Editor's Note: The global oncology community continues to focus on cutting-edge breakthroughs in lymphoma treatment. At an important academic conference, Professor Maruyama from Keio University Hospital in Tokyo, Japan, presented the latest research results on the safety and efficacy of the novel CD19xCD3 T-cell engager AZD0486 (brand name: Suvatomib) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This report detailed the clinically significant efficacy and manageable safety demonstrated by Suvatomib in heavily pretreated DLBCL patients, including those previously treated with CD19 chimeric antigen receptor T-cell (CAR-T-cell) therapy, bringing new treatment hope for this high-risk, refractory disease.Challenges in Relapsed/Refractory DLBCL Treatment and the Development Background of Suvatomib
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma in adults. Although first-line chemoimmunotherapy regimens have achieved significant success, 30%-40% of patients still experience relapsed or refractory (R/R) disease. These patients generally have a poor prognosis, limited treatment options, and face severe challenges such as multiple lines of treatment failure, high-risk features, and resistance to existing therapies. Particularly for patients whose disease has progressed after previous CAR-T-cell therapy or other novel therapies, the clinical need is especially urgent. Therefore, developing innovative therapies to overcome existing treatment bottlenecks and improve the long-term survival and quality of life for R/R DLBCL patients is a crucial goal in the current hematologic oncology field. Suvatomib (formerly AZD0486) is a novel therapy developed to address this unmet need. It is an IgG4 fully human CD19xCD3 bispecific T-cell engager, uniquely featuring a CD3 binding domain with reduced affinity, designed to maximally lower the risk of cytokine release syndrome (CRS) while maintaining potent anti-tumor cytotoxicity. This drug works by simultaneously binding to the CD19 antigen on the surface of DLBCL cells and the CD3 receptor on the surface of T-cells, recruiting T-cells to the vicinity of tumor cells, activating T-cells, and mediating tumor cell lysis.
Overview of Suvatomib (AZD0486) Preclinical and Early-Phase Studies
The development of Suvatomib is based on its promising performance in preclinical studies. Data presented at a recent American Society of Hematology (ASH) meeting showed that Suvatomib has demonstrated encouraging safety and efficacy in heavily pretreated follicular lymphoma patients. In the target dose group of 2.5 mg or higher, the overall response rate (ORR) reached 96%, and the complete response (CR) rate was as high as 85%, indicating Suvatomib’s significant potential in B-cell lymphoma treatment. These early positive results laid the foundation for further exploration of Suvatomib in DLBCL, a more aggressive B-cell lymphoma.
Ongoing Phase 1 Study: Design and Patient Characteristics
Professor Maruyama reported the safety and efficacy data of Suvatomib in an ongoing Phase 1 dose-escalation study for R/R DLBCL patients. The study aims to evaluate Suvatomib’s safety, tolerability, pharmacokinetics (PK), and determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), while also assessing anti-tumor activity as a secondary endpoint. The study enrolled eligible adult patients who met the following criteria: relapsed or refractory CD19-positive B-cell lymphoma, previously received two or more lines of therapy, presence of one or more measurable lesions, no active central nervous system (CNS) disease, no leukemic manifestations, and an ECOG performance status of 0-2. Notably, the study allowed the inclusion of patients previously treated with anti-CD19 therapies, CAR-T-cell therapy, and anti-CD20 T-cell engagers, reflecting a study design aimed at exploring Suvatomib’s application in a more complex patient population with fewer treatment options. In the study, patients received fixed-dose intravenous infusions of Suvatomib for two years. The dose escalation strategy was adjusted, evolving from initial fixed-dose or single-step escalation to a subsequent two-step escalation regimen (escalation on Day 1 and Day 8 of Cycle 1, reaching the target dose on Day 15) to optimize tolerability. Target doses ranged from 2.4 mg to 24 mg, administered every two weeks, with a 28-day cycle, and treatment could last up to three years. To ensure patient safety, all cycle doses were administered in an inpatient setting. For patients achieving CR in two consecutive assessments, the dose could be adjusted to every four weeks after Cycle 6. Professor Maruyama’s updated baseline patient characteristics data showed that a total of 86 R/R DLBCL patients received Suvatomib treatment, among whom 66 patients received Suvatomib at target doses of 7.2 mg or higher. The median age of patients was 66 years, and the median number of prior therapy lines was three, with 44% of patients having received four or more lines of therapy. Over 70% of patients were refractory to their last line of treatment. Importantly, 38 patients (over 40%) had previously received CD19 CAR-T-cell therapy, and 11 patients had received CD20 T-cell engagers. These data fully indicate that the enrolled patients generally had high-risk features and were heavily pretreated, further highlighting the challenging and innovative nature of this study.
Key Efficacy Data: ORR, CR, and MRD Negativity Rate
Among 58 evaluable patients who received Suvatomib at target doses of 7.2 mg or higher, the overall response rate (ORR) and complete response (CR) rate showed a trend of increasing with dose. Specifically, in the 24 mg dose group, the ORR reached 75%, and the CR rate reached 63%, demonstrating significant anti-tumor activity. The study further analyzed the impact of CAR-T-cell treatment history on efficacy. Results showed that both ORR and CR rates were higher in CAR-T-naive patients than in CAR-T-exposed patients. Nevertheless, among patients previously treated with CAR-T-cell therapy, 50% of those receiving Suvatomib at a target dose of 25 mg still achieved CR, indicating that Suvatomib also has therapeutic potential for this refractory patient population. The study also assessed plasma minimal residual disease (MRD) negativity rates using Phase 6 testing. Among MRD-evaluable patients with a best overall response of stable disease (SD) or better, Suvatomib achieved early and sustained MRD negativity in many patients in the 7.2 mg or higher target dose group. Purple bars indicate MRD positivity, while blue bars indicate MRD negativity. The vast majority of patients who achieved CR did so very rapidly and achieved MRD negativity almost simultaneously. A total of 20 out of 21 CR patients (95%) achieved MRD negativity. To date, among the 5 patients who received Suvatomib at a target dose of 25 mg, all achieved CR and MRD negativity, and although the sample size is small, this result is encouraging. Among patients who received Suvatomib at target doses of 7.2 mg or higher, the median duration of response (DoR) and median duration of complete response (DoCR) were not reached. With a median follow-up of six months, the estimated 20-month DoR was 77%, and DoCR was 87%. Despite limited follow-up time and a small number of patients, the data appear to show a potential plateau for DoR and DoCR, suggesting durable treatment effects.
Safety Overview: CRS, ICANS, and Other Adverse Event Management
Regarding safety, any grade treatment-emergent adverse events (TEAEs) with an incidence of 50% or higher among all 86 patients treated with Suvatomib (including fixed-dose and single-step escalation regimens) were summarized. Cytokine release syndrome (CRS) occurred in 49% of patients, with all CRS events being Grade 1 or 2; no higher-grade CRS was observed. Infections occurred in 45% of patients, with 13% being Grade 3 or 4. Neutropenia was common, occurring in 34% of patients, with 70% being Grade 4. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) events in the two-step escalation cohort were analyzed in detail. The incidence of any-grade CRS and ICANS was 49% and 20%, respectively. For CRS, all events were Grade 1 or 2, and the median time to first CRS onset and median resolution time were both 1 day. 27% of patients received tocilizumab. 10 patients experienced Grade 1-2 ICANS events, and 4 patients experienced Grade 3 ICANS; these events were transient and reversible. The median time to first ICANS onset and median resolution time were both 1 day, and no seizures were observed. All CRS and ICANS events in the two-step escalation cohort occurred during Cycle 1, with only one CRS event occurring on Day 1 of Cycle 2. These events were transient and did not lead to treatment discontinuation, demonstrating the good controllability of Suvatomib under optimized dosing regimens.
Typical Case Sharing and Potential for Long-Term Benefit
Professor Maruyama shared a typical case. The patient was a 65-year-old male whose DLBCL had transformed from follicular lymphoma, with a disease history spanning over 20 years, and who had received multiple lines of heavy pretreatment. After transformation, the patient showed poor response to previous therapies and had almost no effective treatment options. Subsequently, the patient received Suvatomib at a dose of 7.2 mg. On Day 1 of Cycle 1, the patient experienced Grade 1 CRS and Grade 1 ICANS. CRS resolved on Day 2, and ICANS quickly disappeared within hours, neither leading to treatment discontinuation. This patient achieved CR at the scheduled efficacy analysis during Cycle 3 and remains in continuous CR to date, without significant treatment-related toxicity. This case vividly demonstrates Suvatomib’s potential to achieve deep and durable remissions in heavily pretreated DLBCL patients with poor prognoses, while confirming its manageable safety. In the subsequent Q&A session, Professor Maruyama mentioned that this patient had stopped Suvatomib treatment after two years of CR and is currently in follow-up, with no recurrence observed, further highlighting the potential for long-term treatment-free remission that Suvatomib may offer.
Summary and Future Outlook
Professor Maruyama concluded that Suvatomib, at target doses of 7.2 mg or higher, demonstrated clinically significant efficacy, durable complete remissions, and manageable safety in R/R DLBCL patients, including those previously treated with CD19 CAR-T-cell therapy. Doses up to 24 mg have been evaluated, and the maximum tolerated dose has not been reached, providing room for further dose exploration in the future. DLBCL patient enrollment is ongoing, and combination therapy studies of Suvatomib are also actively underway. Looking ahead, Professor Maruyama noted that while there is currently no MRD-guided treatment discontinuation strategy, given Suvatomib’s ability to rapidly achieve MRD negativity, an MRD-guided treatment discontinuation strategy is expected to become a reasonable and feasible future treatment direction. These research findings not only bring new hope for R/R DLBCL patients but also provide important data for the development of T-cell engagers in the field of lymphoma treatment. The successful development and initial clinical validation of Suvatomib underscore the tremendous potential of innovative immunotherapies in overcoming challenges in cancer treatment, contributing Chinese wisdom and global cooperation to the long-term survival and improved quality of life for lymphoma patients worldwide. Submitted by / Interview source: Oncology Outlook – Oncology News
