Reviewing Key Efficacy and Safety Data for Tafasitamab Plus Lenalidomide in DLBCL

Gilles Salles, MD

Chief of Lymphoma Service

Steven A. Greenberg Chair

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology^TM: What are your thoughts on the dosing schedule of the phase 2 L-MIND trial (NCT02399085) of tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid)?

SALLES: During cycles 1 to 3, [patients on the L-MIND trial received a] weekly infusion of 12 mg/kg tafasitamab plus daily lenalidomide at 25 mg, which I think is easy to adapt, and then [tafasitamab] every 2 weeks after that.¹ The dose of 25 mg lenalidomide is quite high for many patients and many physicians will start at 20 mg, which is the usual dose reduction for the drug. When they have patients who are older, a lot of physicians with start at 10 mg or 15 mg. I would say it's hard to manage the [disease because of hematologic toxicity]. For tafasitamab, the patient gets the first cycle on days 1, 4, 8, 15, and 21 and then they have weekly infusions for the first 3 months so that’s quite demanding for the patient. It's not chemotherapy, but they have to come [in to receive infusions].

The way the study was designed, it's an immune-based therapy and you have the chance to get the patient a complete response [CR]. [Patients who had stable disease or better after 1 year] continued with tafasitamab every 2 weeks until progression. That was part of the trial so I let patients who I knew were in CR [continue] the trial for 3 years. At this time, when you stop lenalidomide after 1 year, it's very well tolerated…but patients are coming every 2 weeks [until progression], which is demanding.

What were the characteristics of the patients on this trial?

[In terms of] International Prognostic Index [IPI] risk score, half of the patients were lower than 0 to 2. Most of them [75%] had advanced stage disease, and half of them had elevated LDH [lactate dehydrogenase]. The median number of prior lines of therapy was 2. In fact, half of the patients were treated after 1 line and the other half after 2 [or more] lines. There were very few primary refractory patients [19%] because the trial initially [excluded] patients who relapsed within 3 months and [this was later amended] to within 6 months, so there are only a few patients like that.

Forty-four percent were refractory to their [last] prior line of therapy. There were a few post-transplant patients, and few patients were analyzed regarding cell of origin.

What was the efficacy observed in this trial?

The CR rate was 40% and the partial response [PR] rate was 17.5%, with an overall response rate of [57.5%]. What was very surprising and interesting is the median duration of response [of 43.9 months] means that the patients who achieved a CR with this regimen are patients who do relatively well because you have about 80% of these patients who did not relapse at 3 years.^1,2 The patients with PR [include a few] patients who are still alive. These patients got the biopsies and PET/CT scans to make sure this is active disease, and never got the answer for these patients. I'm not convinced that we can keep our patients in PR for more than a couple of months, so these are probably CRs that were not documented.

The median time to response is rather short [2.1 months; range, 1.7-34.7].² If you use this regimen, within 2 to 4 months you should have a response. If you don’t have a response at 4 months, you will not have it. The median time to CR was 6 months but the early responses…probably biased me towards this regimen. [The reason] I can use it when I feel that the patient is a good fit for this regimen is the fact that there are patients with a CR who are alive for long time, probably the majority of the patients with a CR. The bias is that there were very few primary refractory patients, which comprise the majority of patients [with poor outcomes]. This translates into a very favorable progression-free survival [PFS] for the patients who achieve CR, as well as overall survival.

If we look at [30-month PFS rate] based on the clinical characteristics, what you see are the [types of] patients who benefit. The patients who benefited very well are the patients with low IPI at the time of relapse, those with localized disease with low LDH and good performance status. If you go to a patient with high-risk IPI, you get a median PFS that is probably less than 20 months.

Otherwise, male vs female patients, rituximab refractoriness, and refractoriness to their last line of therapy [did not differ greatly in PFS rate]. The PFS rate was a bit less for the primary refractory patients but they were underrepresented. There was no difference post-transplant or pre-transplant, and it was better for those that had only 1 prior line of therapy. It's not a surprise there's no difference based on age. If you feel that CAR T-cell therapy is not an option, or it is not your preferred option, I think [tafasitamab/lenalidomide] is very reasonable for those patients who are not refractory and have very rapid pace of the disease.

For those patients who are treated at first relapse, the CR rate is higher and the median duration of response exceeds 3 years, with a median PFS of [nearly] 2 years. This was 40 [out of the 80] patients.

What were the adverse events (AEs) seen in this trial?

The most common AEs [included] neutropenia—you will expect that with lenalidomide.¹ You can manage that with GCSF [granulocyte colony-stimulating factor], and you can interrupt lenalidomide, so it's quite demanding. That’s the reason you want to see the patient regularly. They have to have a routine with you. I wasn’t impressed by the [rate and severity of] thrombocytopenia. Febrile neutropenia [of grade 3 or higher occurred] 10% of the patients, probably less than what we expect with chemotherapy. Those are most of the [grade 3 or higher] AEs. The other ones are mainly grade 1 or 2, such as classical rash with lenalidomide. There were gastrointestinal AEs that you have with lenalidomide. The other ones were a bit random and essentially grade 1. [Of these, those that were likely to be] grade 2 were rash, back pain in 5%, and urinary tract infection.

Serious AEs [occurred] in half of the patients but only 1 out of 5 had dose interruptions for that. [There were 4 patients whose AEs] led to death, and [those include] infection.

The majority of the AEs come during the combination of tafasitamab/lenalidomide and we may monitor patients for neutropenia, and with some patients [there is a] response and the [physician] stops lenalidomide before [12 months]. I will not necessarily recommend doing that. I had a patient for a second opinion with double-hit disease who got CAR T-cell therapy, and was relapsing after allogeneic stem cell transplant. He came to Johns Hopkins, and he had a CR with tafasitamab/lenalidomide. There was some difficulty to use lenalidomide because of the graft-vs-host disease, so they have to manage that. However, I will [generally] try to continue based on who the patient is and what their situation is.

_^REFERENCES

_{^{1. 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}}

_{^{2. 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. Published 2021 Sep 1. doi:10.3324/haematol.2020.275958}}