CD20 antibodies: type II to tango?

In this issue of Blood, Salles et al and Sehn et al report the results of the first two phase 1 trials with the next generation anti-CD20 mAb obinutuzumab (GA101).^1,2  Both studies show that obinutuzumab is well tolerated and has promising activity in a mixed group of heavily pretreated patients with relapsed or refractory NHL.

Obinutuzumab is a glycoengineered, humanized type II anti-CD20 antibody. As opposed to type I anti-CD20 mAbs (eg, rituximab) it induces no complement-dependent cytotoxicity. However, obinutuzumab is a much stronger inducer of direct cell death and antibody-dependent cellular cytotoxicity.³  Compared with rituximab, obinutuzumab has superior activity in whole-blood B-cell depletion assays, in preclinical human lymphoma xenograft models, and in depleting B cells in nonhuman primates.³  Unlike type I anti-CD20 antibodies it does not induce redistribution of CD20 into detergent-resistant lipid rafts but instead leads to strong homotypic adhesion and actin-dependent lysosome-mediated cell death.⁴  Although it recognizes an overlapping CD20 epitope, obinutuzumab binds to CD20 in a different orientation and at a wider elbow angle than type I anti-CD20mAb,⁵  which might be responsible for the different biologic characteristics of this type II anti-CD20 mAb.

Of course the key question is whether these differences translate into superior clinical activity. In their study of 21 patients, Salles et al achieved an overall response rate (ORR) of 33%. Interestingly, responses were only obtained in the follicular lymphoma patients, resulting in an ORR of 54% (31% complete response) in this subgroup.¹  Sehn et al treated 22 patients with obinutuzumab induction, followed by 2 years of maintenance for 8 patients. At the end of induction the ORR was 23%. In both studies response duration varied from 3 to 21 months.²  These certainly are remarkable results in patients with a median of 4²  to 5¹  prior treatments, including autologous stem cell transplantation. However, a major limitation of both studies is the small number of patients as well as the heterogeneity of the lymphoma subtypes included. This precludes robust conclusions about, for example, the correlation between response and tumor load or response and Fc-γ receptor polymorphism.¹  The same is true for the important question of whether obinutuzumab has activity in rituximab-refractory patients. This was found to be the case in 2 of 9¹  and 2 of 13²  patients, respectively. A preliminary analysis of a randomized phase 2 study comparing 2 different doses of obinutuzumab in relapsed FL showed a 50% response rate in rituximab-refractory patients treated with the higher dose. However, again the numbers were very low (5 of 10 patients).⁶  Although the range of obinutuzumab doses used in the Salles and Sehn studies is comparable, completely different induction schedules have been used, in line with the unfortunate tradition in the field of mAb treatment of lymphoma. Salles et al administered a total of 9 doses, starting with weekly infusions on days 1 and 8 and then once every 3 weeks, whereas Sehn et al gave 4 doses once a week. In both studies responses occurred in all dose groups, without clear evidence of a dose-response relationship. Sehn et al found consistently higher serum concentrations of obinutuzumab in responders, reactivating the chicken-or-the-egg discussion: is the response better because of higher serum levels or are these levels a reflection of a lower initial tumor load in the responders? The small patient cohort again does not allow solid answers to this question.

In both studies the safety profile was found to be comparable with what we know from treatment with rituximab. Most adverse events were infusion related, in general mild and predominantly restricted to the first infusion. Apparently the lack of complement activation by obinutuzumab does not prevent the occurrence of infusion-related reactions. Again, the small number of patients did not allow correlating measured cytokine levels and infusion-related reactions.¹ 

Thus, although the data on obinutuzumab reported in this issue of Blood are novel and promising, they really can be regarded only as a starting point. Crucial for assessment of its future position is the direct head-to-head comparison with rituximab as well as analysis of the efficacy of obinutuzumab in rituximab-refractory patients. In the latter group the results with ofatumumab, a type I anti-CD20 antibody recognizing a different epitope and resulting in increased complement dependent cytotoxicity, have been rather disappointing.⁷  Unfortunately, the molecular basis for rituximab-refractoriness is largely unknown, prohibiting rational approaches to reverse it. Several head-to-head comparisons are ongoing. The preliminary results of the GAUSS study, a randomized phase 2 study comparing obinutuzumab with rituximab in patients with relapsed indolent B-cell lymphoma, were recently presented.⁸  Obinutuzumab resulted in higher overall response rates as assessed by both investigators (44% vs 38%; NS) and a blinded independent review facility (43% vs 28%; P < .01). Thus far there was no difference in progression-free survival. In this study induction treatment consisted of 4 weekly infusions of either obinutuzumab (1000 mg flat dose) or rituximab (375 mg/m²). In patients without evidence of progression this was followed by maintenance treatment with obinutuzumab (1000 mg) or rituximab (375 mg/m²), every 2 months for up to 2 years. Because in general 375 mg/m² will be roughly 25% less than 1000 mg, it is debatable whether this is the most appropriate way to compare these 2 mAbs. Two ongoing large, international, randomized phase 3 studies compare the combination of either obinutuzumab or rituximab with chemotherapy in previously untreated diffuse large B-cell lymphoma and treatment-naive indolent lymphoma patients, respectively. The German CLL Study Group runs a randomized phase 3 study in previously untreated CLL patients unfit for fludarabine-containing regimens, comparing chlorambucil, chlorambucil plus rituximab, and chlorambucil plus obinutuzumab. In the ongoing Gadolin study a total of 360 rituximab-refractory follicular lymphoma patients are randomized between bendamustine and bendamustine plus obinutuzumab followed by maintenance. The results of these pivotal trials are eagerly awaited.

In conclusion, it will take some years before we know whether obinutuzumab is indeed a useful extension of our therapeutic arsenal, that is, whether it improves the clinical outcome in patients with CD20-positive B-cell malignancies.