Obinutuzumab for Indolent Lymphoma

Transcript:Ian W. Flinn, MD: So, we’re forever trying to create a better mouse trap, and there are many ways of improving antibodies. Many have been tried, and some have been successful. Obinutuzumab has been engineered to have more ADCC (antibody-dependent cell-mediated cytotoxicity), but it unfortunately loses some complement anti-tumor effect along the way. But it’s now approved for the treatment of low-grade lymphoma as well as for chronic lymphocytic leukemia. What are your thoughts on that? There are recent studies using it.

Andre Goy, MD, MS: I think in CLL, there was a large pivotal trial that looked at chlorambucil alone versus chlorambucil/rituximab or chlorambucil/obinutuzumab. The data were very impressive in PFS. One has to remember, though, this is a much higher dose of a monoclonal antibody. The dose that we use is 375 mg/m2, and it was somewhat arbitrary in the schedule. Here, this is a more intense schedule, but clearly there are some preclinical data and some clinical data, to some degree now, that suggest that this is a better antibody. And, as you said, it is being tested across the board in B-cell lymphomas, follicular, and large-cell lymphoma?

Krishna V. Komanduri, MD: This concept of there’s less fucosylation and therefore it may be activating NK cells, I think this is something that is supposedly true for obinutuzumab. I think that there are other antibodies in development that have that hypo-fucosylated mechanism of action. Do you think that that’s something that makes sense to you?

Ian W. Flinn, MD: The glycoengineered antibodies?

Krishna V. Komanduri, MD: That’s right, glycoengineered antibodies.

Ian W. Flinn, MD: It seems like it has got a lot of things that we think about with antibodies. And, for many years, trying to understand what the mechanisms of action in vivo versus in vitro consumed decades of research. I was frankly skeptical of how much of an improvement obinutuzumab was over rituximab. Clearly, in CLL, we’re using a backbone of chemotherapy with chlorambucil. It was a no-brainer that that was going to happen, but the results are impressive in MRD in CLL. And the recent studies show even in the frontline setting—there was a press release just a few weeks ago of the frontline use of obinutuzumab in combination with chemotherapy versus chemotherapy in combination with rituximab—it met its primary endpoint. So, I think that’s really where the proof is going to be. We wait for the formal presentation of those results. Hopefully, we’ll see them this year at ASH maybe.

Andre Goy, MD, MS: It’s a really important question we’d like to understand. We alluded to the fact in microenvironment, immunological signature, that we really don’t have a good handle on what makes a patient with follicular lymphoma, where we should use it as a single agent except for the FC polymorphism, right? So, there’s a polymorphism of FC receptor that can make the antibody a bit stickier, if we want to call it simply and, therefore, better ADCC. There’s VV versus FF or FV, and then that gives VV a higher CR rate and higher duration of response. This has not been proven in the context of R-chemotherapy. But the whole understanding of what the T cells involved are, and what’s the degree of activity of NK cells in those patients at the time they received immunotherapy, to my knowledge has not been really documented. There was some attempt at the beginning, when I was at MD Anderson, where we combined it with cytokine and then GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-12, you name it. But there hasn’t really been a huge benefit.

The only real benefit that was seen was when we started combining it with lenalidomide. And then, with lenalidomide and rituximab in follicular lymphoma, talk about NK cells increasing activity in CD8-positive T cells. The results from the phase II trial at MD Anderson were very, very impressive, including the molecular CR. So, based on that, there’s a large randomized trial that we just closed with 1000 patients and we’re waiting for the results. But I think this is going to be something that is going to be important because it might help change the landscape in follicular lymphoma.

Krishna V. Komanduri, MD: What about targets, CD19 versus CD20 versus CD22 versus even CD40? Do you want to comment on that?

Andre Goy, MD, MS: There was not a rich rationale for CD20, except it was a stable molecule, it appeared that it was not internalizing, and it was easier. We know that some antibodies can cap the antibody, but there’s some question that CD20 can internalize or shed. I don’t think this is really sorted out in a clinical consequence, but there are some other antibodies that are targeting CD19, CD30. And this antibody is not really a naked antibody; it’s more of an antibody-drug conjugate. It’s interesting to know that there are five anti-CD30 naked antibodies that were tried in lymphomas with basically no activity. Once we moved into the antibody-drug conjugate approach, that’s the story of brentuximab, which we can also use in large-cell lymphoma, T-cell lymphoma, or in CD30-positive anaplastic large cell lymphoma.

Transcript Edited for Clarity