John P. Leonard, MD:As we move toward other emerging options for relapsed and refractory diffuse large B-cell lymphoma, we have a number of new potential agents that are out there.

One that is undergoing regulatory review right now is the anti-CD19 antibody tafasitamab [tafa]. It's been studied primarily in combination with other agents, including lenalidomide [len]. I know, Kami, you have led some of the trials around tafasitamab. Can you tell us a little bit about what it is first from the audience that may be unfamiliar and some of the initial studies that have been on primarily in relapsed and refractory large cell lymphoma with this agent in combination, particularly lenalidomide?

Kami Maddocks, MD: Tafasitamab is actually a CD19 monoclonal antibody. The Fc portion has been enhanced to increase ADCC [antibody-dependent cell-mediated cytotoxicity] and ADCP [antibody-dependent cellular phagocytosis]. There was a single arm study that looked at the monoclonal antibody tafasitamab alone in relapsed refractory non-Hodgkin lymphoma and they saw some responses in diffuse large B-cell lymphoma but notably there was a handful of patients who achieved a complete remission. The median duration of response in those patients was over 20 months, signaling that there might be some activity in this agent with large cell lymphoma.

The combination of tafasitamab and lenalidomide was evaluated in a phase 2 study that combined the 2 drugs for 12 months. The antibody is given once a week for the first 3 months and then every other week for months 4 through 12. Lenalidomide was given at a dose of 25 mg. After a year of therapy, patients were allowed to continue on tafasitamab maintenance. The further rationale of this trial is that the lenalidomide activates NK [natural killer] cells and that brings more cells for tafasitamab to act on.

The phase 2 trial of the combination showed pretty high response rates. It showed a 60% overall response with a little over 40% of those patients achieving a complete remission. The patient population in the study was allowed to go on trial with relapsed/refractory disease with a median prior therapy of 1 to 3; the population had median prior therapy of 2. These weren't extensively or very heavily pretreated patients.

It was really targeted at those patients who relapsed after their initial therapy or maybe received a first salvage and then are not candidates for autologous stem cell transplant. The therapy was pretty well-tolerated with toxicity mainly being hematologic, fatigue and diarrhea. Really when you look at the toxicities after the first year of treatment, the majority of them resolved, really suggesting that the toxicities that were seen with the combination were primarily what you see with lenalidomide alone. There were very few infusion related reactions. About three quarters of the patients were able to stay on a lenalidomide dose of 20 mg or higher.

John P. Leonard, MD:Matt, I want to ask you your take on this agent. We just talked about CAR [chimeric antigen receptor] T cell data with and we’ll come back to whatever comparisons we can draw. How does this compare with either lenalidomide alone or anti-CD20 alone? Are these patients characteristic of this population? Are they the same people were seeing with CAR T cells? I know that the RE-MIND study tried to make some comparisons, obviously with different cohorts. How do you interpret this phase 2 data regarding this combination in light of the patient population that we may want to apply this combination to in the future?

Matthew Lunning, DO: Dr. Maddocks, correct me if I'm wrong here, but I was just waiting and waiting and waiting for the publication and I think it came out recently in Lancet Hematology because some of the methodology of the study, too, is that the patients couldn't have double-hit or triple-hit biology. My understanding is that you couldn't have been primary refractory to your first line of therapy. If you were refractory to R-CHOP [rituximab cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone]—or any CD20-targeted monoclonal antibody—or dose-adjusted EPOCH [etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone], you couldn't be in the study also.

There are some differences there because we've seen on CAR T-cell therapy those patients, double-hit, CAR T-cell appears to be as agnostic. It doesn't care that you're a double-hit. You can still respond and have durability. The same thing is that if you're primary refractory, you're still going to CAR T-cell likely double refractory with a lot of disease and those people have gone chemotherapy jumping from one to the next.

I think there is certainly a population difference between ZUMA-1, JULIET, and likely TRANSCEND compared to the L-MIND. Now don't get me wrong. The data that tafa and lenalidomide is putting out is impressive, 40% response rates. I think at EHA [European Hematology Association], they just looked at the duration of remission in those people at 2 years. There's definitely some synergy here because lenalidomide alone is not putting up those numbers in relapsed/refractory large cell lymphoma. Your PFSs is around 3 to 4 months.

That's even in combination with rituximab, where you'd say lenalidomide re-sensitizes rituximab. I guess of the one thing that I would have been looking at in the RE-MIND study is in R2 [[lenalidomide (Revlimid) and rituximab] arm compared with the lenalidomide alone arm, I mean they went a lot of patients looking for lenalidomide monotherapy patients that met the criteria for the L-MIND to compare 1 to 1. I think another thing that would've been interesting is, you kind of hinted at that Dr Maddocks, is the GCB [germinal center B-cell] or ABC [activated B-cell] with lenalidomide where we've seen data from other groups, at least retrospectively that maybe there may be some GCB patients that do respond.

With the follicular lymphoma data with R2 that GCB, there has to be some people out there that would respond in that setting also. But the data is impressive. I do have concerns about what is CD19 manipulation or perturbation going to do a CAR T-cell? There is some preclinical data with tafa and looking at cell lines, and that it does engage the same CD19 antigen that you'd expect that the CAR T cell would go after but at least in cell lines, it didn't appear to affect CAR T-cell.

That needs to be bore out in reality because I think we're going to see, if this drug does get a label or is in use, a lot of it getting use because it is an IV therapy, given weekly for a lot of doses up front and an oral therapy that people are very comfortable with using in lymphoma and multiple myeloma. We'll get a lot of use and I think we're going to have to be very, very on top of our game as CAR T-cell lymphoma doctors to really capture the data of those patients who are previously tafa-len exposed that don't respond or get a PR [partial response] and go to CAR T-cell therapy to see what the true durability is. That's only going to come out real-world experience data rather than a commercially funded experience.

John P. Leonard, MD:I'm going to ask both of you, Kami and Matt, in a second if you had both of those approaches available, how would you think about it? But first, I want to ask Nathan, Nathan you’ve been very involved with lenalidomide studies in several different contexts. The RE-MIND study took a historical group of patients treated with lenalidomide alone and then the prospective treated with a combination of tafasitamab and lenalidomide and try to combine them.

We have to be careful about retrospective vs. prospective comparisons, etc, but what's your take on the logic and at least the biology of why lenalidomide might work with this drug, and your take on this combination in this particular setting?

Nathan H. Fowler, MD:Matt said it very well. The thought is with lenalidomide, at least in the lymphoma space, is that there is augmentation of antibody response that's possibly due to change antigen recognition, increasing NK cell activity in T cells. That would make a lot of sense, combining a drug like that with a monoclonal antibody is going to make that monoclonal antibody better. That has a lot of people scratching their head; why is CD19 so much better than CD20 when you add lenalidomide?

D19 probably has some other affects within the microenvironment. We know that it's involved in signaling within the B cell. It's involved in mixed signaling. There may be something else that's different about combining CD19 with rev [Revlimid]; is it somehow affecting the microenvironment? I don't think we truly understand why at least with the data we have, we don't have anything head to head. If you look at the phase 2 studies with R2 which we did here at [The University of Texas] MD Anderson Cancer Center, the response rate and the PFS is dramatically shorter that we see with CD19 plus rev.

If you look at the duration of response in the CR [complete response] patients, it's phenomenal data that they just published in this paper. It's like 80%, 90% in patients achieved a CR. I know that's not the answer to your question. I'm not sure why the mechanism looks so different when you hit CD19 versus CD20 combined with Revlimid. Revlimid has multiple mechanisms, probably related to how they are affecting nonmalignant cells within the microenvironment, and that clearly is important with CD19.

Transcript Edited for Clarity