CD19-Directed Antibody-Drug Conjugates for DLBCL
While antibody-drug conjugates have shown promise in patients with relapsed/refractory diffuse large B-cell lymphoma, there are other options that can help patients before moving on to CAR T-cell therapy.
Looking beyond the use of antibody-drug conjugate loncastuximab (Zynlota) for a patient with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), at a live virtual event Justin Kline, MD, discussed the use of different CD19-targeting treatments before moving onto CAR T-cell therapy.
Can you discuss the confirmatory phase 3 trial (NCT04384484) of loncastuximab (Zynlonta) plus rituximab vs gemcitabine/oxaliplatin plus rituximab?
KLINE: It’s a 2-part study, the initial patient population will have loncastuximab for 8-doses and a higher dose for 2 cycles and then the 75 µg/kg 6 times every 3 weeks.1 Then, patients will be randomized 1:1 with gemcitabine-oxaliplatin plus rituximab. So, is this therapy less or more effective than something we typically use off the shelf? Well, I think that’ll be an important study to get a sense of how effective loncastuximab as compared with standard chemotherapy-based combinations that we use in transplant-ineligible and transplant-refractory patients.
Are there other approved treatment options for this patient population?
A recently approved option for R/R DLBCL was tafasitamaub [Monjuvi] in combination with lenalidomide. That was approved by the FDA last summer based on the results of the L9 study [NCT04058535].2
It’s mechanism of action is thought to be by enhancing ADCC, or antibody-dependent cellular phagocytosis. [The belief is that] tafasitamaub can induce direct cytotoxicity, although the mechanism for that, to me, seems unclear but as a single agent it did show some activities in patients with R/R DLBCL.
What were the patient characteristics and design of the phase 2 L-MIND (NCT02399085) study that looked at the combination of tafasitamab and lenalidomide?
[The patients on the study had to have] 1 to 3 prior regimens of therapy and were considered ineligible for autologous transplantation…These are often considered the most difficult patients, so there’s a bit of cherry picking here, but nevertheless patients in cycles 1 to 3 received 12 µg/kg tafasitamab every 4 weeks, plus lenalidomide at 25 µg/kg days 1 to 21. Then in cycles 4 to 12 the tafasitamab was given every 2 weeks.3
Lenalidomide was continued for a year, after which patients were still tolerating therapy and had not progressed, and they were eligible to continue with tafasitamab monotherapy that was given every 2 weeks. The primary end point here was overall response rate [ORR] with similar secondary end points to the LOTIS study [NCT04384484].
The median age of [patients on the trial was 72 years old] and most patients had only 1 prior line of treatment. Forty-three percent of patients had 2 prior lines of treatments, and I think one of the criticisms of the L-MIND study is that the patients were not heavily pre-treated.
What was the efficacy data from the study?
With greater than 35 months of follow up, the median follow up showed 40% of patients had achieved a complete response.4 About 18% had a partial response, and 16% stayed with disease. The overall disease control rate was 74% while the ORR was 58%. The median duration of response was 43.9 months, which is hard to believe it’s so good.
For patients who had a complete response, [it looked] better than CAR T-cell therapy….For patients with stable disease or partial response, [it was not as] encouraging, but for patients who achieved complete response, these are remarkable results. I mean, again, almost unbelievable, even though these patients weren’t heavily pretreated.
Were there any notable adverse events (AEs) with this treatment?
There are some adverse hematologic events, although, in my experience they’re not terribly difficult to deal with. You do see some neutropenia, and some mild thrombocytopenia, but neutropenic fever is not very common.5
There were relatively few grade 3 and grade 4 events, and skin rash is probably one of the more common AEs that you’ll see, at [27% in this study], most likely due to lenalidomide. Overall, it is a well-tolerated combination.
As far as serious AEs, [20% of patients experiencing AEs were judged as treatment related], but only 12% of patients discontinued due to AEs which is remarkable in this patient population. There were a few treatment-emergent AEs leading to death. But this is a high-risk patient population, and these were not presumed to be related to the study treatment.
How concerned are you about loss of CD19 antigen expression with use of anti-CD19 therapies, and implications for subsequent CAR T-cell therapy candidacy?
1. Linhares Y, Gandhi M, Chung M, et al. Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma. Presented at Presented at: 2020 ASH Annual Meeting and Exposition. Abstract 2107.
2. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. News release. August 8, 2020. Accessed November 11, 2021. https://bit.ly/3wD54PH
3. Salles G, Duell J, González Barca E, Tournilhac O, 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 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4
4. 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 Sep 1;106(9):2417-2426. doi: 10.3324/haematol.2020.275958
5. Nowakowski G, Rodgers T, Marino D, et al. RE-MIND study: A propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). J Clin Oncol. 2020 May 25;38(15):8020-8020. doi: 10.1200/JCO.2020.38.15_suppl.8020