Pharmaceuticals, Roche, Conatus-IDMC, and serves on the board of directors for Tesaro. Dr Longo has disclosed no relevant financial relationsihps.
New Engl J Med. Published online October 5, 2016.
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