Obinutuzumab: the more the merrier?

In this issue of Blood, Byrd et al present data from a randomized phase 2 study in which 78 previously untreated patients with chronic lymphocytic leukemia (CLL) received 8 cycles of either 1000 mg (the current standard dose) or 2000 mg of the anti-CD20 monoclonal antibody (mAb) obinutuzumab.¹  The authors report a higher overall response rate with higher doses of obinutuzumab (67% vs 49%), but there was no significant difference in progression-free survival (PFS) between groups.

Obinutuzumab (GA101) is a novel type 2 humanized anti-CD20 mAb that was glycoengineered to reduce attachment of fucose residues to the crystallizable fragment (Fc) portion of the mAb. This enhances the affinity of the antibody for binding to Fcγ receptors of the IIIA subgroup (FcγRIIIA or CD16a) on effector cells, thus improving antibody-dependent cell-mediated cytotoxicity (ADCC). Being a type 2 antibody, obinutuzumab mostly relies on ADCC and direct cytotoxic effects. In contrast, type 1 antibodies (rituximab and ofatumumab) display stronger complement-dependent cytotoxicity, less ADCC, and minimal direct cytotoxicity.

Over the past 2 decades, anti-CD20 mAbs have become a cornerstone of therapies for patients with B-cell malignancies, including CLL. As a single agent, rituximab was initially perceived as a relatively inactive agent in CLL, with response rates ranging between 5% and 14%. The characteristic low CD20 expression, which distinguishes CLL from other mature B-cell malignancies, presumably contributes to these relatively low response rates. However, more dose-dense²  or higher-dose regimens³  increased the response rates to single-agent rituximab and invigorated the interest in treating CLL patients with CD20 mAbs. The most established use of anti-CD20 mAbs in CLL is as a partner in chemoimmunotherapy (CIT) regimens combined with conventional agents. In these combinations, anti-CD20 mAbs improved PFS and overall survival when added to fludarabine and cyclophosphamide,^4,5  bendamustine,⁶  or chlorambucil.^7,8  Furthermore, single-agent anti-CD20 mAbs are commonly used (especially in the United States) in CLL patients who are unfit for chemotherapy-based regimens because of advanced age and/or poor performance status.

The data presented by Byrd et al¹  demonstrate that obinutuzumab as a single agent can induce complete remissions in 5% of CLL patients treated with standard-dose and in 20% of patients treated with higher-dose obinutuzumab, an indicator of the high efficacy of obinutuzumab, which was highlighted in the pivotal trial.⁷  On the basis of these data, one could speculate that obinutuzumab, currently approved for use in combination with chlorambucil for untreated CLL patients who are unfit to undergo CIT, will increasingly be used as a single agent. The data clearly corroborate that obinutuzumab has high single-agent activity, but they do not definitively answer what dose is optimal or whether obinutuzumab is best used alone or in combination. Cross-trial comparisons have many limitations, but the 18-month PFS with standard-dose obinutuzumab (59%) reported in the article by Byrd et al appears shorter than what was reported for obinutuzumab plus chlorambucil (∼80% at 18 months),³  and the authors argue that this may favor the use of higher-dose obinutuzumab in which the PFS at 18 months was more similar to that in the data for the chlorambucil combination. However, at later time points, the PFS curves of the 2 obinutuzumab dose regimens merged (see Figure 2 in the article by Byrd et al that begins on page 79), and there was no significant PFS benefit that favored the higher-dose obinutuzumab or that would change current dosing practice. These data indicate that higher-dose obinutuzumab has only limited advantage; it achieves deeper remissions which, after finishing the 6 months of treatment, do not translate into any major PFS benefit when compared with standard-dose obinutuzumab. Accordingly, current trials use standard dosing of obinutuzumab and favor obinutuzumab maintenance strategies over the higher-dose obinutuzumab used in combination trials (see table).

The most obvious combination partners for obinutuzumab are the standard CIT regimen (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in which rituximab is replaced by obinutuzumab to achieve more complete and/or durable responses. We also need to take into account that the use of CIT in CLL patients, especially in patients with high-risk disease, is declining because of superb data and broader availability of kinase inhibitors targeting B-cell receptor signaling (ie, the Bruton’s tyrosine kinase inhibitor ibrutinib,⁹  the phosphatidylinositol 3-kinase delta inhibitor idelalisib,¹⁰  and the B-cell lymphoma 2 antagonist GDC-0199). These agents are changing the current landscape of CLL therapy; the high number of obinutuzumab trials in combination with novel agents (see table) reflects this ongoing major change in clinical practice. With the addition of these new effective agents, including obinutuzumab, to our therapeutic armamentarium, long-term disease control can be achieved in more and more CLL patients, even those with high-risk features. Conversely, the high costs of long-term treatment with these agents to maintain remissions will increase the burden on our health care systems and our patients. Combination treatment strategies to eradicate CLL, allowing for treatment discontinuation, would therefore be desirable, and clinical trial efforts with this goal are currently ongoing (eg, NCT02401503).

In summary, the study by Byrd et al¹  highlights the high activity of obinutuzumab as a single agent in patients with CLL and corroborates earlier trial experience showing that there is a dose response with anti-CD20 mAbs in CLL.^2,3  Thus, despite the limitations of the trial by Byrd et al, which does not provide a robust rationale for use of higher-dose obinutuzumab in the short-term because of the lack of any major PFS benefit, we should not discard the possibility of a revival of higher-dose obinutuzumab in the future, for example in combination strategies in which achievement of deep remissions is the goal.