Valemetostat Demonstrates Clinically Meaningful Efficacy in R/R PTCL

Stefan K. Barta, MD, MS

Valemetostat tosilate (Ezharmia) elicited responses and was safe in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), according to data from the phase 2 VALENTINE-PTCL01 trial (NCT04703192) presented at the 2024 SOHO Annual Meeting.¹

Findings showed that patients in the efficacy-evaluable population (n = 119) achieved an overall response rate (ORR) of 43.7% (95% CI, 34.6%-53.1%), which included a complete response (CR) rate of 14.3% and a partial response (PR) rate of 29.4%. The median time to response was 8.1 weeks (range, 5-37), and the median duration of response (DOR) was 11.9 months (95% CI, 7.8–not evaluable [NE]).

“The VALENTINE-PTCL01 study demonstrated that valemetostat monotherapy is tolerable and provides a clinically meaningful benefit for patients with relapsed/refractory PTCL,” presenting study author Stefan K. Barta, MD, MS, said during the presentation. Barta is the director of the T-Cell Lymphoma Program, executive officer of the AIDS Malignancy Consortium, and associate professor of clinical medicine (hematology-oncology) at Penn Medicine in Philadelphia, Pennsylvania.

Valemetostat is a novel, potent, and selective EZH2 and EZH1 dual inhibitor. Barta explained that EZH2 overexpression is a known cancer driver in various malignancies, including PTCL. However, he noted that EZH2 gene mutations are rare in patients with PTCL.

In June 2024, Japan’s Ministry of Health, Labor and Welfare approved valemetostat for the treatment of adult patients with relapsed/refractory PTCL, based on previously reported findings from cohort 2 of VALENTINE-PTCL01.²

VALENTINE-PTCL01 Overview and Design

The global, multicenter, open-label, single-arm trial enrolled patients at least 18 years of age with confirmed PTCL per WHO 2016 classification. At least 1 prior line of systemic therapy was required, and those with anaplastic large cell lymphoma (ALCL) were required to have undergone prior treatment with brentuximab vedotin (Adcetris). All patients also needed to have an ECOG performance status of 0 to 2.

Investigators enrolled 133 patients with relapsed/refractory PTCL, including 119 who had their disease histology confirmed by central pathology. All patients received 200 mg of valemetostat once per day in continuous 28-day cycles until disease progression or unacceptable toxicity.

CT-based ORR per blinded independent central review (BICR) following at least 10 months of follow-up served as the trial’s primary end point. Secondary end points consisted of DOR, duration of CR, CR rate, PR rate, progression-free survival (PFS), overall survival (OS), and safety/tolerability. PET-CT–based ORR per BICR assessment was an exploratory end point.

Among 175 patients screened between June 2021 and July 2022, investigators enrolled 133 patients, who were all included in the safety analysis set. Of these patients, 119 were evaluable for efficacy.

At the May 5, 2023, data cutoff and a median follow-up of 9.7 months, 24.1% of patients (n = 32) were still on treatment. Among the 75.9% of patients who discontinued treatment, reasons for discontinuation included disease progression (48.9%), adverse effects (AEs; 9.8%), hematopoietic stem cell transplant (HCT; 9.0%), other (3.8%), death (2.3%), patient withdrawal (1.5%), and loss of follow-up (0.8%).

In the safety population, the median age was 69.0 years (range, 22-85), and 68.4% of patients were male. Baseline ECOG performance status was 0 (43.6%), 1 (48.9%), 2 (6.8%), or 3 (0.8%). Patients received a median of 2.0 prior lines of therapy (range, 1-12); 27.1% of patients received 1 prior line of therapy, 27.1% were given 2 prior lines of therapy, 21.8% were administered 3 prior lines of therapy, and 24.1% received at least 4 prior lines of therapy. Additionally, 26.3% of patients underwent prior HCT, including autologous HCT (24.1%) and allogeneic HCT (3.8%). Notably, 29.3% of patients were relapsed to their last line of treatment and 60.2% were refractory to their last therapy. Response to last treatment was not assessable or unknown in 10.5% of patients.

PTCL subtypes included on the trial consisted of angioimmunoblastic TCL (31.6%), nodal PTCL with T follicular helper (TFH) phenotype (6.0%), follicular TCL (2.3%), PTCL not otherwise specified (30.8%), ALK-positive ALCL (5.3%), ALK-negative ALCL (1.5%), monomorphic epitheliotropic intestinal TCL (0.8%), CD8-positive primary cutaneous aggressive epidermotropic cytotoxic TCL (0.8%), primary cutaneous gamma delta TCL (0.8%), and other TCL (9.8%). All those patients were included in the efficacy-evaluable population. Patients with non-TCL or undetermined PTCL (4.5%) or missing classification (6.0%) were included in the safety population.

Valemetostat Displays Further Efficacy and Safety

In the efficacy-evaluable population, the median PFS was 5.5 months (95% CI, 3.5-8.3) at a median follow-up of 11.3 months (95% CI, 11.1-13.8), and the median OS was 17.0 months (95% CI, 13.5-NE) at a median follow-up of 12.3 months (95% CI, 11.8-13.8).

The ORR was 52.8% (95% CI, 35.5%-69.6%) in patients who received 1 prior line of therapy (n = 36), 46.7% (95% CI, 28.3%-65.7%) in those who received 2 prior lines of therapy (n = 30), and 35.8% (95% CI, 23.1%-50.2%) in patients who underwent 3 or more prior lines of therapy (n = 53). In patients who were relapsed to their last line of therapy (n = 49), the ORR was 55.1% (95% CI, 40.2%-69.3%); those who were refractory to their last line of therapy (n = 60) achieved an ORR of 36.7% (95% CI, 24.6%-50.1%).

Ten patients (8.4%) proceeded to allogeneic HCT, including 6 patients (5.0%) who experienced a CR.

“Responses were observed across all subtypes and were numerically higher in the THF subtypes,” Barta noted.

The PET-CT–based ORR was 52.1% (95% CI, 42.8%-61.3%), including 26.9% of patients who experienced a complete metabolic response and 25.2% of patients who had a partial metabolic response.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) occurred in 96.2% of patients; the rates of grade 3 or higher and serious TEAEs were 57.9% and 39.8%, respectively. Any-grade treatment-related AEs (TRAEs) were reported in 79.7% of patients, including 36.8% who had grade 3 or higher TRAEs and 6.8% who experienced serious TRAEs.

TEAEs led to death, treatment discontinuation, dose reduction, and dose interruption in 11.3%, 9.8%, 15.8%, and 49.6% of patients, respectively. No deaths were reported due to TRAEs. TRAEs led to treatment discontinuation, dose reduction, and dose interruption in 6.8%, 12.0%, and 31.6% of patients, respectively.

The most common TEAEs reported in at least 15% of patients included thrombocytopenia (any-grade, 49.6%; grade 3/4, 23.3%), anemia (35.3%; 18.8%), diarrhea (29.3%; 3.8%), dysgeusia (28.6%; 0%), neutropenia (26.3%; 17.3%), COVID-19 (21.1%; 3.0%), nausea (17.3%; 0.8%), pyrexia (15.0%; 0%), and cough (15.0%; 0%).

Thrombocytopenia led to treatment discontinuation in 2.3% of patients, dose reductions in 5.3% of patients, and dose interruptions in 16.5% of patients. Other TEAEs that led to dose modifications included anemia (dose reduction, 3.8%; dose interruption, 9.8%), COVD-19 (1.5%; 8.3%), and neutropenia (2.3%; 5.3%).

“Thrombocytopenia was very manageable with either dose interruptions or modifications and supportive therapies,” Barta concluded.

References

1. Horwitz SM, Izutsu K, Mehta-Shah N, et al. Valemetostat for patients with R/R peripheral T-cell lymphomas (PTCLs): a phase 2 VALENTINE-PTCL01 trial. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, TX. Abstract TCL-394.
2. Ezharmia approved in Japan as first dual EZH1 and EZH2 inhibitor therapy for patients with peripheral T-cell lymphoma. News release. Daiichi-Sankyo. June 24, 2024. Accessed September 6, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202406/20240624_E2.pdf