Paper Details

ABSTRACT

Background: Dysregulation of the epigenetic enzyme protein arginine methyltransferase 5 (PRMT5) plays a critical role in cell proliferation, differentiation, and oncogenesis. First-generation PRMT5 inhibitors lacked tumor selectivity and had limited clinical activity and challenging safety profiles. AZD3470 is a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor that preferentially binds to the MTA-bound state of PRMT5, enabling selective activity in MTAP-deficient cancer cells, where MTA accumulates. As >80% of tumor samples from patients (pts) with classic Hodgkin lymphoma (cHL) are MTAP deficient (Urosevic J, ASH 2023), this synthetic lethality represents a promising therapeutic target in cHL. The first-in-human Phase 1 PRIMAVERA trial (NCT06137144) evaluates AZD3470 safety and efficacy in pts with relapsed/refractory (r/r) cHL.

Methods: Eligible pts were ≥18 years (≥15 years in the optimization part) with r/r cHL after ≥3 prior lines of therapy, including brentuximab vedotin (BV) and a PD-1 inhibitor. In dose escalation, pts received oral AZD3470 monotherapy once daily (QD) at ascending doses using an mTPI-2 design. Two doses were selected for optimization to identify the recommended phase 2 dose. Primary endpoints were incidence and severity of treatment-emergent adverse events (TEAEs) and dose-limiting toxicity (DLT). Secondary endpoints included overall response rate (ORR) and complete response rate (CRR) (Lugano 2014 criteria). ctDNA levels were assessed using Foresight CLARITY as an exploratory assay. Soluble thymus and activation-regulated chemokine (TARC) plasma concentrations were measured using an MSD platform.

Results: As of April 10, 2026, 69 pts had received AZD3470 at doses of 25–600 mg QD, including 20 pts at 450 mg and 21 pts at 600 mg. Most pts had stage IV disease (74%); median age was 45 years (range 22–78). Pts had received a median of 5.5 prior lines of anticancer therapy (range 3–15); 99% had received BV and anti-PD1 treatment, and 49% and 12% had received autologous and allogeneic hematopoietic stem cell transplantation, respectively. 48% of pts were refractory and 52% had relapsed following most recent treatment. MTAP deficiency by IHC was confirmed in 45/46 (98%) pts evaluated for MTAP. Median duration of exposure was 18 (range 3–66) weeks, with treatment ongoing in 29 pts (42%). TEAEs occurred in 93% of pts (71% related); the most common were anemia (39%), fatigue (30%), and nausea (20%). Grade ≥3 TEAEs occurred in 42% of pts, most commonly anemia (12%) and neutrophil count decreased (6%). Serious TEAEs occurred in 13 (19%) pts, with 3 (cellulitis, influenza, hypertriglyceridemia) considered possibly related to AZD3470. Dose reductions due to TEAEs occurred in 9 (13%) pts, most commonly due to hematologic toxicity. No DLTs, treatment discontinuations, nor deaths due to TEAEs were reported. For 68 pts evaluable for efficacy, ORR was 51% (80% CI 43%, 60%); CRR was 19%. Among 20 patients evaluable at each of the 450 mg and 600 mg dose levels, ORR/CRR was 70%/20% and 65%/45%, respectively. At most recent follow up, median duration of response was immature. PK exposure increased dose-proportionally with AZD3470 up to 600 mg QD. Steady-state PK was achieved by approximately Day 3, Cycle 1, with an accumulation ratio of approximately 1.4 for AUC. Preliminary exposure–response analyses suggested that higher AZD3470 exposure correlated with higher response rates. Median reduction in plasma TARC at first assessment from baseline for responders was 83% (n=5) and 87% (n=6) at 450 and 600 mg QD, respectively. For patients with ctDNA available across all dose levels, pts with CRs showed the greatest decrease from baseline at first disease assessment (log-fold change in hGE/mL: −2.5 CR vs −1.1 PR vs 0.38 PD). On-treatment biopsies were collected to explore resistance mechanisms and potential MTAP re-expression; MTAP deficiency was maintained at progression in 1 patient with CR.

Conclusion: AZD3470 was well tolerated up to 600 mg QD, with no DLTs, discontinuations, or deaths due to AZD3470-related AEs. AZD3470 demonstrated a high response rate in pts with heavily pretreated r/r cHL with a clear dose-dependent increase up to 600 mg, where ORR and CRR were 65% and 45%, respectively. Dose optimization is ongoing, with further results to be reported.