Saeed Discusses Long-Term Outcomes and Real-World Data for Tafasitamab/ Lenalidomide in R/R DLBCL

Hayder Saeed, MD

Associate Member

Malignant Hematology Program

Moffitt Cancer Center

Tampa, Florida

Peers & Perspectives in Oncology: What data support the use of tafasitamab (Monjuvi) plus lenalidomide (Revlimid) in patients with relapsed/ refractory (R/R) DLBCL?

Saeed: This was based on the L-MIND study [NCT02399085]. It enrolled patients with DLBCL who were relapsed or refractory after 1 to 3 lines of treatment and not eligible for [hematopoietic cell] transplant. Patients got [tafasitamab] plus lenalidomide. The goal was 25 mg lenalidomide per day on day 1 through 21, but there are data that show that if you give those patients less than 20 mg, they don’t do as well as if you give them 20 to 25 mg, so I try to keep the patient at that level if I can.¹ If the patient has severe toxicities, you have to lower the dose, but I try to push for the higher dose compared with when I treat follicular lymphoma, where I start sometimes with 5 mg, then go up to 10 or 15 mg depending on their tolerance. With DLBCL, I start with the higher dose and then go down because we need up-front control on the disease with lenalidomide.

The tafasitamab was given weekly for the first 3 cycles and then subsequently every other week, and they continued after 1 year, [indefinitely], or until disease progression or toxicity. When the primary analysis came out, the overall response rate was almost 60%, with a 40% complete response [CR] rate.² There is a lot of argument about that, saying they picked patients who were not as refractory. Patients were still allowed to be on the study if they relapsed within 6 months from their last treatment.

They still had patients who relapsed within the first 12 months of the last treatment regimen. At the beginning of the study, they allowed patients who had relapsed up to 3 months. They separated those who relapsed between 3 to 6 months because they were more refractory than the rest of the study.

What are the long-term data for this regimen, and what is the significance of durable CRs?

At 5 years’ update, all the numbers stand the same, with [over] 40% of the patients in CR.¹ [Looking at] long-term progression-free survival [PFS], [over 30%] of the patients [had no progressive disease] at 60 months. We need longer follow-up to see how they do…but we still have patients who are continuing, going into 5 to 6 years.

When you look at [PFS], 50% of patients [experience progression] within the first year.… My experience has been that in the first 3 months, you know if a patient will continue or not. If they pass the first 3 to 6 months, [and] they have response, they will do well [and] at least they match the [median] PFS of 11 months on the study.

Are they’re going to be cured? Nobody can say that; even if you look at CAR T-cell therapy…patients with DLBCL [sometimes] don’t have relapse for a long time. I don’t think tafasitamab/lenalidomide is a type of treatment that puts the disease in a frozen state. It kills the cells, and patients’ characteristics might make them very sensitive to this regimen. That’s why you have this subgroup of patients who may do well for a long time.

[The study] excluded those who are primary refractory and those who have early relapses, [and] those who have bulky disease…but you also have some patients who did well for a long time.

Did patients who responded continue to receive tafasitamab for the duration of follow-up?

Some of them are still on therapy: [8 of 26 who had 5 years of follow-up for survival]. The treatment needs to be continued until toxicity or progression. However, it’s not about how many of your patients can stop; it’s that some patients stopped and they still had remission. Let’s say we reached 1 or 2 years, and the patient doesn’t want to continue or is having problems. It’s OK to stop it if they have toxicity or if the patient doesn’t want to do it anymore. Some of them did well. But some of them relapsed after stopping.

When I choose to use this [regimen], I follow the study. I continue if I can, but if the patient comes to me, regardless of the response—I would be encouraged more if they have a CR for 2 years to stop it easily—but if they have a partial response which still has some marginal activity when we repeat the scan, I would be concerned about stopping it. But sometimes the patient comes and says, “I don’t want to.”

What tolerability concerns are there with tafasitamab/lenalidomide?

The toxicity from the combination is the same toxicity you would expect from lenalidomide. The majority have some cytopenias: neutropenia, thrombocytopenia, anemia. Once you stop lenalidomide after the first year of therapy, and beyond 2 years, the cytopenias go away…. I don’t think there’s any toxicity with tafasitamab other than what you would expect with rituximab.

How were the results of this single-arm study compared with other treatments?

The RE-MIND2 study [NCT04697160] looked at patients who had treatment for DLBCL in the relapsed setting, and those patients were cross-matched with the tafasitamab-lenalidomide patient population…in the L-MIND study, trying to retrospectively find patients who had very similar characteristics from baseline and see how those patients did. The primary analysis was between BR [bendamustine/ rituximab] and R-GemOx [rituximab, gemcitabine, and oxaliplatin]. [They used] BR because Pola-BR [polatuzumab vedotin (Polivy) plus BR] was [available] in that retrospective [cohort]…. There is expanded analysis with Pola-BR, lenalidomide/rituximab, and CD19- CAR T-cell therapy, but that’s not published in this [report].

If you look at the overall survival, if we combine the R-GemOx and BR [groups] together, patients who had tafasitamab/lenalidomide in the second line did better than patients who got tafasitamab/lenalidomide beyond the second line, but overall they did better than other systemic therapies [Table³]. If we separate the BR and R-GemOx, they follow the same trend. But doing it in the second line will have better outcome because [the patients are derived from] the L-MIND study data. [Similarly, there was benefit in] duration of response. We usually expect from Pola-BR, BR, or R-GemOx that you lose a lot of the patients right after treatment, compared with tafasitamab/lenalidomide [where] you have a flatter curve with slower decline.

What do the real-world data on the use of tafasitamab/ lenalidomide show?

These real-world data are more relevant [than prior reports], because these patients were treated in the community [setting], not an academic medical center. Approximately 180 patients were treated with tafasitamab/ lenalidomide.… This analysis was trying to separate it by second line vs third line. [Nearly] three-fourths of the patients were treated in the second line with tafasitamab/lenalidomide in the community.⁴ The median age was [71.1 overall: 72.1 in the second line and 67.7 in the third line]. The majority of the patients had GCB [germinal cell B-like cell of origin] compared with only 33% non-GCB. Lenalidomide works mostly in the ABC [activated B-cell] subtype, but the majority of the patients were GCB. The patients’ ECOG performance status was [primarily] 1 to 2, and they mostly had advanced stage at diagnosis. Eighty percent of them had higher International Prognostic Index risk at diagnosis.

Twenty-six percent of them were primary refractory when they got treated, [which is] technically [off label]. But it’s important to recognize that when we talk about outcome in the real world compared with a study, 50% of the patients were either primary refractory or had early relapses. The majority of the patients would not have made it to that study. If you look at the overall response rate, it’s 75%, but looking at the CR rate, it was much lower than what we’ve seen in the study [18.5%; 95% CI, 12.6%-24.3%]. It’s understandably much lower because it selected patients that are a little bit more refractory. I’m not surprised to see that, but it’s good to see they have some response and control of disease.

Many of them should have gotten CAR T-cell therapy, [but] this is community practice treatment. Not all your patients would want to go CAR T-cell therapy or can make it to CAR T-cell therapy. Those patients [who were able to receive CAR T-cell therapy] are not the target of this. It’s not head-to-head [vs] CAR T-cell therapy.

This is one of those things that you always have doubts about any regimen when you look at L-MIND, because if I talk about my experience with this regimen…by the time the patient makes it to that regimen, they would have had a slew of other options… because they have access to clinical trials and other immunotherapy options. It’s good to see that the majority of the patients had some responses, [although] their response is not the CR that we expect to see [based on] the clinical trial.

REFERENCES:

1. Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study. Haematologica. 2024;109(2):553-566. doi:10.3324/haematol.2023.283480

2.Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

3. Nowakowski GS, Yoon DH, Peters A, et al. Improved efficacy of tafasitamab plus lenalidomide versus systemic therapies for relapsed/ refractory DLBCL: RE-MIND2, an observational retrospective matched cohort study. Clin Cancer Res. 2022;28(18):4003-4017. doi:10.1158/1078-0432.CCR-21-3648

4. Saverno K, Zimmerman Savill KM, Feinberg B, et al. Tafasitamab for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the US real-world setting. Blood. 2023;142(suppl 1):265. doi:10.1182/blood-2023-173143