A new phase 2 clinical trial has shown promising results for valemetostat, a novel dual inhibitor of EZH1 and EZH2, in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The open-label, single-arm VALENTINE-PTCL01 study was conducted at 47 hospitals across 12 countries in Asia, Europe, North America, and Oceania. Funded by Daiichi Sankyo, the results were published in The Lancet Oncology on October 29, 2024.
The primary purpose of the study was to investigate the clinical activity and safety of valemetostat in patients with relapsed or refractory PTCL. A secondary objective was to assess the safety and tolerability in patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL).
Between June 16, 2021, and August 10, 2022, the trial enrolled 133 patients with relapsed or refractory PTCL and 22 patients with ATLL. Key inclusion criteria were age 18 years or older, Eastern Cooperative Oncology Group performance status of 0-2, relapsed or refractory disease after one or more previous lines of systemic therapy, and at least one measurable lesion. For patients with anaplastic large-cell lymphoma, previous treatment with brentuximab vedotin was required.
The median age of PTCL patients was 69.0 years, with 68% male and 32% female. The most common PTCL subtypes were angioimmunoblastic T-cell lymphoma (32%) and peripheral T-cell lymphoma not otherwise specified (31%). Patients had received a median of 2 previous lines of therapy, and 26% had undergone previous hematopoietic cell transplantation.
Patients received oral valemetostat at 200 mg daily in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for PTCL patients was objective response rate by blinded independent central review using CT-based 2014 Lugano response criteria.
After a median follow-up of 12.3 months, the objective response rate in 119 efficacy-evaluable PTCL patients was 44% (95% CI 35-53), including 14% complete responses and 29% partial responses. The median time to first response was 8.1 weeks. Responses appeared durable, with a median duration of response of 11.9 months (95% CI 7.8-not evaluable). Median progression-free survival was 5.5 months (95% CI 3.5-8.3) and estimated median overall survival was 17.0 months (95% CI 13.5-not evaluable).
Notably, 10 patients (8%) proceeded to allogeneic hematopoietic cell transplantation after valemetostat treatment, with 6 in complete response at the time of transplant. This suggests valemetostat may serve as an effective bridge to potentially curative therapy for some patients.
The safety profile was generally manageable. The most common grade 3-4 adverse events in PTCL patients were thrombocytopenia (23%), anemia (19%), and neutropenia (17%). Serious treatment-emergent adverse events occurred in 40% of PTCL patients, with 7% considered treatment-related. No treatment-related deaths were reported.
Cytopenias were the most frequent reason for dose modifications, but were typically manageable without discontinuing treatment. The overall discontinuation rate due to adverse events was 10% in PTCL patients, which compares favorably to rates seen with other monotherapies for relapsed/refractory PTCL.
Exploratory biomarker analyses found TET2 and RHOA mutations were common, particularly in angioimmunoblastic T-cell lymphoma, while EZH2 and EZH1 mutations were rare. There were trends toward higher response rates in patients with TET2 or RHOA mutations, though the clinical significance of this finding requires further study.
The authors concluded that valemetostat demonstrated a favorable risk-benefit profile in relapsed/refractory PTCL, with high and durable responses observed. They noted the results compare favorably to other monotherapies for this difficult-to-treat patient population, where treatment options are limited.
Key limitations of the study include its single-arm design without a comparator group and the small numbers of patients for some PTCL subtypes. Additionally, longer follow-up will be needed to further assess durability of responses and overall survival.
Nevertheless, these results provide strong rationale for further investigation of valemetostat in PTCL. Based on the VALENTINE-PTCL01 data, valemetostat was approved in Japan in June 2024 for treatment of relapsed/refractory PTCL. A confirmatory randomized trial is warranted to definitively establish the role of valemetostat in the treatment landscape for PTCL.
The potential clinical impact of these findings is significant. PTCL comprises a heterogeneous group of aggressive non-Hodgkin lymphomas with generally poor prognosis, particularly in the relapsed/refractory setting. Current treatment options are limited, with no universal standard of care. The 44% objective response rate and nearly 12-month median duration of response observed with valemetostat are encouraging in this context.
If confirmed in larger randomized trials, valemetostat could emerge as an important new treatment option for patients with relapsed/refractory PTCL. Its oral administration and manageable toxicity profile are additional favorable features. The ability to induce durable responses and potentially bridge select patients to curative-intent hematopoietic cell transplantation is particularly noteworthy.
Furthermore, as the first dual inhibitor of EZH1 and EZH2 to show clinical activity in PTCL, valemetostat validates this as a therapeutic target in T-cell lymphomas. This may spur further research into epigenetic therapies for these challenging malignancies.
In conclusion, the VALENTINE-PTCL01 trial represents a significant step forward in the treatment of relapsed/refractory PTCL. While further study is needed, valemetostat shows promise as a novel targeted therapy that could meaningfully improve outcomes for patients with limited options. Clinicians treating PTCL should follow ongoing research with this agent with great interest.
References
Zinzani PL, Izutsu K, Mehta-Shah N, et al. Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2024;25(12):1602-1613. doi:10.1016/S1470-2045(24)00503-5
