John M. Burke, MD: Greg, tell us about the RE-MIND study that you were involved in and how that contributed to the approval of tafasitamab and lenalidomide.

Grzegorz S. Nowakowski, MD: Yes, John. The RE-MIND study was done to support approval of this doublet in the relapsed and refractory space because neither lenalidomide nor tafasitamab is approved as a single agent. As you can see, it’s a paradigm shift where the FDA recognized that the activity of the doublet is critical for the efficacy of this combination.

The study aimed to differentiate the impact of lenalidomide from tafasitamab in the combination. One of the obvious solutions would be to conduct a randomized study and randomize patients simply to lenalidomide or tafasitamab and lenalidomide. However, we all felt this type of study would not be feasible. We have studied lenalidomide now for a long time in relapsed/refractory diffuse large B-cell lymphoma and consistently across different studies, including with the addition of rituximab, the response rate was somewhere between 25% and 30% and the duration of response—even with rituximab—was limited, measured in about 3 to 4 months.

Because of that, clinically, to design a randomized study would be quite difficult. This is where the agency supported the innovative idea of using the real-world data to differentiate the impact of lenalidomide from the doublet in this combination. To do that, we identified the patients who met the same inclusion criteria. They were matched for 9 predefined covariates.

This was a large global study: 490 patients were treated with lenalidomide monotherapy at 25 mg daily from days 1 through 21. The standard dose was identified. Then patients were matched to baseline covariates. Because close matching was needed, at the end there were 76 patients, both in the L-MIND cohort and in the RE-MIND cohort, who were matching for those characteristics. The patients in both cohorts were then compared for their outcomes.

If you look at the L-MIND study, as we mentioned before, the response rate was 67%. If you look at the patients treated with lenalidomide monotherapy with the same clinical characteristics—same performance status and multiple covariates—the best overall response rate was 34%. The addition of tafasitamab doubled the response rate in those patients.

Similarly, if you look at the progression-free survival [PFS], there was a significant benefit in terms of the progression-free survival and overall survival for the doublet vs lenalidomide monotherapy. For example, median PFS for lenalidomide monotherapy, consistent with previous studies, was about 4 months. In the L-MIND cohort, the median PFS was 12 months. The median overall survival, somewhat consistent with the previous studies of lenalidomide alone, was about 9 months. For the doublet, the median overall survival was 20 months. Therefore, the outcomes improved significantly with the doublet, which provided the momentum for the clinical approval of the combination.

John M. Burke, MD: Instead of doing a randomized phase 3 trial, they did a retrospective trial, and you get a good comparison of lenalidomide alone vs the lenalidomide-tafasitamab combination.

Grzegorz S. Nowakowski, MD: Exactly. As I said, this will be a new paradigm, which we’ll likely see more and more because we have a lot of exciting agents in the pipeline in diffuse large B-cell lymphoma under study. Many of these agents will not be able to be tested in randomized studies for different reasons. If we can use some of the real-world data—the data we already have—to support development of those agents, particularly if they are used in combination, it will help accelerate development in the field, just as we have seen with L-MIND.

John M. Burke, MD: Accelerate development of new drugs, and reduce the cost of development of new drugs. All that might translate to good things for all of us.

Grzegorz S. Nowakowski, MD: Absolutely.

John M. Burke, MD: Let’s take a couple of clinical scenarios. One is you have a patient in front of you who you’re thinking might get to CAR [chimeric antigen receptor] T-cell therapy. Of course, your CAR T-cell therapies are going to be targeting CD19. Should you use or not use monoclonal antibody tafasitamab in a patient where you’re going to have the same target? What do we know about tafasitamab and its effect on CD19 on the B cells? Similarly, if you have a patient who has relapsed after CAR T-cell therapy, do you think this is a treatment that should work or could be tried? Or should it be avoided if your patient has already been exposed to a CD19-targeting CAR T-cell therapy?

Grzegorz S. Nowakowski, MD: This is a great question. It goes back to the mechanism of how those drugs work. Saad Kenderian from the Mayo Clinic in Rochester, Minnesota, recently presented his preclinical work, which showed that the epitopes recognized by CAR T cells are different from those recognized by tafasitamab. This gives you the idea that those treatments still could be effective, provided expression of CD19 is present.

There are unfortunately limited data on resistance to tafasitamab. In the setting of CLL [chronic lymphocytic leukemia], where the blood was collected again, there was no evidence of CD19 loss in patients who were treated with tafasitamab. It appears that a resistance to tafasitamab is not mediated through CD19 loss. It will be important in future studies to collect more biopsies from patients with diffuse large B-cell lymphoma at the time of relapse and see if this is the case in large cell lymphoma as well.

The other anecdotal evidence comes from the clinical studies, where there was a patient who was treated with tafasitamab-lenalidomide and, after progression, went to CAR T-cell therapy. This patient responded to CAR T-cell therapy with durable benefit. There is some anecdotal experience that CAR T cells are still effective after progression on tafasitamab-lenalidomide. We are using it more and more and will see more data regarding efficacy of CAR T cells after tafasitamab-lenalidomide.

What about the other way around? That’s an important question because there are some frontline trials done in this setting as well. Based on what we know about the CAR T-cell resistance, some of the patients may have CD19 loss. On the other hand, a significant proportion of the patients treated with CAR T cells did not have CD19 loss. This is either disappearance of the CAR T cell’s clone or some other mechanism of resistance we don’t fully understand yet. Those patients who have CD19 would definitely be candidates for tafasitamab and lenalidomide treatment. As we see more and more of those patients and use tafasitamab in practice, we will get more experience in how effective this treatment really is in patients who are progressing after CAR T-cell therapy.

Because there is promising and high response rate and activity in the relapsed/refractory setting, there is a plan to move this doublet to frontline therapy with the addition of R-CHOP [rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone]. As you know, lenalidomide had been studied with R-CHOP [rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone] therapy in patients with newly diagnosed diffuse large B-cell lymphoma, called R2-CHOP [lenalidomide, rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone]. Unfortunately, R2-CHOP [lenalidomide, rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone] did not improve the outcomes of patients with newly diagnosed diffuse large B-cell lymphoma. The study was a randomized phase 3 study called ROBUST.

There was another study called E1412 that showed some signal of activity toward lenalidomide, but this was a much smaller study. Because there is such a synergy between tafasitamab and lenalidomide, there is now interest in moving this to the frontline setting. The phase 1b study, which was recently completed, is looking into the feasibility of adding tafasitamab to R2-CHOP [lenalidomide, rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone] backbone and moving it forward to the future randomized trials.

John M. Burke, MD: Stay tuned on that.

Transcript Edited for Clarity

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