Valemetostat Monotherapy in Patients with Relapsed or Refractory Large B-Cell Lymphoma: Primary Results of the Phase 2 Valym Study from the Lysa

Introduction. Large B-cell lymphoma (LBCL) is the most frequent type of lymphoma. Despite significantly improved outcomes following the advent of chimeric antigen receptor T cells and anti-CD20-CD3 bispecific antibodies, a high proportion of patients will relapse and ultimately die from the disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for patients with relapsed/refractory (R/R) LBCL treated with valemetostat in the open-label, single-arm, phase 2 VALYM study (NCT04842877). Methods. Eligible patients with LBCL previously treated with ≥2 lines of systematic therapy (including at least anthracyclines and an anti-CD20 monoclonal antibody) received oral valemetostat as a single agent 200 mg QD in continuous 28-day cycles until disease progression, unacceptable toxicity or death, whichever occurred first. The primary endpoint was best overall response rate (ORR) assessed by the investigator according to PET-based Lugano 2014 criteria. Secondary endpoints included best complete response rate (CRR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and toxicity according to the CTCAE classification version 5.0. Exploratory endpoints included response rates and survival according to LymphGen classification or EZH2 mutation status. Experimental treatment was considered as ineffective if ORR was < 15% and as promising if ORR was > 30%. A sample size of at least 40 patients was required. Results. As of December 31, 2023, 41 patients with LBCL were enrolled in the study and had a median follow-up of 22.6 months. Median age was 75 years (range, 18-91). Eleven patients had refractory disease to last treatment line, 21 patients had IPI ≥3 and the median number of previous lines was 4 (1-8). Nineteen (46%) and 9 (22%) patients had previously received a chimeric antigen receptor (CAR) T cell or an anti-CD20-CD3 bispecific antibody, respectively. All patients received at least one dose of valemetostat. Treatment discontinuation occurred in all patients due mainly to progression (N=32, 78%), adverse event (N=8, 20%) or death (N=1, 2%). All 41 patients were considered in the efficacy analysis. Patients without any response assessment (N=6) due to whatever reason were considered as non-responders. ORR was 36.6% (N=15) and CRR was 12.2% (N=5). The median PFS was 2.6 months (95% CI, 1.7-5.2) and the median DOR was 2.9 months (2.5-3.0). The median OS was 7.7 months (4.3-17.9). ORR and CRR were 30% and 7% in patients with wild-type EZH2 LBCL (N=30) compared with 83% and 50% in patients with mutant EZH2 LBCL (N=6). 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. All 41 patients were included in the safety set. Ninety percent experienced at least one treatment-emergent adverse event (TEAE) and 51% a grade ≥3 TEAE. Most frequent TEAEs of any grade were thrombocytopenia (29%), diarrhea (24%), anemia (19%), fatigue (19%), alopecia, COVID-19 infection, decreased appetite, nausea and neutropenia (15% each). Most frequent grade ≥3 TEAEs were thrombocytopenia (22%), neutropenia (15%), anemia and COVID-19 infection (7% each). No TEAE related to valemetostat led to treatment discontinuation. Only 7 and 1 patients had treatment interruption and dose reduction due to a related TEAE, respectively. Twenty-eight patients died, mostly from progression (N=26, 93%). One patient died from acute respiratory failure and one from a septic shock. No second primary malignancy was observed. Conclusions. In this phase 2 study of valemetostat in LBCL, an encouraging ORR of 36.6% was observed in a very elderly and heavily pretreated patient population with nearly a half previously treated with CAR T cells. Despite the limited sample size, biomolecular analyses supported higher overall and/or complete response rates in case of EZH2 mutation or EZB subtype. TEAEs were manageable and safety profile was similar to that of the phase I first-in-human study. This suggests valemetostat could be used in combination for future development.