In a comprehensive discussion about the evolving landscape of hematology treatment, Professor Kim Tae-min of the Department of Hemato-Oncology and Medical Oncology at Seoul National University Hospital shared insights into the remarkable progress being made with bispecific antibodies, particularly highlighting the promising developments with AstraZeneca's investigational drug AZD-0486 and other emerging therapies.

"The data for bispecific antibodies has been flooding in," Professor Kim said, emphasizing the particular promise of AZD-0486 in the follicular lymphoma treatment setting. 

The drug, which targets CD20 and CD3 like its predecessor, blinatumomab, has shown extraordinary results.

"In the second-line failure setting, AZD-0486 achieved a complete response (CR) rate of 83 percent - it's unprecedented,” he said. “When odronextamab showed 73 percent, people thought that was incredible, but this goes even further."

CR rates are particularly critical in follicular lymphoma, and these numbers are extraordinary, Kim added, noting that AZD-0486’s fixed-duration treatment design and favorable safety profile have set a new benchmark.

The success of these treatments represents a significant advancement in lymphoma care.

Professor Kim stressed that while mosunetuzumab showed a 60 percent complete response rate and epcoritamab reached 63 percent, the newer therapies are pushing these boundaries even higher. However, he emphasizes that each drug has its distinct characteristics, particularly regarding cytokine release syndrome (CRS) profiles.

Safety remains a top priority in bispecific antibodies development, Kim stressed. Although cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common with T-cell engagers, AZD-0486 has shown promise with manageable toxicity.

"Most CRS cases are Grade 1 or 2 and resolve after the first cycle," he explained. ICANS occurrences have been low-grade and transient. "This is the safest bispecific antibody we’ve seen so far," Kim added.

The development process for these antibodies has become increasingly sophisticated. Professor Kim detailed how AZD-0486's development utilized the NGS-based selection of heavy and light chains, which allowed for the selection of variants with lower cytokine release while maintaining efficacy.

Clinical trials and regulatory approval

A significant development for AZD-0486 in Korea is the approval of first-line phase 3 trials from the Ministry of Food and Drug Safety (MFDS).

"Thanks to the impressive CR rates seen in second-line therapy, MFDS has approved these trials,” Kim said. “We're currently running safety learning phases, and out of nine patients enrolled, three are from our hospital with two more in screening.”

The interview also touched on the evolving treatment paradigms. Professor Kim explains that bispecific antibodies are increasingly moving toward front-line therapy, particularly in follicular lymphoma.

The strategy varies by disease type - while follicular lymphoma is already seeing chemotherapy-free approaches becoming standard, DLBCL (Diffuse Large B-Cell Lymphoma) requires more careful consideration.

Future directions and combination strategies

Looking toward the future, Professor Kim sees multiple promising directions.

"We're now seeing trials combining bispecific antibodies with other targeted therapies,” he said. “For instance, in mantle cell lymphoma, we're exploring combinations with BTK inhibitors.”

The field is also moving toward more sophisticated approaches using both Signal 1 and Signal 2 targeting strategies, he added.

He elaborates on the development of new combination approaches.

"Current bispecific antibodies only utilize Signal 1 for T-cell activation,” he said. “However, we're now seeing early clinical trials of combinations that engage Signal 2 costimulatory molecules, such as 4-1BB ligand”

Some companies are even developing bispecifics that specifically redirect CD8 T-cells, rather than engaging all T-cells, he added.

However, while the development of new drugs is a good sign, addressing the challenges of access and cost still remains an issue in Korea.

Professor Kim acknowledges that these innovative therapies come with significant financial implications.

"As a result, clinical trials become crucial in this context. They're not just about research - they're currently the primary way for patients to access these treatments in Korea," he said. “This is particularly relevant given that many of these treatments, except for Blincyto, are not yet covered by insurance in Korea.”

Regarding the duration of treatment, Professor Kim suggests a balanced approach.

"While some treatments are designed for indefinite use, we might need to consider a hybrid reimbursement system where insurance covers the initial period, with different payment models for extended treatment,” he said. “This is similar to what we see with checkpoint inhibitors, where treatment is typically capped at two years."

Quality of clinical research

Addressing concerns about long-term data collection in Korean clinical trials, Professor Kim strongly defended the quality of research conducted in Korea.

"The perception that Korean sites can't maintain long-term follow-up isn't accurate,” he said. “Modern trials include clear documentation for survival data collection, and companies now specify these requirements from the start.”

Korean sites are actually very successful at maintaining long-term follow-up, he added.

Kim also highlighted the importance of Korea’s involvement in early-stage trials.

"Our center focuses heavily on early-phase trials to lead global developments," he said. The participation of Korean patients and physicians in such trials not only accelerates data collection but also enhances global recognition.

The role of NGS and MRD testing

The discussion turned to the crucial role of next-generation sequencing (NGS) and minimal residual disease (MRD) in hematologic malignancies.

Professor Kim offered insights into the current state of these diagnostic tools in Korea and their importance in treatment decision-making.

"In hematologic malignancies, NGS is more critical for diagnosis than treatment as MRD is essential because it directly guides treatment decisions and helps determine whether we need to proceed with consolidation therapy or restart induction therapy,” he said

Regarding the recent changes in NGS reimbursement policies in Korea, where the out-of-pocket expense for hematologic malignancies has increased, Professor Kim acknowledged the complexity of the situation.

"While it's concerning to see coverage being reduced after it was initially provided, Korea still offers NGS testing at remarkably affordable rates compared to other countries,” Kim said.

He particularly emphasized the importance of checking for MRD in specific conditions.

"MRD monitoring is especially crucial in diseases like CML, ALL, and multiple myeloma, where the detection methodology is highly precise,” he said. “For diseases like CLL where we're dealing with circulating cells, or in cases involving bone marrow, MRD provides valuable insights."

However, Professor Kim notes that lymphoma presents unique challenges.

Lymphoma, despite being classified as a hematologic malignancy, involves lymphoid tissues rather than primarily the blood system. This makes NGS testing more complex compared to other blood cancers.

Looking toward the future, Professor Kim suggests that advanced sequencing technologies might eventually help identify patients who can avoid transplantation.

"This is likely a development for the distant future, but as DNA sequencing technology becomes more sophisticated, we might be able to identify patients who don't require autologous transplantation,” he said.

As the field continues to advance, Professor Kim emphasizes the importance of maintaining a balance between innovation and practicality.

The future of lymphoma treatment appears to be moving toward more targeted, personalized approaches, with bispecific antibodies playing an increasingly central role in treatment strategies.

"The challenge now," Professor Kim concludes, "is not just about developing effective treatments, but making them accessible and sustainable for patients.”

While healthcare professionals now have these incredible new tools, they need to think carefully about how to implement them in ways that benefit the most patients possible, he added.