Long-Term Combination Data Show Most Benefit in Second-Line DLBCL

Stephen J. Schuster, MD

Director, Lymphoma Program

Director, Lymphoma Translational Research

Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research

Penn Medicine

Philadelphia, PA

Targeted Oncology: What led to the use of the tafasitamab (Monjuvi) plus lenalidomide (Revlimid) regimen in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?

SCHUSTER: The L-MIND study [NCT02399085] is what the tafasitamab/lenalidomide regimen is built upon. The eligibility criteria included 1 to 3 prior regimens, and these were patients [that couldn’t receive a] transplant.¹ These patients were not necessarily [considered for] CAR [chimeric antigen receptor] T-cell therapy, but CAR T-cell therapy is still an option if they’ve had this regimen.

These are the patients [whose disease] is growing, who have less stable disease or progressive disease during treatment with R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone]. Those patients are not good candidates for CAR T-cell therapy unless you can stabilize disease; honestly you need fast action and it is probably best to immediately go to a platinum-based regimen, in my opinion, but they’re the worst actors. I would say you don’t want to use tafasitamab/lenalidomide in those patients because it was an exclusion criteria in this trial.

The tafasitamab dosing schedule [was] pretty labor intense: weekly for the first 4 weeks, then twice a month, and after the first year you can stop the lenalidomide. You can dose reduce the lenalidomide if you have to. The data are [in Lancet Oncology] and they have guidance in the manuscript to what they did in the protocol. But I can tell you that some patients with lymphoma can’t tolerate 25 mg of lenalidomide [daily]. You can try 15 mg, you can try 10 mg, and [in older patients] you can try 5 mg, and we manage to still see success.

They kept patients at the end of the year on tafasitamab/lenalidomide. Even patients with stable disease were allowed to stay on the tafasitamab continuously.

What are the most recent data on the L-MIND study?

There are updated…AACR [American Association for Cancer Research] data for 2023.² [It analyzed] patients with 1 prior line of therapy, greater than or equal to 2 prior lines of therapy, and all patients—which is the way this study was initially designed to be analyzed. The breakdown of male to female patients was not too much different. Most patients had advanced-stage disease and that was balanced between all subsets. Primary refractory disease [was] defined as no response to, or progression/relapse within, 6 months of frontline therapy. They only include patients who relapsed during the first 6 months, but you always have to look at the fine print because everybody defines it differently. For me, if you respond and it comes back, that’s a relapse and it’s an early relapse, less than a year. Primary refractory means no response. This was intended for patients who were not considered transplant eligible, but some of them were not eligible because they already had autologous stem cell transplant. There were a few patients like that. [For] cell of origin, the non-germinal center B would be the activated B-cell type, less common in this study than the germinal center variety. In practice, it tends to be less common as well.

What is new about these data from AACR is the best response at 5-year follow-up. We [are looking] at the whole study and we look at the numbers of patients who have complete remissions. [Patients with] 1 prior line of therapy had significantly more complete remissions than [those who had] greater than or equal to 2 prior lines. This was in 30% [in the 2 or more prior lines group] to a little over 50% [for the 1 prior line group].

But if you look at overall response rate, which includes partial response, there it went from 47.5% for [2 or more prior lines to over] two-thirds of patients responding [after 1 prior line]. This would be their best response at the time of the data cutoff. The overall is an average of [the 2 subgroups]. I’d say that it’s better if…you think you might want to use this regimen. In my opinion, it is probably best to use it as your first rather than your second thought.

What did the long-term data show about how durable this regimen’s efficacy was for these patients with DLBCL?

The duration of response at 5 years follow-up [was reported in] the AACR presentation.² What’s interesting is when I look at the [Kaplan-Meier] curves, it doesn’t jump out to me that significantly. As you get to where the curve stabilizes, the numbers of patients [are] small. There are a couple more going out further in the 1 prior line of therapy group than the 2 [prior lines group]. I still think 1 prior line of therapy is good, but I think these curves are telling you…that overall 60% of [responding] patients are going to continue to respond [for several years].

For progression-free survival [PFS], the curves separate a little bit more. For [patients with] 1 prior line of therapy, [tafasitamab/lenalidomide] does better than the other [patients]. The median PFS was approximately 2 years, and it was only a little over 6 months for [patients who had] more than 2 [prior lines]. If you’re looking at all patients treated, it seems as though you begin to see a difference more dramatically [based on the number of] prior lines of therapy. All patients fall in between those 2 subsets. So try [tafasitamab/lenalidomide] early, not late.

The swimmer plot [showed 19 patients] are continuing on therapy. The question becomes how many patients have stopped therapy and stayed in remission, and I don’t know the answer to that question…because this was a study where you just continued on with the tafasitamab after the first year.

How was toxicity handled in the L-MIND trial?

Treatment-emergent adverse events [(AEs) included significantly more] non-hematologic AEs [than] hematological AEs. It has to be [because of] lenalidomide because the tafasitamab is almost without symptoms in [most patients]. The serious AEs are grade 3 or greater…that’s probably a vanishingly small proportion of the events that you see. And, if you see them, you see them mostly during the first year when they’re getting both drugs and less during the second year, although they’re continuing first year events added to the second year. Beyond [that] you see it drops off pretty low.

For hematological AEs, [most oncologists are] familiar with lenalidomide. We worry about blood counts and blood clots. I’m not aware that any patient on this study who had a blood clot. There were cytopenias [including] neutropenia, as you’d expect most commonly with lenalidomide. When patients were beyond 2 years, you could see these vanishingly small number of events, [such as] the occasional patient that gets neutropenia but it was pretty well tolerated. Most of the AEs are going to be up front in the first year. These AEs are generally manageable by withholding the medicine [and using] growth factors. They did not see any grade 5 AEs.

[The investigators presented] safety results with exposure-adjusted comparisons. What I’m looking for are blood clots. I haven’t seen any yet. C-reactive protein increase, [which was reported in 10 patients], could be a good thing sometimes, particularly when you start lenalidomide. I don’t know that that’s an AE.

[One patient] had a hepatitis B reactivation, [and 1 had] progressive multifocal leukoencephalopathy]. Myelosuppression is the primary thing. There was a low incidence of infusion-related reactions. Most AEs are going to be blood count related, hematological, [and those are] going to be lenalidomide related. These are pretty easy to work around with holding doses, dose reductions, and growth factors.

_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, Abrisqueta P, Andre M, et al. Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study. Presented at: American Association for Cancer Research Annual Meeting 2023; April 14-19, 2023; Orlando, FL. Accessed May 12, 2023. https://bit.ly/3MmShus}