Around 40% of peripheral T-cell lymphomas (PTCL) are linked to Epstein-Barr virus (EBV), which is associated with poor prognosis and 5-year overall survival rates as low as 20%. EBV is latent in tumors: most viral genes, bar those driving host cell growth and apoptosis blockade, are silenced. However, novel therapeutics aim to target EBV-positive (EBV+) tumors by reinstating viral gene expression to activate the nucleoside analogue ganciclovir (GCV) that inhibits viral and tumor DNA synthesis and prompts cell death. The safety and efficacy of this strategy was evaluated here with the histone deacetylase inhibitor nanatinostat (Nstat) and the oral pro-drug of GCV, valganciclovir (VGCV), in patients (pts) with EBV+ PTCL.

This Phase 1b/2 study (NCT03397706) assessed Nstat+VGCV in pts aged ≥18 years with EBV+ relapsed/refractory lymphoid malignancies who had ≥1 prior systemic therapy and no viable curative treatment options. EBV status was determined by the site or central laboratory on a specimen representative of the current disease. Phase 1b evaluated safety (from first drug administration until 28 days post-last dose or until the start of a new anticancer therapy) and established the recommended Phase 2 dose. Phase 2 assessed efficacy (overall response rate [ORR]). Here, subgroup analysis data from pts with PTCL (angioimmunoblastic T-cell lymphoma [AITL] and PTCL not otherwise specified [PTCL-NOS]), are reported.

Thirteen patients with nodal PTCL (8 AITL, 5 PTCL-NOS) were enrolled. The median age was 68.4 years, 69% were male, and 92% had stage 3–4 disease. At data cut-off (May 4, 2023), all pts had ≥1 treatment-emergent adverse event (TEAE). The most common (reported in ≥10% of pts) any-grade TEAEs were decreased white blood cell (WBC)/lymphocyte count (n = 6, 46%), fatigue and diarrhea (both n = 5, 38%) (Table 1). Grade ≥3 TEAEs included decreased WBC/lymphocyte count (n = 4, 31%) and decreased neutrophil count (n = 3, 23%). The most common any-grade, study drug-related TEAEs were nausea and increased blood creatine (both n = 4, 31%); anemia, fatigue, diarrhea, decreased neutrophil count, decreased appetite and decreased WBC/lymphocyte count were the next most common (all n = 3, 23%). Of the most common study drug-related TEAEs, most (76%) were grade 1/2. Three pts had ≥1 serious TEAE, including infection, gastrointestinal disorders and new neoplasm. No serious adverse reactions or deaths due to events related to the study drugs were reported. Eight pts were evaluable for efficacy (5 pts non-evaluable due to TEAEs [ n = 3], investigator decision [ n = 1] and EBV− status [ n = 1]). Three pts (37.5%) had complete responses (CR), 1 (12.5%) had a partial response (PR), 1 had stable disease (SD) and 3 had progressive disease. The ORR was 50%, with a 62.5% disease control rate (DCR [CR+PR+SD]). The median duration of response (DoR) was 17.3 months (mos). ORR and DCR were similar in AITL and PTCL-NOS, but DoR was longer in pts with AITL (n = 2, 38.3 mos) compared with PTCL-NOS (n = 2, 6.1 mos).

Encouraging safety and efficacy findings were observed with Nstat+VGCV in PTCL. Hematologic toxicities were consistent with the VGCV safety profile. An ongoing Phase 2 study (NCT05011058) will provide further data on this novel therapy for EBV+ lymphomas. Editorial support for this abstract was funded by Viracta.