CD19-Directed Antibody-Drug Conjugates for DLBCL

Part 2: Shah Discusses Challenges in Using Lenalidomide Plus Tafasitamab for Patients With DLBCL

Looking at the combination of lenalidomide plus tafasitamab for patients with diffuse large B-cell lymphoma shows promise for patients' treatment, but challenges remain that clinicians need to address.

During a live virtual event with other physicians, Bijal Shah, MD, MS, reviewed the efficacy and data for the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid) for patients with diffuse large B-cell lymphoma (DLBCL), Targeted OncologyTM had the chance to ask Shah about his rational surrounding this drug for patients who were relapsed or refectory to this disease.

Targeted OncologyTM: Can you discuss the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid)?

Tafasitamab was granted FDA approval in July 2020 based on data from the L-MIND trial [NCT02399085].1 L-MIND studied tafasitamab in combination with lenalidomide at 25 mg given orally on days 1 through 21 of a 28-day cycle.

Lenalidomide has been with us for a long time. When I was a resident, I remember doing a presentation on transplant-ineligible multiple myeloma, and this new crazy drug derived from thalidomide—lenalidomide—was showing activity in this space. Lenalidomide has a lot of mechanisms of action, and, honestly, I don’t think we even know them all. We know that [lenalidomide is associated with] T-cell and natural killer cell activation and expansion, which seems to be dependent on Ikaros and Aiolos transcription factors, and that same mechanism seems [to bring about] cell killing.2

We talk a lot about lenalidomide modulation of cereblon, [and how it affects treatment outcomes] in multiple myeloma, but in DLBCL it's less clear what else is driving that cytotoxicity signature. Certainly, lenalidomide [works as an E3 ubiquitin ligase inhibitor], affecting other proteins through the Ikaros and Aiolos ubiquitination system that drives degradation of [various] proteins and possibly cell death. This mechanism of degradation is important. [For example,] degraders targeting Bruton tyrosine kinase [BTK] or other cell signaling proteins use the same molecular system that we identified with lenalidomide.3

How does lenalidomide work for this patient population?

Lenalidomide induces T natural killer cell [expansion]. The question is whether we can use a monoclonal antibody to direct those T cells and natural killer cells, which is exactly what tafasitamab is [designed to] do. Tafasitamab is going to have antibody-dependent cellular cytotoxicity as well as antibody-dependent cellular phagocytosis, which are similar [mechanisms of action as in] daratumumab [Darzalex]. Tafasitamab may, in some cases, cause direct cell death through those mechanisms and will be synergistic with lenalidomide.2

In the phase 2 L-MIND trial, tafasitamab was given at 12 mg/kg weekly for three [28-day cycles] and then continued biweekly [for 9 cycles]. Lenalidomide was given at 25 mg/kg daily on days 1 through 21 [of all 12 cycles]. All patients included in the trial had had 1 to 3 prior regimens and were not eligible for transplant.4

I’ve given a lot of lenalidomide. I participated in the New England Journal of Medicine study [that evaluated] lenalidomide for mantle cell lymphoma.5 Lenalidomide is a great drug, but it's also not always an easy drug to deliver because of the AEs associated with it, such as cytopenias, rash, and gastrointestinal effects. [Nevertheless], I‘ve found that across lymphomas, including chronic lymphocytic leukemia, if the dose is above 10 mg/kg, [patients benefit]. Of course, if the patient has renal disease, the dose should be reduced to a bioequivalent dose of 10 mg/kg. The 10-mg dose seems to be the magic threshold for lenalidomide activity, and that’s what I try to keep my patients above.

What was the efficacy for patients in the L-MIND trial?

Patients enrolled in L-MIND were older patients [with a mean age of 72 years old]. A little more than half of them had an elevated LDH, [approximately] 20% of patients had primary refractory disease, and 44% [of patients had disease that was] refractory to last prior therapy. In total, 11% of patients had had a stem cell transplant, and the cell of origin was non-GCB or other in almost 90% of patients.4

At a median follow-up of at least 35 months, 40% of patients achieved a CR with lenalidomide/tafasitamab, and [an additional] 17% had PRs. The median DOR with extended follow-up was 43.9 months.2,6-8

Among patients who had a CR to the combination, PFS was quite long [median PFS, not reached], which is very reassuring. [However], as we saw with loncastuximab monotherapy in the LOTUS-2 trial, patients who had a PR [had a short duration of] response. For patients with a PR to lenalidomide/tafasitamab, the median PFS was 7.4 months. The median OS for patients who had a CR was fantastic [median OS, not reached], but for patients who didn’t, it was shorter [median OS, 22.5 months]. For patients with stable disease, progressive disease, or disease that was non evaluable, [OS was approximately] 10 months, and for patients with a PR, the OS was 22 months.2,6,7

What adverse events [AEs] should be noted with lenalidomide?

As I mentioned before, lenalidomide is not always an easy drug to give. In L-MIND, the most common nonhematological AEs included fatigue, diarrhea, cough, [peripheral] edema, and respiratory tract infections.2 In my experience, the infections associated with lenalidomide have largely been mild. Some patients on lenalidomide develop hypogammaglobulinemia and some [may develop] sinonasal, upper respiratory, and lower respiratory infections. This is something [clinicians should] be aware of when using lenalidomide. I want to make sure to mention thrombosis; it's rare in patients with lymphoma, but it can happen. [To reduce the risk of thrombosis], I give my patients baby aspirin when I put them on lenalidomide therapy.

Serious AEs occurred in 50% [of patients in L-MIND], of which a little fewer than half were thought to be treatment-related. [Some treatment-related AEs] culminated in treatment discontinuations. Approximately half of the patients had to have at least 1 dose reduction, but [77% of patients] were able to receive lenalidomide at 20 mg/kg or higher for the duration of treatment.

How does the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid)compare with lenalidomide alone?

The RE-MIND study [NCT04150328] evaluated this question by conducting a propensity score-based, matched comparison of patients using real-world data. [Results of RE-MIND] showed that tafasitamab adds a considerable benefit to lenalidomide-based therapy, leading to [a dramatic] increase in the complete response [CR] rate from 13% to 39% [and an increase in the PR rate] from 21% to 27%.9 These increases were significant, and we can anticipate the addition of tafasitamab to lenalidomide.

What I would have loved to [have seen] and what wasn’t evaluated in this analysis was the effect of adding rituximab to lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma [R/R DLBC]. It also would have been interesting to see the effects of lenalidomide plus other monoclonals, such as obinutuzumab [Gazyva], ublituximab, ofatumumab [Arzerra], [or other] monoclonals targeting CD20 that are in the pipeline.

We know that lenalidomide activates T cells, but without a monoclonal drug such as rituximab or obinutuzumab to direct them [to the tumor cells], the impact of lenalidomide isn’t being optimized.

REFERENCES

1. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed June 6, 2021. https://bit.ly/3bodb9v

2. Salles G, Duell J, González Barca E, et al. Primary analysis results of the single-arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. https://bit.ly/3hDJh4l

3. Dobrovolsky D, Wang ES, Morrow S, et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood. 2019;133(9):952-961. doi:10.1182/blood-2018-07-862953

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. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237

6. 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

7. Düll J, Maddocks KJ, Gonzalez-Barca E, et al. Long-term analyses from L-MIND, a phase II study of tafasitamab (MOR208) combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). J Clin Oncol. 2021;39(suppl 5):7513. doi:10.1200/JCO.2021.39.15_suppl.7513

8. Salles G, Duell J, 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

9. Nowakowski GS, Rodgers RD, 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;38(suppl 15):8020. doi:10.1200/JCO.2020.38.15_suppl.8020