ASCO26: AstraZeneca’s AZD-3470 Demonstrates PRMT5 Inhibitor Safety for cHL Patients

AstraZeneca's AZD-3470 Shows Promising Safety and Efficacy in cHL

AstraZeneca presented initial safety and efficacy data for AZD-3470, a PRMT5 inhibitor, in its Phase I PRIMAVERA study (NCT06137144) for relapsed/refractory classical Hodgkin Lymphoma (cHL) at the ASCO 2026 Annual Meeting. The dose-escalation cohort of 39 heavily pretreated patients showed an acceptable safety profile with no dose-limiting toxicities or treatment discontinuations. Encouraging efficacy was observed in patients receiving ≥450mg, with an objective response rate (ORR) of 58% and a complete response (CR) of 35%. For the 600mg dose, ORR rose to 63% and CR to 44%, comparable to existing anti-PD1 agents.

• The Phase I PRIMAVERA study demonstrated an acceptable safety profile for AZD-3470 in relapsed/refractory cHL patients. Among 39 heavily pretreated patients, 85% experienced treatment-emergent adverse events (TEAEs), mostly mild, with anaemia (28%) and nausea (15%) being the most common. Grade 3 or higher events occurred in 28% of patients, primarily neutropenia and hypokalemia. Crucially, no dose-limiting toxicities, treatment discontinuations, or deaths due to TEAEs were reported, even up to the maximum tested dose of 600mg.
• AZD-3470 showed promising efficacy, particularly at higher doses, in a challenging patient population. In patients treated with ≥450mg (N=31), the objective response rate (ORR) was 58%, with a complete response (CR) of 35%. This improved further in the 600mg dose group (N=16), achieving an ORR of 63% and a CR of 44%. These response rates are considered clinically meaningful for patients resistant to existing options and are comparable to those seen with anti-PD1 monotherapies like Keytruda and Opdivo in similar patient populations.
• AstraZeneca's AZD-3470 is strategically positioned as the first PRMT5 inhibitor to be trialed for haematological malignancies, potentially differentiating it in an emerging market. While other major pharma companies are developing PRMT5 inhibitors for solid tumours, AstraZeneca's focus on cHL could provide a competitive advantage. The PRMT5 inhibitor market is projected to reach $1.2 billion globally by 2031, highlighting the significant commercial potential for this new drug class, especially given the unmet need in cHL since PD-1s emerged in 2016.

Addressing Unmet Needs in Relapsed/Refractory cHL

Recent research has identified several critical unmet needs and target populations in classical Hodgkin lymphoma (cHL), reflecting the evolving treatment landscape and persistent challenges despite advances in therapy. These efforts focus on addressing gaps in care for specific patient subgroups and optimizing treatment approaches to balance efficacy with long-term safety.

• Patients with poor performance status and organ impairment represent a particularly challenging population, especially those with gray zone lymphoma where optimal first-line treatment remains undefined, with brentuximab vedotin showing promise as bridge therapy in cases of severe liver impairment

• Advanced-stage disease management continues to require optimization of the risk-to-benefit ratio, as demonstrated by the BrECADD regimen which achieved superior outcomes with significantly lower treatment-related morbidity (42% vs 59%) compared to eBEACOPP while maintaining excellent 4-year progression-free survival (94.3%)

• Toxicity reduction strategies remain a priority given that combination chemotherapy and radiotherapy continue as treatment cornerstones with significant short- and long-term side effects, including increased risk of secondary cancers, particularly breast cancer emerging as a leading cause of mortality decades after therapy

• Refractory disease populations benefit from novel immunotherapeutic approaches, with anti-PD-1 antibodies (nivolumab and pembrolizumab) demonstrating success by restoring immune system recognition of cancer cells through checkpoint pathway modulation

• Young populations in specific geographic regions show distinct epidemiological patterns, particularly in Saudi Arabia where the median age at diagnosis (20-30 years) is lower than other nations, with concerning annual percentage changes of 2.94% for males and 3.67% for females

• EBV-positive lymphomas represent a treatment-resistant subset exhibiting poorer responses and worse survival compared to EBV-negative counterparts, with targeted approaches like Withaferin A showing selective cytotoxicity through EBNA1 degradation

• Resource-limited settings require adaptation of response-guided therapy protocols, with studies in Kurdistan Region and Vietnam supporting broader integration of interim PET/CT-based strategies in Southeast Asian populations where region-specific data remains limited

AZD-3470's Promising Safety and Efficacy in PRIMAVERA

The AHOD2131 trial represents a significant advancement in pediatric Hodgkin lymphoma care through the Children's Oncology Group's implementation of real-time central review protocols for PET scans, target volumes, and radiation therapy plans. This frontline therapy approach incorporates both involved-site radiation therapy (ISRT) and PET-directed residual-site radiation therapy (pRSRT) with rigorous quality assurance measures. Early experience demonstrates the critical value of this systematic approach in identifying protocol deviations and enabling timely corrections before treatment initiation, with common correctable errors including omission of initially involved disease sites and over-generous target volume contouring.

Recent efficacy data from Harbor-UCLA Medical Center's 15-year retrospective cohort (2009-2024) of 69 adult patients receiving first-line ABVD demonstrated robust clinical outcomes with a complete response rate of 78.3% and overall response rate of 82.6%. Long-term survival metrics showed five-year progression-free survival of 70.7% across all stages and five-year overall survival of 95.4%, with notably superior outcomes in early-stage disease (100% five-year overall survival for stages I-II versus 91.5% for stages III-IV). However, safety concerns emerged with bleomycin-associated lung toxicity occurring in 14.5% of patients, including one treatment-related death, reinforcing the rationale for bleomycin-sparing regimens.

The therapeutic landscape has evolved significantly with nivolumab-AVD emerging as the preferred frontline regimen for advanced-stage disease, delivering high cure rates with minimal toxicity across age groups. Nordic registry data spanning 1,569 older patients (≥60 years) from 2000-2021 demonstrated that AVD without bleomycin achieved superior overall survival and progression-free survival compared to standard ABVD, while maintaining comparable efficacy to CHOP-based regimens but with improved tolerability profiles. This growing evidence base supports the transition toward less toxic, equally effective treatment paradigms in classical Hodgkin lymphoma management.

AZD-3470: A New Horizon for PRMT5 Inhibition in cHL

The recent presentation of initial Phase I data for AstraZeneca's AZD-3470 in relapsed/refractory classical Hodgkin Lymphoma (cHL) offers a compelling glimpse into the potential of PRMT5 inhibition in a specific hematologic malignancy. For years, the PRMT5 inhibitor class has faced challenges, with agents like JNJ-64619178, PRT543, and GSK3326595 showing limited broad efficacy in solid tumors and myelodysplastic syndromes, often with responses confined to rare indications like adenoid cystic carcinoma. This context makes AZD-3470's reported objective response rates of up to 63% and complete response rates of up to 44% in heavily pretreated cHL patients particularly noteworthy.

These early efficacy signals, described as comparable to existing anti-PD1 agents, suggest AZD-3470 could carve out a significant role in the cHL treatment paradigm. This positions AstraZeneca to potentially establish a novel mechanism of action in a disease where new options are always sought, especially for patients who have exhausted standard therapies. However, the path forward is not without its considerations:

• While initial safety appears acceptable, the class-wide propensity for hematologic toxicities, notably thrombocytopenia and anemia, will require close monitoring in subsequent trials. Previous PRMT5 inhibitors have identified these as dose-limiting toxicities, and their emergence could impact the optimal dosing strategy for AZD-3470.

• The impressive response rates observed in this heavily pretreated Phase I cohort need to be validated in larger, later-phase studies across a broader spectrum of cHL patients to confirm durability and generalizability.

• The broader PRMT5 inhibitor landscape has struggled with identifying clear biomarkers to predict patient responsiveness. Developing such biomarkers for AZD-3470 in cHL will be crucial for optimizing patient selection and maximizing clinical benefit, ensuring the drug reaches those most likely to respond.

Should these early positive trends hold, AZD-3470 could represent a significant advancement, offering a new therapeutic avenue for cHL patients and providing a much-needed success story for the PRMT5 inhibitor class in a well-defined indication. Further clinical development will be critical to fully understand its long-term safety, efficacy, and precise positioning within the evolving cHL treatment landscape.