ASH 2025 | Pembrolizumab and pralatrexate for R/R peripheral T-cell lymphomas

The next abstract that was presented by our group at ASH was a study of pembrolizumab and pralatrexate for relapse or refractory peripheral T-cell lymphomas. So as we all know, T-cell lymphoma patients have limited treatment options and poor prognosis, and they do represent a great unmet medical need. There is some preclinical data that suggests that antifolates may induce immunogenic cell death and modulate the tumor microenvironment, and that enhances antigen presentation and reduces immunosuppression, while immune checkpoint inhibitors may restore T-cell function. And so together, synergistically, they would be promoting robust antitumor immunity. And so based on this rationale, we thought that this combination of pembrolizumab and pralatrexate together would be synergistic. And so we did this study. 

Essentially, patients who were 18 years and older with relapsed/refractory mature peripheral T-cell lymphoma or transformed mycosis fungoides who had received at least one prior line of therapy were eligible. And these patients essentially received pralatrexate administered at escalating doses. Dose level one was 20 milligrams per meter squared. Dose level two was 30 milligrams per meter squared on days one and eight of a 21-day cycle. This was combined with pembrolizumab, 200 milligrams on day one of each cycle. And the primary objective of this study was to determine the maximum tolerated dose of pralatrexate using a modified rolling six design. 

So overall, we had 13 patients initiated this study. Patients had anaplastic large cell lymphoma, transformed mycosis fungoides, angioimmunoblastic T-cell lymphoma, extranodal NK/T-cell lymphoma, and cutaneous T-cell lymphoma as well. And essentially what we saw was that there were five patients who were treated at dose level one. Two of them were not available for DLT due to clinical progression during that DLT assessment window. Among the other three, there were no other DLTs observed, and then six patients were subsequently treated at dose level two. Out of the six, one was inevaluable due to progression after one cycle, and then among the other five, two experienced DLTs. One was grade three fatigue lasting more than two weeks, and another one was grade 3 hypertension that resolved to grade 1 after seven days or more. And so based on the patients that were treated with this regimen, whether it was dose level 1 or 2, patients either had clinical progression before the DLT window was over, or they experienced DLTs. And so because of those results in the initial 13 patients, the study was prematurely discontinued due to what we were seeing. 

And so to conclude, the combination of pralatrexate and pembrolizumab was not well tolerated in this patient population. We saw an unacceptable rate of DLTs across dose levels. And furthermore, the overall response rate that we observed for the patients who did not experience a DLT, it was lower than historical benchmarks for pralatrexate monotherapy. And so based on this, you know, future development of this regimen with the current dose and schedule is not warranted.

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