Tafasitamab/Lenalidomide Shows Efficacy, Tolerability for R/R DLBCL

Brian T. Hill, MD, PhD

Director, Lymphoid Malignancies Program

Staff Physician

Cleveland Clinic Taussig Cancer Institute

Cleveland, OH

Targeted Oncology^TM: Please describe the study design and patient population of the L-MIND study (NCT02399085) of tafasitamab (Monjuvi) and lenalidomide (Revlimid).

HILL: The L-MIND study was a single-arm, open-label, multicenter, phase 2 study of tafasitamab plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma [DLBCL], having anywhere from 1 to 3 prior lines of therapy. Patients could not be eligible for high-dose chemotherapy and autologous stem cell transplant. Patients with primary refractory DLBCL were excluded, which is something that we should take into account when interpreting the results.

The treatment was tafasitamab which is an intravenously administered monoclonal antibody targeting CD19. It was given at a standard dose on days 1, 8, 15, 22 for 3 [28-day] cycles, meaning weekly for 12 weeks. The cycles overlapped with a full 25 mg dose of lenalidomide on days 1 to 21, with 7 days off on 28-day cycles. For patients who were responding after 3 cycles, the tafasitamab was reduced to every other week starting in cycle 4 and continued up to 12 cycles. For patients who had stable disease or better after 12 cycles, they could continue tafasitamab without lenalidomide until disease progression. The primary end point was overall response rate [ORR], with secondary end points including progression-free survival [PFS].

There were 81 patients with a median age of 72 years old, with a pretty wide range [from 41 to 86]. International Prognostic Index scores were [evenly divided between 0-2 and 3-5].¹ Most of the patients had advanced stage disease and elevated LDH [lactate dehydrogenase]. They had a median of 2 lines of prior therapy. There were some primary refractory patients, [making up] 19%; I believe the study was amended somewhere along the line to exclude those, but about 44% were refractory to the prior line of therapy. Most of these patients have not had a prior stem cell transplant, and cell of origin was skewed towards non-germinal center or indeterminate cell type.

What were the results of this study in terms of efficacy?

The complete remission [CR] rate was 40%, with 17% partial responses [PR], 16% stable disease, and 26% who had either progressive disease or were not evaluable. The ORR was 57%, and the median duration of response was 44 months.

[In terms of] PFS for all comers, [median PFS was 11.6 months, and] there are patients who had a CR who had very good [long-term] outcomes, and I think it is pretty remarkable that the lenalidomide was only given for 12 months, and beyond that they just were getting infusions with tafasitamab every 2 weeks. There was almost a plateau in the PFS curves going out 3 to 4 years. And so, the median overall survival [OS] after 3 and a half years of follow-up, was [33.5] months.

Looking at the efficacy based on number of prior lines of therapy, not surprisingly, patients with 1 prior line of therapy tended to do better. The CR rate was almost 50% [in patients with] 1 prior line of therapy, whereas it dropped down to 32% in patients with 2 or more prior lines of therapy. The ORR was 67% for patients with 1 prior line of therapy, whereas it was down to 47% [in those with] 2 or more prior lines of therapy. And similarly, OS was much better in the patients with 1 prior line of therapy.

What was the toxicity profile observed in the L-MIND trial?

I’m sure many physicians are using lenalidomide for their patients with multiple myeloma, or those with myelodysplastic syndrome, so they are familiar with the adverse event [AE] profile of lenalidomide. There was a cumulative rate of neutropenia: 27% had grade 3, and 21% had grade 4. There was a total of 12% who experienced grade 3 or grade 4 febrile neutropenia.

[In terms of] common non-hematologic AEs, they mirror what probably should look familiar for lenalidomide, which is that diarrhea can occur in about a third of patients. You have these other unusual AEs like cough, edema, arthralgias, and back pain. Interestingly, 16% experienced constipation. I’m never sure which way to tell whether patients are going to get diarrhea or are they going to get constipation; it’s hard to predict. There are other AEs like muscle spasms, nausea, abdominal pain, and so forth. They are not much different than the AEs that we see with lenalidomide in general.

The neutropenia is much more common in the 12 months of the combination with lenalidomide, with almost 50% having some neutropenia. Anemia, thrombocytopenia, diarrhea, asthenia are follows. For patients who go a full year, and then get on to the maintenance phase of tafasitamab every other week, AEs were pretty minimal.

The rate of serious AEs was 51%, but the rate of serious AEs suspected to be treatment-related was 19%. So, a lot of the AEs may have been disease-related. [The rate of] discontinuations due to AEs was 12%.

AEs of special interest included AEs like secondary cancers, tumor flare reaction, deep vein thrombosis [DVT], and so forth. What I thought was interesting is that there were, that I can tell, no pulmonary embolism [PE] or DVT deaths, because thrombosis is a known toxicity or risk factor with lenalidomide, and patients did need to have DVT and PE prophylaxis on this study.²

The rate of AEs leading to death was 13%.¹ There were 4 deaths out of 30 [in the safety cohort] that were treatment-emergent AEs leading to death. None were considered to be related to study treatment. If there is a death on a clinical trial from some complication, but the investigator deems it not related to the study treatment, then it gets counted as a study-related death, but then the attribution is not always clear. This is a high-risk patient population for AEs.

What did the RE-MIND study (NCT04150328) show about the tafasitamab/lenalidomide combination?

One of the concerns about single-arm trials is, “What are we comparing it with?” [Data from the RE-MIND study] was presented at the 2021 American Society for Clinical Oncology annual meeting.³ It was an attempt to compare the benefit of tafasitamab when combined with lenalidomide, compared with lenalidomide by itself.

This is a retrospective analysis where [the investigators] collected data on several hundred patients with DLBCL who were treated with lenalidomide as a monotherapy; and then, attempted to adjust for all these baseline co-variants with a matched propensity scoring method, and wound up with patients they felt were reasonably matched, and showed that there was a much higher ORR, CR rate, and PR rate with tafasitamab compared with lenalidomide monotherapy. I’m not sure how much weight to put into these results [since] it wasn’t a randomized trial, but I think it does suggest that the tafasitamab is doing something, it’s not just the lenalidomide that’s doing the heavy lifting here.

_References:

_{1. Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958}

_{2. Lenalidomide (Revlimid). Prescribing information. Celgene Corporation; 2013. Accessed May 23, 2022. https://bit.ly/3wEwczG}

_{3. Zinzani PL, Rodgers T, Marino D, et al. RE-MIND: Comparing tafasitamab + lenalidomide (L-MIND) with a real-world lenalidomide monotherapy cohort in relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2021;27(22):6124-6134. doi:10.1158/1078-0432.CCR-21-1471}