‘As bispecific antibodies change DLBCL treatment paradigm, Epkinly draws attention’

Diffuse large B-cell lymphoma (DLBCL), a malignant transformation of B-lymphocytes, the key cells of the immune system, is a blood cancer with a rapidly growing number of patients in Korea. In 2023, over 14,000 patients struggled with the disease, more than double the number from a decade ago.

DLBCL is the most common subtype of non-Hodgkin's lymphoma, accounting for 40 percent of cases, and can occur anywhere in the body, making early detection and appropriate treatment crucial. However, even with the current first-line standard of care, R-CHOP combination chemotherapy, 30-40 percent of patients experience relapses, and the prognosis for patients who relapse after second-line autologous stem cell transplantation (ASCT) is known to be even worse.

CAR-T cell therapy can be considered a third-line treatment. Still, the manufacturing process takes considerable time, and the treatment effect may be limited in some patients, so additional treatment alternatives are needed. The newly introduced bispecific antibody Epkinly (epcoritamab) is attracting attention in this situation.

Epkinly is a bispecific antibody that simultaneously acts on CD20 of B cells and CD3 of T cells. It can be administered through subcutaneous injection within one minute and was approved by the Ministry of Food and Drug Safety in June for treating adult patients with DLBCL who have relapsed or refractory after two or more systemic treatments.

Korea Biomedical Review spoke to Professor Lorenzo Falchi, M.D., a lymphoma specialist in the Department of Hematologic Malignancies and Medical Oncology at the Memorial Sloan Kettering Cancer Center in New York City, to discuss the latest treatment trends in DLBCL and the clinical significance of Epkinly.

Professor Falchi is an active researcher and a member of several leading societies, including the American Society of Hematology, the American Society of Clinical Oncology, the American Association for Cancer Research, and the Society for Cancer Immunotherapy.

Question: Would you explain what DLBCL is? What are its characteristics compared to other lymphomas?

Answer: DLBCL is a lymphoma caused by the malignant transformation of B-lymphocytes, one of the immune cells in the blood. More than 100 types of lymphomas have been identified, with DLBCL being the most common. DLBCL accounts for more than one-third of all lymphomas worldwide. While most lymphomas are slow-growing, DLBCL is aggressive, with rapidly growing cancer cells that require immediate treatment.

Although DLBCL is an aggressive cancer, it can be cured with chemotherapy and immunotherapy. Vesicular lymphoma or extranodal cell lymphoma, on the other hand, aims to achieve a state of remission where no cancer cells or lesions are visible. These differences affect treatment approaches and how patients are counseled.

Q: What is the current global treatment strategy for DLBCL?

A: First-line treatment for patients with DLBCL usually combines chemotherapy and immunotherapy. Currently approved treatments include R-CHOP regimens, or R-CHP plus polatuzumab, a combination of R-CHP plus the recently approved polatuzumab vedotin (Polivy in trademark name). The overall cure rate for patients is around 60-65 percent. However, specific cure rates may vary by country, depending on patient-specific factors, such as age, comorbidities, and the International Prognostic Index (IPI).

CAR-T therapy is indicated in settings where it is approved and available for second-line treatment of early relapses after first-line treatment. However, in areas where CAR-T treatment is not yet available, other types of chemotherapy may be used in addition to first-line chemotherapy or a combination of high-dose chemotherapy and autologous stem cell transplantation. These treatment approaches can cure some patients in the second line. However, the cure rate drops significantly if the disease relapses after second-line treatment and requires a third or subsequent treatment.

Q: New DLBCL treatments have emerged in recent years. Could you explain the latest trends?

A: New drugs for DLBCL are primarily being developed for third-line and beyond. This is because the unmet need is greatest in the third-line setting, and there is an urgent need for effective treatments. For example, polatuzumab vedotin has emerged as a treatment regimen that can be used in combination with bendamustine and rituximab. While it was originally developed for third-line use, it is now being expanded to include frontline use.

Tafacitumab (Minjuvi in trademark name) is an antibody that targets CD19 and is not highly active alone but is known to increase activity when combined with lenalidomide. It is particularly active in patients who have failed chemotherapy.

There is also an antibody-drug conjugate (ADC) called loncastuximab tesirine, which has not yet been introduced in Korea. It combines an antibody with chemotherapy and has similar properties to polatuzumab vedotin. This agent is primarily used in third-line or later treatment. An oral treatment is selinexor (Xpovio in trademark name), but the efficacy data are weaker than other agents. Bispecific antibodies emerge in this context.

Q: What is the role and significance of bispecific antibodies in hematologic tumors?

A: Bispecific antibodies are expected to be a breakthrough in treating DLBCL. The existing drugs have limited long-term remission or response maintenance, and the median progression-free survival (mPFS) in clinical practice is often short.

Bispecific antibodies are expected to be the third milestone in treating lymphoma. If the first was rituximab and the second was CAR-T, bispecific antibodies are expected to be the third innovation that could change the current treatment paradigm.

Bispecific antibodies have two different epitopes. One binds to the CD20 antigen expressed on tumor cells and the other to the CD3 antigen on immune cells, T cells, bringing the two cells into physical proximity. It's like two arms pulling the two cells close together. This allows the T cells to get close to the lymphoma cells and destroy them cytotoxically.

They are only active when the target cell is present, and their activity naturally decreases when the target is absent. Adverse events are usually seen in the early stages when there are many targets and activity is high and decreases as targets are lost.

Q: What are the currently licensed bispecific antibody therapies?

A: Currently, there are four bispecific antibody therapies licensed for treating B-cell lymphoma -- epcoritamab (Epkinly), glofitamab (Columvi), mosunetuzumab (Lunsumio), and odronextamab (Ordspono). Epkinly and glofitamab have been approved in Korea for treating third-line or higher. Epkinly is a subcutaneous agent that binds to CD20 and CD3 in a 1:1 ratio, while glofitamab is an intravenous agent with a 2:1 ratio.

Q: What are bispecific antibodies' technical differences and therapeutic benefits compared to CAR-T?

A: CAR-T is a cell-based therapy in which a patient's T cells are extracted and engineered. The receptors outside the cells are designed to bind to the CD19 antigen, persist in the body for months to years, and exhibit serial killing properties. The three drugs approved for DLBCL – lisocaptagene maraleucel (Liso-cel with trademark name of Breyanzi), axicabtagene ciloleucel (Axi-cel, Yescarta), and tisagenlecleucel (Tisa-cel, Kymriah) -- were quickly approved due to high overall response and complete response rates. Notably, lisocaptagene maraleucel and axicabtagene ciloleucel have become second-line treatments because of their superiority over chemotherapy and autologous stem cell transplantation.

CAR-T therapy and bispecific antibodies differ significantly in how the treatment is administered. The process of CAR-T therapy is quite complex. It depends not only on the patient's disease characteristics but also on the treatment infrastructure and cost. It can take weeks to months to harvest a patient's T cells from leukapheresis, send them to a manufacturer, engineer them, and then administer them to the patient. Bispecific antibodies, conversely, are “off-the-shelf” therapies that are ready to use as soon as the decision to administer them is made.

The important question is not which of these two classes is better but how to sequence them. For example, bispecific antibody therapies may be the next best option for patients who first tried and failed CAR-T, as they offer a better chance of achieving a CR.

Q: In June, Epkinly was approved for DLBCL in Korea. What are its efficacy and safety as seen in clinical trials?

A: One hundred and fifty-seven patients were enrolled in the dose-finding study (EPCORE NHL-1), and the median number of prior therapies was about three. About one-third of the patients had received prior CAR-T therapy and were refractory. The study showed an overall response rate (ORR) of 61.9 percent and a complete response (CR) of 40.1 percent, similar to those experienced with CAR-T therapy.

The safety profiles of tisagenlecleucel and the two bispecific antibodies licensed in Korea are similar. The main adverse event was cytokine release syndrome (CRS) due to immune cell activation. Immune cell-associated neurotoxicity syndrome (ICANS) can also occur, but the incidence is significantly lower with Epkinly and glofitamab compared to CAR-T therapy.

Q: There is much experience prescribing Epkynly in the U.S. Are the clinical results consistent in real-world practice?

A: Epkinly is a potent yet easy-to-use treatment that is effective in RCT studies and real-world practice. It is administered subcutaneously and is rated as one of the most potent bispecific antibodies in in-vitro studies.

A “step-up process” is applied in the first cycle to manage adverse events in clinical practice. The initial and intermediate doses are set low, and the final target dose is used in the third dose. At this point, most clinicians will keep patients under hospital observation for 24-48 hours. CRS occurs in about half of patients but is mostly grade 1, with grade 2 rare and no grade 3 or higher reported. This adverse event profile suggests the potential for outpatient administration.

However, it is too early to answer whether RCT studies are reproducible in real-world practice. Real-world patient numbers are limited, follow-up periods are short, and study exclusion criteria differentiate real-world and study patient populations. The study excluded bone marrow or organ transplant patients, dialysis patients, patients with renal or hepatic impairment, and patients with CNS issues, resulting in less than 50 percent overlap with the real-world patient population. While Epkinly is showing positive signs in real-world practice, more data is needed to confirm the consistency of the findings.

Q: What are the benefits and advantages of Epkinly for Korean patients?

A: It is important to remember that bispecific antibodies are life-saving treatments in the third-line setting. Many patients who would otherwise have succumbed to lymphoma have survived thanks to this powerful treatment. Bispecific antibodies have an incomparably superior therapeutic effect compared to other single agents except for CAR-T therapy. Many of my colleagues in Korea hope that we can safely incorporate this agent into our practice and make it available to all deemed appropriate patients.

Q: Do you have a message for the Korean medical community, patients, and government regarding DLBCL treatment?

A: I would like to offer a message of hope to patients who are undergoing difficult treatment for DLBCL. While the follow-up period is still short, many patients prescribed Epkinly are expected to be DLBCL-free for quite some time. I would also like to encourage Korean patients to be hopeful, as Epkinly has been approved in Korea.

I would like to make two suggestions to Korean medical professionals: First, please take the time to gradually familiarize yourself with the bispecific antibody by working with a medical team that has experience with it. A multidisciplinary approach is essential with hematology-oncology and nurses, pharmacists, ward teams, emergency departments, intensive care units, neurology, etc. Second, spend time educating patients and their caregivers. Patient and caregiver understanding is essential for rapid recognition and response to adverse events, and close monitoring is critical, especially during the initial dosing cycle.

Governments and regulatory authorities are more important than ever in bringing the latest cancer treatments to patients. They understand that therapies like Epkinly are life-saving treatments for patients at a critical point in their cancer journey. Balancing financial sustainability with patient benefit is not easy, but we expect them to make decisions that prioritize the health and well-being of their patients.