Monoclonal Antibodies for Treatment of R/R DLBCL

Transcript:

Kami Maddocks, MD: We’ve talked a lot about CAR (chimeric antigen receptor) T-cell therapies. Dr Miklos mentioned all these available products that target CD19, but we have other agents targeting CD19 that aren’t CAR T-cell therapy. Dr Nowakowski, you’ve been involved in a lot of trials and studies with some of these non-CAR T CD19-targeted therapies. Do you want to tell us a little about these agents and the data out there to support their use?

Grzegorz S. Nowakowski, MD: Thank you, Dr Maddocks. You’re absolutely right. CD19 turned out to be an extremely important target. We knew it for a while. There were different therapies being developed, and we have capitalized on the years of work targeting CD19. In addition to CAR T-cell products, there are molecular antibody-drug conjugates which also target CD19 and are quite effective in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

In terms of the naked monoclonal antibody, there’s an antibody called tafasitamab that targets CD19. It’s engineered to increase direct cytotoxicity of the antibody and also activation of effector cells. This antibody by itself showed about a 25% to 30% response rate in patients with relapsed/refractory diffuse large B-cell lymphoma. What really made a difference is this additional antibody with lenalidomide. We know that lenalidomide has pleiotropic effects on the microenvironment of malignant cells itself, but tends to synergize with antibodies. We have seen it with R2 (lenalidomide plus rituximab) and other antibodies as well.

This combination of tafasitamab and lenalidomide studied in the L-MIND study (NCT02399085) showed a very high response rate and durability of responses. In patients who aren’t transplant candidates, the response from this combination was approximate 60%, and many of those responses were CRs (complete responses). When we talk about such a high response rate, there’s always anxiety over how long it will last. We now have extended follow-up on the L-MIND study, which showed that the duration of response is approaching 44 months, which is excellent in this patient population with relapsed/refractory diffuse large B-cell lymphoma. The median overall survival was approximately 35 months. For the antibody-IMiD (immunomodulatory imide drugs) combination, it’s a very high bar. It was previously unprecedented in the relapsed/refractory diffuse large B-cell lymphoma space, apart from maybe…therapies, which we discussed.

What’s also important is that this therapy is well tolerated. The toxicities are mainly hematological, as you’d expect with lenalidomide, and infusion reactions to the antibodies aren’t very common. It can be adopted and embraced in the community, particularly in patients who aren’t candidates for more escalated therapies, which we were just discussing. When you have such effective therapy, there’s always a question of how it compares within the same patient population. Is there a selection of patients who factor in its efficacy? How do you measure it against what else is available? With all the new approvals we have, there are novel therapies in development, and it’s clear that we won’t be able to do randomized trials of all those therapies against each other; it’s just impossible. But in the real world, in real practice, we have those questions of which therapy you should choose. Is it based on toxicity, residual toxicity, previous patient exposure? We take all this into account in how we compare those therapies.

There are a number of studies looking at this, and there’s increased interest and awareness of performing real world studies. We were just discussing real-world studies for CAR T cells, and this is also going on with agents that aren’t CAR T cells. There’s a study called RE-MIND2 (NCT04697160) that looked at the comparison of the combination of tafasitamab and lenalidomide with other therapies that are used in this space. In this study, the first comparison was with R-GemOx (rituximab, gemcitabine, and oxaliplatin) and BR (bendamustine, rituximab) and pulled analysis of different therapies that are endorsed by both the NCCN (National Comprehensive Cancer Network) and ESMO (European Society for Medical Oncology) in this setting.

The primary endpoint of RE-MIND2 was overall survival. How those studies are designed is extremely interesting because you’re starting with a very large number of patients to begin with—over 4500 patients—and then you’re acquiring those patients, and you match for the patients who meet the inclusion criteria for the study quite strictly. Then they’re prospectively designed in matching a certain number of covariates. Those patients are very closely matched in clinical and prognostic characteristics. What was informative about this comparison is that this combination of tafasitamab and lenalidomide performed better than R-GemOx and BR and the polatuzumab therapies.

In additional analysis in the study, we also explored the efficacy of this antibody against polatuzumab-BR—which has since been approved as well—, R2, which is still commonly used in this setting, and CAR T cells. Those were very interesting as well because it showed that the primary end point of overall survival was superior for the combination of tafasitamab and lenalidomide when compared with polatuzumab-BR and R2 in this study. The results were comparable to what we have seen with CAR T cells. The number of patients in the CAR T cell comparison is limited. We’d like to see more data and more mature data. But this prototype targeting CD19 in the right patients is important. You can do it in many different ways, and antibody IMiD combinations could be one of those ways.

Another antibody targeting CD19 is loncastuximab tesirine, an antibody-drug conjugate. That’s another interesting way of approaching it, and we now see many more antibody-drug conjugates in development and moving into the clinic. The antibody LOTIS-2 study (NCT03589469) showed a nearly 50% response rate in patients with relapsed/refractory diffuse large B-cell lymphoma. What I found particularly exciting about this study is that it included a fair share of patients who were post–CAR T-cell therapy, and in the signal of activity in those patients, although that number was limited, it showed that the response rate was maintained, which is very encouraging. We had a lot of discussion here about the CAR T cells’ utility, and we didn’t talk much about potential mechanisms of resistance—one of them could be loss of an antigen. But at least in patients who at the time of study entry still had a CD19, the response rate to loncastuximab tesirine in post-CAR T-cell relapses was maintained.

This therapy is also associated with nice durability of response toxicities, primarily hematological. There’s also some peripheral edema, which can be monitored and managed. But overall, this therapy is available off the shelf and in practices and for patients who sometimes aren’t candidates for those escalated therapies. As you can imagine, with any therapies like these, with tafasitamab and lenalidomide or loncastuximab tesirine, those therapies can then be combined with other therapies as well. There’s this whole revolution of different concepts and ways that we can now sequence or combine those therapies to improve outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma.

Finally, to be completely inclusive of all the trials that are approved in the antibody-drug conjugate situation, we discussed polatuzumab vedotin extensively in the frontline setting. It has been approved for quite some time in combination with BR chemotherapy in the relapsed and refractory setting, and it’s frequently used in this setting. It’s sometimes used with bendamustine in a bridging-like approach to CAR T-cell therapies. This old field is expanding quite rapidly, and some of those using real-world data, which are studies that I mentioned, will help inform us how we can best choose those therapies based on prior toxicities and how we can best sequence them to benefit our patients.

Jason Westin, MD: I want to comment very briefly on the RE-MIND studies that Dr Nowakowski pointed out. They’re wonderful and an important way for us to try to compare across trials. Unfortunately, the way that we have the data right now, it’s trials vs standard of care, and we all know that trial patients tend to do a little better. What we’d love to see is real-world data with tafasitamab compared with real-world data for CAR T-cell polatuzumab-BR. Greg, we look forward to RE-MIND3, or 4, or 5—whatever it’s going to be—to see those real-world data.

Kami Maddocks, MD: There aren’t any real guidelines for sequencing these agents. Can you give us some insight into whether you have an approach for how you sequence these agents? Or is it all situation specific? Is there anything that you try to avoid?

Grzegorz S. Nowakowski, MD: That’s a very interesting question. Obviously, we need more clinical studies on the sequencing. There was a very interesting presentation by Dr Saad Kenderian, who was looking at the preclinical models of CD19 antibody tafasitamab and CAR T-cells in different in vitro models because there’s anxiety that if you have CD19 expression, if you block it with the antibodies, CAR T cells could be less effective in this setting. It turns out that there’s quite a lot of CD19 antigen in the cells, and you don’t necessarily need all of them to be targeted by the antibody or CAR T cells for effectiveness. He’s showing that there could be some synergy between those approaches and decreasing some of the very early CAR T-cell activation can decrease apoptosis of those CAR T cells and lead to more robust expansion in the long term. This is very provocative.

Transcript edited for clarity.