Abstract T106

Phase 1 PRIMAVERA Study of the PRMT5 Inhibitor AZD3470 in Patients with Relapsed/Refractory Classic Hodgkin Lymphoma

Background: Protein arginine methyltransferase 5 (PRMT5) is critical for cell proliferation and differentiation and its dysregulation is associated with cancer development. Methylthioadenosine (MTA), an endogenous partial inhibitor of PRMT5, accumulates in cancer cells deficient in MTA phosphorylase (MTAP). In classic Hodgkin lymphoma (cHL), >80% of primary patient (pt) tumor samples are MTAP deficient (Urosevic J, ASH 2023). The MTA-cooperative PRMT5 inhibitor AZD3470 preferentially binds to MTA-bound PRMT5, increasing its target engagement to MTAP-deficient cancer cells. We present safety and preliminary efficacy of AZD3470 from a Phase 1 study in relapsed/refractory (r/r) cHL (NCT06137144).

Methods: Eligibility: ≥18 years; r/r cHL; ≥3 prior lines of therapy (including brentuximab vedotin (BV) and anti-PD-1). Pts received oral AZD3470 monotherapy QD in ascending dose levels (DLs) using an mTPI-2 design. Primary endpoints: incidence and severity of treatment-emergent adverse events (TEAEs) and dose-limiting toxicity (DLT). Secondary endpoints: overall response rate (ORR) and complete response rate (CRR) (Lugano 2014 criteria).

Results: As of 25/11/25, 39 pts (male, 62%; stage IV, 77%; median age, 42 [range 25–78] years; median prior lines of anticancer therapy, 6 [range 3–14]) had received AZD3470 at DL 1 to 8. All pts had had prior BV and anti-PD1 therapy; 20 (51%) and 5 (13%) pts had had prior autologous and allogeneic hematopoietic stem cell transplantation, respectively. All pts 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%). Grade ≥3 TEAEs occurred in 28% of pts, most commonly neutropenia (related) and hypokalemia (n=2 each). Serious TEAEs occurred in 5 pts (13%). 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 31 evaluable pts, 14 had an objective response, with responses at ≥DL4. The highest response rate was observed at ≥DL7 (n=10) with ORR 80% and CRR 50%.

Conclusions: AZD3470 monotherapy was well tolerated, with no DLTs and mainly low-grade AEs. Both ORR and CRR were dose-dependent and notably high in this heavily pretreated cHL population. Dose optimization is ongoing.