A phase 1 study of the PRMT5 inhibitor AZD3470 in patients with relapsed/refractory classic Hodgkin lymphoma (PRIMAVERA).

Abstract

7003 Background: The epigenetic enzyme protein arginine methyltransferase 5 (PRMT5) plays a critical role in cell proliferation and differentiation; PRMT5 dysregulation is associated with cancer development. Methylthioadenosine (MTA) is an endogenous partial inhibitor of PRMT5 that accumulates in cancer cells deficient in MTA phosphorylase (MTAP). In classic Hodgkin lymphoma (cHL), we previously reported that >80% of primary patient (pt) tumor samples are MTAP deficient (Urosevic J, ASH 2023). The MTA-cooperative PRMT5 inhibitor AZD3470 preferentially binds to the MTA-bound state of PRMT5, increasing its target engagement to MTAP-deficient cancer cells. Here, we present safety and preliminary efficacy of AZD3470 from a first-in-human Phase 1 study in relapsed/refractory (r/r) cHL (NCT06137144). Methods: Eligible pts were ≥18 years with r/r cHL after ≥3 prior lines of therapy (including brentuximab vedotin (BV) and anti-PD-1). In dose escalation, pts received oral AZD3470 monotherapy QD in ascending dose levels (DLs) using an mTPI-2 design. Primary endpoints were incidence and severity of treatment-emergent adverse events (TEAEs) and dose-limiting toxicity (DLT). Secondary endpoints were overall response rate (ORR) and complete response rate (CRR) per Lugano 2014 criteria. Results: As of Nov 25, 2025, 39 pts had received AZD3470 at DLs ranging from 1 to 8. Most pts were male (62%) with stage IV disease (77%) and a median age of 42 (range 25–78) years. Pts had received a median of 6 prior lines of anticancer therapy (range 3–14); all had had prior BV and anti-PD1 treatments, and 20 (51%) and 5 (13%) pts had had prior autologous and allogeneic hematopoietic stem cell transplantation, respectively. All patients evaluable for MTAP protein expression were MTAP deficient. Median duration of exposure was 15 weeks (range 0.1–45.1), with treatment ongoing in 16 pts (41%). TEAEs occurred in 85% of pts, predominantly grades 1 or 2. The most common TEAEs (any grade) were anemia (28%) and nausea (15%), followed by asthenia, constipation, fatigue, and neutropenia (13% each). Grade ≥3 TEAEs occurred in 28% of pts, most commonly neutropenia (related) and hypokalemia (n=2 each). Serious TEAEs occurred in 5 (13%) pts. Two pts had dose reductions due to TEAEs (grade 4 hypertriglyceridemia and grade 3 esophagitis). No DLTs, treatment discontinuations nor deaths due to TEAEs were reported. Of the 31 pts evaluable for efficacy, 14 had an objective response, with responses at doses ≥DL4. The highest response rate was observed at doses ≥DL7 (n=10) with an ORR of 80% and CRR of 50%. Conclusions: AZD3470 monotherapy was well tolerated up to DL8, with no DLTs and mainly low-grade AEs. Incidences of grade ≥3 AEs and SAEs were low. Importantly, both the ORR and CRR were dose-dependent and notably high in this heavily pretreated cHL population. Dose optimization is ongoing and further safety and efficacy will be reported. Clinical trial information: NCT06137144 .