Part 1: Tafasitamab/Lenalidomide Shows Durable Responses in R/R DLBCL

Philippe Armand, MD, PhD

Chief of Division of Lymphoma

Senior Physician

Associate Professor of Medicine

Dana-Farber Cancer Institute

Boston, Massachusetts

Targeted Oncology^TM: What led to the approval of tafasitamab (Monjuvi) and lenalidomide (Revlimid) for diffuse large B-cell lymphoma (DLBCL)?

PHILIPPE ARMAND, MD, PhD: Tafasitamab is a naked antibody. It’s an anti-CD19 antibody, but it’s engineered to have increased antibody-dependent cellular cytotoxicity and antibody-drug conjugate toxicity, and it has single-agent activity in a variety of [types of] B-cell non-Hodgkin lymphoma, and lenalidomide has this [unusual] mechanism of action that probably has to do with cereblon binding and down-regulation of ikaros and aiolos [proteins]. This combination of tafasitamab/lenalidomide was approved by the FDA for patients with relapsed/refractory DLBCL who are not eligible for autologous stem cell transplant after at least 1 line of therapy.¹

This regimen is approved in the second line, unlike polatuzumab vedotin [Polivy] and loncastuximab tesirine [Zynlonta].^1-3 [I believe] it’s the only thing that’s FDA-approved in the second line for DLBCL. The data that led to this approval are from the L-MIND study [NCT02399085].

Please describe the patient population and study design of the L-MIND trial.

L-MIND was a phase 2, single-arm trial. The patients were definitely more selective than the [phase 2 study (NCT02257567) of pola-BR], and I think that’s very important to remember. They could only have 1 to 3 prior regimens, they couldn’t have primary refractory disease, and they couldn’t have double-hit or triple-hit disease. It’s not exactly [representative of the] large-cell lymphoma population. The treatment is also a little bit heavier, so tafasitamab is given every week for the first 3 cycles, and then it goes to every 2 weeks. It’s given with lenalidomide for the first year, and then, after 1 year, if patients at least had stable disease or better, they continued tafasitamab every 2 weeks, which is a fair amount of infusion time. This continued until disease progression.

The median number of prior therapies was 2, a range of 1 to 4, and if you look at the distribution, half of the patients were treated in the second line, and most of the others were treated in the third line.

What was the efficacy found in the L-MIND trial?

The overall response rate was 58% and 40% were complete responses [CR].⁴ The median duration of response [DOR], which is very important, is approximately 44 months. The [Kaplan-Meier] curves are pretty impressive to me. The 40% of the patients with a CR have a very impressive DOR. The progression-free survival [PFS] data show that 4 years out, two-thirds are still alive and progression-free. The overall survival [OS], not surprisingly, tracks the curves fairly closely.

What was the toxicity found in this trial?

There were some hematologic adverse events [AEs] on this study. They are probably related to the tafasitamab and the lenalidomide, which definitely adds hematologic toxicity, particularly neutropenia.⁴

In terms of non-hematologic AEs, at least the most common ones, there is smattering of grade 3 AEs, mostly rash, which is from the lenalidomide. The toxicity overall mimics what we expect for a lenalidomide-based regimen, but outside of the rash, there are not a lot of grade 3 treatment-related AEs.

The percentage of patients who have discontinued therapy because of AEs is 12%.⁴ The AEs leading to death, which is an important number here, is 13%, but I think they were all not considered to be treatment-related, and this is always a tough one on these studies. The pola/BR study also had at least 10% infectious death per arm.⁵ But a lot of the time, the investigators don't ascribe these deaths to the study drug, which is a debatable call, but it makes it difficult to compare the fatal AEs between regimens.

What was the significance of the RE-MIND study (NCT04150328)?

The recently published RE-MIND study was a retrospective match comparison between the trial patients who received tafasitamab/lenalidomide and then patients were drawn from a multicenter experience, from real-world treatment, compassionate use, or some other clinical trials, who got lenalidomide alone. They matched the patients based on major characteristics and then, compared their outcomes, and argued that the response rate was better for tafasitamab/lenalidomide at 67% versus 34% for lenalidomide; the CR rate was better: 40% versus 13%; and they also had better PFS and better OS.⁶

I think one can question the strength of the conclusion, given that it's a clinical trial versus a non-trial population, and even in that comparison, I think there were more patients who received tafasitamab/lenalidomide had been treated in the second line,⁴ but still, these are the results and they suggest that tafasitamab does add something, which I think we would all probably believe.

_References:

_{1. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Published July 31, 2020. Accessed March 3, 2022. https://bit.ly/3vxLHZR}

_{2. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. FDA. Published April 23, 2021. Accessed March 3, 2022. https://bit.ly/3vGStNf}

_{3. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. Published June 10, 2019. Accessed March 3, 2022. https://bit.ly/3sDHphN}

_{4. 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}

_{5. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172}

_{6. 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}