Editor's Note: In the field of relapsed/refractory classical Hodgkin lymphoma (R/R cHL), although the application of immune checkpoint inhibitors (such as anti-PD-1) and antibody-drug conjugates (such as Brentuximab Vedotin, BV) has significantly improved patient prognosis, clinical challenges remain severe for patients who fail multiple lines of therapy. Recently, at an international academic conference, Professor Enrico Derenzini, on behalf of the PRIMAVERA research team, shared the Phase I study results of the PRMT5 inhibitor AZD3470 in patients with R/R cHL. This journal has summarized the key points of the meeting to provide a deep analysis of this innovative therapy targeting MTAP deficiency and utilizing the "synthetic lethality" mechanism, representing a latest breakthrough in the field of hematologic malignancies.Text Interpretation: Mode B Academic Deep Dive
01 Clinical Pain Points and Mechanistic Innovation: Highly Prevalent MTAP Deficiency in cHL
The treatment of classical Hodgkin lymphoma (cHL) has made great strides over the past decade. However, for patients who progress again after Brentuximab Vedotin (BV) and anti-PD-1 therapy, current standard of care (SOC) options are extremely limited, and there is an urgent need to extend median survival. Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic regulatory enzyme that regulates cell growth and survival by performing symmetric dimethylation modifications on histones and non-histone proteins. Methylthioadenosine phosphorylase (MTAP) is a metabolic enzyme in the methionine salvage pathway. In approximately 15% of solid tumors, the MTAP gene and the tumor suppressor gene CDKN2A are frequently co-deleted due to their proximity on chromosome 9p21. However, Professor Enrico Derenzini pointed out that in cHL, the rate of MTAP protein loss is as high as 80%. Its mechanism differs from the gene deletion seen in solid tumors; it is primarily driven by epigenetic silencing due to high methylation of the MTAP promoter. The loss of MTAP leads to the intracellular accumulation of its substrate, methylthioadenosine (MTA), which is a natural allosteric inhibitor of PRMT5. This partial inhibition at baseline makes MTAP-deficient tumor cells highly sensitive to pharmacological PRMT5 inhibitors, a phenomenon known as the “synthetic lethality” effect. AZD3470, as an MTA-cooperative second-generation PRMT5 inhibitor, was designed to utilize this mechanism to precisely kill MTAP-deficient tumors.
02 PRIMAVERA Study Design: Dose Exploration for Heavily Pretreated Populations
PRIMAVERA is a modular, multi-center, open-label Phase I/II dose-escalation and expansion study aimed at evaluating the safety, tolerability, and preliminary efficacy of AZD3470 monotherapy in patients with R/R cHL. • Inclusion Criteria: o Age ≥18 years; o Histologically confirmed relapsed/refractory classical Hodgkin lymphoma; o ECOG performance status of 0 or 1; o Previously received at least 3 lines of systemic therapy, which must include Brentuximab Vedotin and anti-PD-1 therapy. • Administration: AZD3470 administered orally once daily (QD). • Study Process: Part A is the dose-escalation phase, exploring 7 dose levels (up to 600 mg/day); Part B is the currently ongoing dose expansion and optimization phase. • Study Endpoints: Primary endpoints are safety, tolerability, dose-limiting toxicity (DLT), and recommended Phase II dose (RP2D); secondary endpoints include objective response rate (ORR), complete response rate (CR), progression-free survival (PFS), and overall survival (OS).
03 Patient Baseline Characteristics: Challenging the Limits of “Clinical Refractoriness”
As of February 23, 2026 (data cutoff date), a total of 68 patients received AZD3470 treatment. The baseline characteristics of the patient population demonstrated extreme clinical difficulty. • Median Age: 45 years. • Disease Stage: The vast majority of patients were in the progressive stage. • Previous Lines of Treatment: Median of 6 lines, with more than 20% of patients having received 10 or more prior lines of therapy. • Prior Therapy Coverage: More than 40% of patients had previously received autologous stem cell transplantation (ASCT); 100% of patients met the inclusion requirement of having received anti-PD-1 and BV therapy. • Biomarker Status: Among the 33 patients whose MTAP status was evaluated, 32 (97%) were confirmed to have MTAP deficiency (detected via immunohistochemistry IHC), validating the biological characteristic of prevalent MTAP loss in cHL.
04 Safety and Tolerability: Favorable Therapeutic Window and Manageable Toxicity
In explorations up to the highest dose of 600 mg QD, AZD3470 demonstrated satisfactory safety. • DLT and Dose Reduction: No dose-limiting toxicities (DLTs) were observed in the study. Only 3% of patients required dose adjustments or interruptions due to treatment-related adverse events; no treatment discontinuations or deaths occurred due to treatment-emergent adverse events (TEAEs). • Treatment Exposure: Median exposure time was 13 weeks, with 51% of patients still receiving treatment at the data cutoff. • Common Adverse Events (TEAEs): o Anemia: The most common treatment-related AE, occurring in 20% of patients, with Grade 3 or higher anemia accounting for only 7%, suggesting that overall hematologic toxicity is manageable. o Fatigue: Incidence was 21%. o Decreased Appetite/Dysgeusia: Incidence was approximately 15%. o Overall, the toxicity profile of AZD3470 was primarily characterized by low-grade non-hematologic toxicity and manageable hematologic toxicity, which is particularly important for multi-line pretreated cHL patients whose bone marrow reserve function may be compromised.
05 Clinical Activity Data: High Response Rates Ignite Treatment Hope
Regarding efficacy evaluation, AZD3470 demonstrated encouraging dose-dependent clinical activity in heavily pretreated cHL patients. • Overall Efficacy: Among 59 evaluable patients, preliminary efficacy data showed a positive trend. • High-Dose Group Performance: In the two high-dose groups (450 mg and 600 mg, totaling 31 patients), the objective response rate (ORR) reached 58%, and the complete response (CR) rate reached 35%. • Case Presentation: Professor Derenzini presented three typical cases in the report. One patient, who had failed 11 prior lines of treatment, showed a significant reduction in tumor burden (70%-100% reduction) via PET/CT after 3 cycles of AZD3470, achieving a complete response (CR). • Durability of Response: According to the Swimmers Plot, although the follow-up time is still short (median follow-up is ongoing), most patients in the high-dose group who achieved a response maintained it and remained on treatment at the data cutoff.
06 Conclusion and Outlook: Opening a New Chapter for PRMT5 Inhibitors in Hematologic Malignancies
The PRIMAVERA study is the world’s first clinical trial to evaluate a PRMT5 inhibitor in classical Hodgkin lymphoma. Based on current Phase I data, the following conclusions can be drawn:
- Mechanism Successfully Validated: The prevalent MTAP protein deficiency in cHL provides an excellent targeting opportunity for PRMT5 inhibitors. Clinical data preliminarily confirms the effectiveness of this “synthetic lethality” strategy.
- Strong Efficacy: In extremely refractory patients who failed multiple lines of therapy (including BV and PD-1 inhibitors), AZD3470 achieved an ORR of nearly 60% and a CR rate exceeding 30%, with an impressive depth of response.
- Superior Safety: No DLTs were reached at doses up to 600 mg QD, and the incidence of Grade 3 or higher toxicity was extremely low, providing the possibility for future combination therapies or maintenance treatment.
Future Directions: Professor Enrico Derenzini emphasized that further dose optimization and expansion studies are actively progressing. Due to the unique safety profile and precision-strike capability against specific metabolic defects, AZD3470’s exploration in frontline cHL treatment, combination with other immunotherapies or targeted drugs, and its application in other MTAP-deficient hematologic malignancies hold high academic value and clinical significance.
