Pembrolizumab and pralatrexate for relapsed or refractory peripheral T-cell lymphomas Free

Background

T-cell lymphomas (TCL) have limited treatment options and poor prognosis, representing an unmet medical need. Pralatrexate and pembrolizumab have each demonstrated modest single-agent efficacy in TCL. Preclinical data suggest that antifolates may induce immunogenic cell death and modulate the tumor microenvironment to enhance antigen presentation and reduce immunosuppression, while immune checkpoint inhibitors may restore T-cell function, together synergistically promoting robust anti-tumor immunity (Schaer et al, Clin Cancer Res 2019). Based on this rationale, we hypothesized that the combination of pralatrexate and pembrolizumab could improve therapeutic efficacy. We report the safety, tolerability, and efficacy of this regimen in patients with TCL.

Methods

We conducted a multicenter, prospective, phase I/II, single-arm, open-label trial in patients aged ≥18 years with relapsed or refractory (R/R) mature peripheral T-cell or NK-cell lymphomas, including transformed mycosis fungoides (MF), who had received at least one prior line of therapy. Patients with prior exposure to anti–PD-1 or pralatrexate without evidence of objective response were excluded. The study included a dose-escalation phase followed by a dose-expansion phase once the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of pralatrexate was determined, using a modified rolling 6 design. Pralatrexate was administered IV at escalating doses (Dose Level [DL] 1: 20 mg/m², DL 2: 30 mg/m²) on Days 1 and 8 of a 21-day cycle, combined with pembrolizumab 200 mg IV on Day 1 of each cycle. Supportive care, including leucovorin, was provided per institutional standards. Dose-limiting toxicities (DLTs) were defined as grade ≥4 hematologic or grade ≥3 non-hematologic treatment-related adverse events, with protocol-specified exceptions, occurring during the first two cycles of therapy. The primary endpoints were determination of the MTD/RP2D of pralatrexate and overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety.

Results

Thirteen patients initiated study treatment. Histologic subtypes included anaplastic large cell lymphoma (n=6), transformed MF (n=3), angioimmunoblastic T-cell lymphoma (n=1), T-follicular helper lymphoma, NOS (n=1), extranodal NK/T-cell lymphoma (n=1), and cutaneous T-cell lymphoma, NOS (n=1). The median age was 63 years (range, 49–84). Nine patients (69%) had advanced-stage disease, and one (8%) had undergone prior autologous stem cell transplant. Five patients were treated at DL 1. Two were not evaluable for DLT due to clinical progression during the DLT assessment window. Among the 3 evaluable patients, no DLTs were observed, allowing for escalation to DL 2. Six patients were subsequently treated at DL 2; one was inevaluable due to progression after one cycle. Among the five evaluable patients, two experienced DLTs: one had Grade 3 fatigue lasting >2 weeks, and another developed Grade 3 hypertension that resolved to Grade 1 after >7 days. As per protocol, the occurrence of ≥2 DLTs at this level prompted de-escalation back to DL 1. Two additional patients were enrolled at DL 1 following de-escalation. One experienced a DLT (Grade 3 rash >7 days), while the other was inevaluable due to disease progression before completing the DLT period. The median number of treatment cycles administered across all patients was 3 (range, 1–7). No on-treatment deaths occurred. The ORR and CR rate were 23% and 15%, respectively. Median PFS was 2.4 months (95% CI: 0.72-2.9) and median OS was 5.6 months (95% CI: 3.5-15.7). At a median follow-up of 5.7 years, 1 patient remains alive and progression-free.

Conclusion

The combination of pralatrexate and pembrolizumab was not well tolerated in R/R TCL, with an unacceptable rate of DLTs across dose levels, despite the absence of unexpected toxicities. Furthermore, the ORR observed with this combination was lower than historical benchmarks for pralatrexate monotherapy, which may be attributable to the reduced pralatrexate dosing in this study and potential direct growth stimulation of malignant T cells by pembrolizumab. Given the limited efficacy and safety concerns, further development of this regimen as studied is not warranted.