Introduction. B-cell lymphomas comprise a broad spectrum of diseases, with clinical courses ranging from frequently relapsing indolent forms to less frequent but challenging cases of aggressive, relapsed or refractory (R/R) large B-cell lymphoma. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1. Here, we report primary results for patients with relapsed/refractory (R/R) B-cell lymphoma treated with valemetostat in the international, mutlicenter, open-label, single-arm, phase 2 VALYM study (NCT04842877).

Methods. Eligible patients with various B-cell lymphoma histologies treated with ≥2 lines of systematic therapy received oral valemetostat as single agent 200 mg QD in continuous 28-day cycles until disease progression, unacceptable toxicity or death, whichever occurred first. Five subcohorts of patients were considered: cohort 1 with large B-cell lymphoma (LBCL), cohort 2 with follicular lymphoma (FL), cohort 3 with mantle cell lymphoma (MCL), cohort 4 with marginal zone lymphoma (MZL) and cohort 5 with Hodgkin lymphoma (HL). The primary endpoint was best overall response rate (ORR) assessed by the investigator according to PET-based Lugano 2014 criteria.

Results. As of December 3, 2024, 120 patients with R/R B-cell lymphoma were enrolled in the study with a minimum follow-up of 12 months. Overall, 41 patients with LBCL, 40 patients with FL, 9 patients MCL, 10 patients MZL, and 20 patients with HL. All patients received at least one dose of valemetostat and were included in the efficacy and safety sets. Ninety percent of patients had confirmed histological diagnosis by central review. The median follow-up was 28.6 months. Median age was 71 years (range, 18-92). Most patients (94.2%) had at least one nodal involvement at baseline and 67.5% had at least one extra nodal involvement. The majority of patients had a performance score < 2 (91%) and Ann Arbor stage III-IV disease (83%). Thirthy-five percent of patients with LBCL, 46% of patients with FL, 62.3% of patients with MCL, 40% of patients with MZL and 68% of patients with HL presented with high-risk disease according to IPI, FLIPI, MIPI, MZL-IPI and IPS scores, respectively. Treatment discontinuation occurred in 30 patients due mainly to progression (35%), adverse event (30% overall, 17% deemed related to valemetostat) or death (5%), while 10 patients (25%) were still on treatment at data cut-off.

Best ORR, the primary endpoint, was 17.1% for LBCL, 62.2% for FL, 11.1% for MCL, 20.0% for MZL and 20% for HL. Best complete response rate (CRR) was 12.2% for LBCL and 20.0% for FL. No CR was observed for patients with MCL, MZL or HL. Median progression-free survival were 2.6 (95% CI, 1.7-5.2), 9.7 (5.4-16.5), 2.0 (0.3-5.5), 6.0 (0.7-NA), and 2.7 (2.6-3.3) months for LBCL, FL, MCL, MZL and HL, respectively. Median duration of response was 13.8 months (4.2-NA) for FL and 2.9 months (2.5-3.0) for LBCL.

ORR and CRR were 33% and 25% in the EZB subtype (N=12) compared with 29% and 7% in non-EZB subtypes (N=14) according to the LymphGen classification. ORR and CRR were 64% and 18% in patients with wild-type EZH2 FL (N=28) compared with 58% and 25% in patients with mutant EZH2 FL (N=12).

Among all patients, 108 (90%) patients had at least one treatment emergent adverse event (TEAE). The most frequent were diarrhea (25%), asthenia (22%), and thrombocytopenia (21%). The most frequent grade ≥3 AEs reported in more than 10% of patients were thrombocytopenia (27%), neutropenia (27%), COVID-19 (13%) and anemia (11%). Three patients had a second primary malignancy (one basal cell carcinoma, one melanoma in situ and one bladder carcinoma). Sixty-seven patients (56%) died. Among them, 50 (75%) died due to lymphoma, 7 patients (10%) from concurrent illness, 4 patients (6%) due to toxicity of additional treatment, 4 patients (6%) from Covid-19 and 2 patients (3%) from unknown cause.

Conclusions. In this phase 2 study of valemetostat in B-cell lymhoma, modest activity was observed in MCL, MZL and HL while an encouraging ORR of 62% was observed in FL. Interestingly, ORR and CRR were 33% and 25% in 12 patients with EZB LBCL molecular subtype, pointing out potential selective activity. Importantly, a manageable safety profile was observed in heavily pretreated and elderly patient population supporting further development in combination.

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2025
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