On 30 May at the American Society of Clinical Oncology (ASCO) 2026 Annual Meeting, AstraZeneca released the first safety and efficacy data of AZD-3470, in its Phase I PRIMAVERA (NCT06137144) study for relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL).
AZD-3470 is an inhibitor of protein arginine methyltransferase 5 (PRMT5), which becomes upregulated upon epigenetic silencing of methylthioadenosine phosphorylase (MTAP), observed in more than 80% of cHL patients. The presented data focuses on the trial’s first dose-escalation cohort comprising 39 R/R cHL patients, ages 18 and over, heavily pretreated with a median of six prior lines of therapy (including standard of care agents, brentuximab vedotin and anti-PD1s). Patients received AZD-3470 as a monotherapy at ascending doses (25mg to 600mg), until either severe treatment-emergent adverse events (TEAE) or dose- limiting toxicity arose.
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By the time of the report, the median duration of exposure of 15 weeks and TEAEs were experienced by 85% of patients, most commonly anaemia (28%) and nausea (15%). These were mostly mild, and events grade 3 or higher were experienced in 28% of patients, most commonly neutropenia and hypokalemia (two patients each). No dose-limiting toxicity (DLT), treatment discontinuations, nor deaths due to TEAEs were reported, indicative of an acceptable safety profile up to the maximum tested dose; by the time the study concluded, 51% of patients were still receiving treatment.
Encouragingly, positive efficacy was indicated in patients treated with ≥450mg of the drug (N=31), with an objective response rate (ORR) of 58%, and complete response (CR) of 35%. This rose to an ORR of 63% and a CR of 44% in patients receiving the 600mg dose (N=16). Secondary outcomes, including longer term efficacy data like progression-free survival, durability of response, and overall survival, will take longer to emerge, and the trial will remain ongoing as it recruits at scale to include 161 patients across 29 reported sites globally. High ORRs with favourable safety in these populations are comparable to trials with anti-PD1 agents as monotherapy to similarly heavily pre-treated cHL patients, including Merck & Co’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s (BMS) Opdivo (nivolumab), which achieved OR rates of 71.4% (Keynote-087) and 69% (Checkmate-205), respectively. Having a clinically meaningful response to treatment in R/R cHL patients resistant to all existing options is a significant step forward, particularly for an indication that hasn’t had a new first-in-class drug enter the market since PD-1s emerged in 2016, and further dose optimisation and cohort expansion are planned to improve these further.
These results are the latest affirmation of enthusiasm in PRMT5 inhibitors as an emerging drug class, as MTAP deficiency has been observed across 15% of solid tumours, and epigenetic silencing is observed in haematological cancers. Major pharma companies, including BMS, Tango Therapeutics, Johnson & Johnson, and Bayer, are all developing assets in the space.
BMS’s navlimetostat and Tango Therapeutics’s vopimetostat are the current frontrunners for treating solid tumours, already holding FDA fast-track designations and favourable Phase I safety data, comparable to that seen in the PRIMAVERA trial. If successfully launched, GlobalData’s analyst consensus forecast suggests the PRMT5 inhibitor market may reach $1.2 billion globally by 2031. AstraZeneca has also launched a Phase I/II trial, PRIMROSE (NCT06130553), with AZD-3470 to treat solid tumours, but as competition is increasing in this space, its current position as the first company to trial PRMT5 inhibition for haematological malignancies may be a powerful safeguard to allow its PRMT5 inhibitor to differentiate in this emerging market. This market will remain speculative until registrational trial data emerges, but this will be an interesting race as major players compete to differentiate their assets across the oncology sector.
