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GADOLIN and the Perplexing Role of Obinutuzumab in the Treatment of B-Cell Malignancies



Collectively, these data indicate that just because obinutuzumab-based chemotherapy in CLL was better than rituximab-based therapy, one should not extrapolate and substitute rituximab with obinutuzumab in other regimens and for other B-cell malignancies.
— Anas Younes, MD

After several dose-finding phase I and II studies in a variety of B-cell malignancies, the potential clinical role of the newer anti-CD20 monoclonal antibody obinutuzumab (Gazyva) remained unclear. These early trials tested low and high doses as well as weekly and every-3-week schedules of obinutuzumab. Patients with relapsed and refractory B-cell lymphoma and chronic lymphocytic leukemia (CLL) were evaluated, including patients who were refractory to prior rituximab (Rituxan)-based therapy. The conclusions of most of these early trials suggested the clinical activity of obinutuzumab was “promising.”

Supporting Data in CLL

Based on these encouraging results, several randomized trials were conducted in patients with CLL and B-cell lymphoma. In the phase III randomized trial reported by Goede et al,1 obinutuzumab was compared head to head with rituximab, both in combination with chlorambucil, in 781 newly diagnosed patients with CLL with coexisting conditions. Obinutuzumab plus chlorambucil was superior to rituximab plus chlorambucil. After 6 cycles of therapy, obinutuzumab plus chlorambucil produced an overall response rate of 78%, compared with 65% for rituximab plus chlorambucil. Furthermore, the median progression-free survival achieved with obinutuzumab plus chlorambucil was significantly higher than with rituximab plus chlorambucil (27 months vs 15 months).

These results led to the first U.S. Food and Drug Administration (FDA) approval of obinutuzumab for the treatment of B-cell malignancies. Given this success in patients with CLL, the obvious next step would be to perform randomized trials in other B-cell malignancies, aiming to replace rituximab with the newer, more potent obinutuzumab.

Initial Experience in B-Cell Lymphoma

This initial excitement was dampened by the results of a randomized phase II study (GAUSS trial) comparing single-agent rituximab with single-agent obinutuzumab in 175 patients with relapsed indolent B-cell lymphoma.2 Patients were randomized to receive 4 weekly doses of either drug, followed by 2 years of maintenance therapy (1 dose every 2 months). Only 10% of the patients had rituximab-refractory lymphoma.

In the 149 patients with follicular lymphoma, the overall response rate after 4 weeks of “induction” therapy was higher with obinutuzumab than rituximab (44.6% vs 26.7%), but the best overall response rate was not significantly different (66% for obinutuzumab vs 64% for rituximab). Similarly, there was no significant difference in the 2-year progression-free survival between the two drugs.

Trials Leading to Second Indication

Despite these rather disappointing results, two large obinutuzumab-based randomized trials were conducted in patients with indolent lymphoma. The GADOLIN trial focused on patients with rituximab-refractory disease,3 and the GALLIUM trial focused on newly diagnosed patients.4 The results of the GADOLIN trial—recently published in The Lancet Oncology3 and summarized in this issue of The ASCO Post—led to the second FDA approval for obinutuzumab.

Briefly, 396 patients with relapsed or refractory indolent B-cell lymphoma (321 had follicular histology) who were refractory to rituximab were randomly assigned to receive therapy with single-agent bendamustine (Bendeka, Treanda) or bendamustine in combination with obinutuzumab for 6 cycles followed by 2 years of maintenance given every 2 months. The overall response rate after induction therapy was similar for obinutuzumab plus bendamustine vs bendamustine alone (69% vs 63%). However, the median event-free survival was significantly higher in those treated with obinutuzumab plus bendamustine (26.8 months vs 13.7 months). Interestingly, there was no control arm that included rituximab.

Questions Remain

Given the disappointing results of the GAUSS study, and the equal response rates achieved with bendamustine and the bendamustine/obinutuzumab combination, the GADOLIN study raised many questions. One obvious question is what is the true definition of rituximab-refractory disease? And was prolonged progression-free survival simply driven by the unequal length of the treatment arms? And if so, should we treat patients with concurrent bendamustine plus obinutuzumab followed by obinutuzumab maintenance, or would a simple sequential therapy of single-agent bendamustine followed by single-agent obinutuzumab be as good?

These questions and any doubts about the role of obinutuzumab in the treatment of indolent and follicular lymphoma may be better answered in the GALLIUM study, in which 1,401 untreated patients with indolent lymphoma (1,202 with follicular lymphoma) were treated with rituximab-chemotherapy or obinutuzumab-chemotherapy regimens, each followed by 2 years of antibody maintenance. Based on a recent press release by the trial’s sponsor,4 obinutuzumab-chemotherapy produced longer progression-free survival than did rituximab-chemotherapy.

If that is not confusing enough, a second recent press release of a phase III randomized trial in patients with newly diagnosed diffuse large B-cell lymphoma comparing standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) with obinutuzumab-CHOP showed no difference in progression-free survival.5

Collectively, these data indicate that just because obinutuzumab-based chemotherapy in CLL was better than rituximab-based therapy, one should not extrapolate and substitute rituximab with obinutuzumab in other regimens and for other B-cell malignancies. Certainly this is very disappointing, as we will have to perform many trials for each individual indication, all over again. Stay tuned! ■

Disclosure: Dr. Younes has received honorarium from Roche.

Dr. Younes is Chief, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York.

References

1. Goede V, Fischer K, Busch R, et al: Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101-1110, 2014.

2. Sehn LH, Goy A, Offner FC, et al: Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: Final analysis of the GAUSS study. J Clin Oncol 33:3467-3474, 2015.

3. Sehn LH, Chua N, Mayer J, et al: Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): A randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. June 23, 2016 (early release online).

4. Genentech’s Gazyva showed superior progression-free survival compared to Rituxan in people with previously untreated follicular lymphoma [GALLIUM study]. Press release, May 26, 2016. Available at http://www.gene.com/media/press-releases/14628/2016-05-26/genentechs-gazyva-showed-superior-progre. Accessed August 5, 2016.

5. Genentech provides update on phase III study of Gazyva in people with previously untreated diffuse large B-cell lymphoma [GOYA study]. Press release, July 17, 2016. Available at http://www.gene.com/media/press-releases/14633/2016-07-17/genentech-provides-update-on-phase-iii-s. Accessed August 5, 2016.


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