‘Broader access to CAR-T cell therapy needed for DLBCL’

Yescarta builds improved survival evidence in second-line treatment through clinical studies

“For relapse/refractory patients within 12 months after first-line therapy, shifting treatment strategy is crucial”

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive hematologic malignancy in which a significant number of patients achieve a cure with first-line therapy, but prognosis worsens sharply once relapse or treatment resistance occurs.

In particular, patients who relapse or become refractory within 12 months after first-line therapy often struggle to achieve meaningful outcomes with conventional high-dose chemotherapy followed by autologous stem cell transplantation alone. Experts therefore stress the importance of shifting treatment strategies at an earlier stage.

Against this backdrop, Gilead’s CAR-T therapy Yescarta (axicabtagene ciloleucel) is emerging as a new alternative based on clinical evidence accumulated in second- and third-line treatment settings.

Professor Yun-seok Choi of Seoul St. Mary’s Hospital and Tony Li, Executive Director and Head of Medical Affairs at Kite International Region (Gilead’s oncology subsidiary), emphasized in a recent meeting with Dailypharm, “For DLBCL, the time to relapse and the number of treatment lines directly correlate with prognosis. This is why we must actively consider introducing CAR-T cell therapy at the second-line treatment stage.”

Tony Li, Head of Medical Affairs at Kite International Region; Yun-seok Choi, Professor of Hematology-Oncology at Seoul St. Mary’s Hospital

DLBCL is the most common subtype of aggressive non-Hodgkin lymphoma. Despite the standard first-line therapy R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone), a substantial number of patients either relapse or become refractory to treatment.

The problem is that after just one relapse, treatment response rates and survival prospects decline rapidly. High-dose chemotherapy and autologous hematopoietic stem cell transplantation, which have been the mainstay second-line therapy, require stringent patient selection and still carry a considerable risk of relapse even after treatment.

In Korea, Yescarta was approved in August last year for DLBCL and primary mediastinal B-cell lymphoma (PMBCL), and its reimbursement criteria were established in January for third-line treatment by the Cancer Disease Deliberation Committee. However, reimbursement criteria for second-line use in patients who relapse or become refractory within 12 months of first-line therapy have not yet been established.

Experts highlight unmet needs in the DLBCL treatment landscape, emphasizing the clinical value of Yescarta and the need for earlier CAR-T introduction in the second-line setting.

Q. What are the practical difficulties or limitations of conventional treatments for DLBCL patients who relapse or become refractory after first-line therapy?

[Professor Choi] Traditional second-line therapy consists of high-dose chemotherapy followed by autologous stem cell transplantation. However, this approach can only be applied to patients who meet certain conditions, such as being relatively young and having good overall health. Furthermore, relapsed DLBCL is often biologically aggressive, making treatment challenging.

[Executive Director Tony Li] Standard first-line regimens like R-CHOP are highly effective, with about 70% of patients achieving a cure. However, treatment becomes increasingly difficult for patients with relapsed or refractory disease. Cure rates inevitably decline with each subsequent treatment line.

Stem cell transplantation requires high-dose chemotherapy before the transplant, meaning patients must be in excellent physical condition to endure the entire process. They must be able to withstand the process of receiving anticancer treatment, responding to it, and then undergoing the transplant. Even among patients who successfully undergo transplantation, about 50% eventually relapse, and the prognosis for these patients is not optimistic.

Q. In some countries, CAR-T or bispecific antibodies are reimbursed as second-line therapy. What clinical value does Yescarta have in real-world practice?

Tony Li

[Executive Director Tony Li] Yescarta has been approved in more than 20 countries and is recommended as a Category 1 option for second-line treatment of DLBCL in the National Comprehensive Cancer Network (NCCN) guidelines. This demonstrates that Yescarta has established itself as an evidence-based treatment option in the global clinical setting.

Yescarta’s efficacy as a second-line therapy was demonstrated in the ZUMA-7 clinical trial. In this prospective controlled trial comparing Yescarta with standard stem cell transplantation therapy, Yescarta achieved results surpassing the existing standard therapy for the first time in 25 years. The median event-free survival (EFS), the primary endpoint, was 8.3 months in the Yescarta group, representing a significant improvement of approximately four times compared to the 2 months observed in the transplant group.

It is also the first and only currently available CAR-T therapy to demonstrate statistically significant overall survival (OS) in a second-line setting.

The drug also has accumulated meaningful long-term data. ZUMA-7 has accumulated nearly four years of follow-up data, showing a flattening of the OS curve. In the third-line setting, the 5-year follow-up results from ZUMA-1 confirmed that approximately 43% of patients survived, suggesting the potential for long-term survival.

[Professor Choi] DLBCL is a disease with a high likelihood of death if the condition is not adequately controlled in the first line. This is the natural course of DLBCL observed in clinical practice.

Even when high-dose chemotherapy followed by autologous stem cell transplantation is performed, the success rate is about 50%, meaning the number of patients rescued by this treatment is limited. In ZUMA-7, the OS curve for the standard-treatment group did not reach a complete plateau.

In this context, Yescarta demonstrated statistically significant survival benefits compared to standard treatment, reducing the risk of death. Particularly significant is that CAR-T therapy has, for the first time in the history of DLBCL salvage therapy, presented survival data in a patient population with high mortality risk.

Furthermore, the 5-year follow-up analysis of ZUMA-1 reported a 5-year OS estimate of 42.6% for patients treated with Yescarta. This suggests that approximately 4 out of 10 patients can expect long-term survival. Additionally, the fact that Yescarta demonstrated a survival benefit in the second-line setting in the ZUMA-7 study is also significant.

Q. In January, reimbursement criteria for third-line Yescarta were established. How might this change third-line treatment strategies?

[Professor Choi] Comparing the OS curves, Yescarta's data shows a relatively higher position compared to Kymriah (tisagenlecleucel). Although this was not confirmed through a direct head-to-head trial, many clinicians believe Yescarta may have stronger anti-lymphoma activity, not only in DLBCL but also in follicular lymphoma. This perception could influence drug selection decisions to some extent going forward.

Another factor is that Yescarta transports cells to manufacturing facilities without freezing them, which reduces certain regulatory burdens associated with human cell handling permits (such as GMP) required for some CAR-T therapies, potentially enhancing accessibility from the healthcare provider's perspective. This characteristic could also influence future drug selection and market share to some extent.

Q. I understand that some countries overseas have approved Yescarta’s reimbursement as a second-line treatment. What are the benefits of using Yescarta in second-line therapy?

[Executive Director Tony Lee] In the A8 countries referenced by Korea for drug pricing, Yescarta is reimbursed for both second- and third-line treatments. Clinical study results have consistently shown that using CAR-T therapies at earlier stages is associated with superior treatment outcomes. This trend was reported in studies ranging from ZUMA-1 to ZUMA-7.

Additionally, the ZUMA-12 study, which evaluated Yescarta's efficacy in the first-line treatment of LBCL patients, also yielded positive results. The ZUMA-23 study, comparing standard therapy with Yescarta in first-line treatment, is also underway.

The healthier the T cells, the higher the likelihood of producing effective CAR-T therapies. This is because patients are less exposed to chemotherapy at earlier stages, meaning their overall condition is likely better, and their immune function is more preserved. These conditions provide the rationale for earlier use of CAR-T therapy, as better treatment outcomes can be expected when CAR-T is administered under such circumstances.

Q. Why is reimbursement for Yescarta necessary in second-line treatment?

Yun-seok Choi

[Professor Choi] Yescarta is a therapy that has demonstrated clinical efficacy in the second-line setting through clinical studies. Based on this evidence, it is evaluated as a meaningful treatment option for clinicians.

For immunotherapies that rely on T-cell activation, T-cell fitness is extremely important. While it is challenging to quantitatively assess a patient's T-cell status, this remains an area of ongoing research.

Anticancer drugs used in lymphoma treatment are agents that can selectively affect lymphocytes. Therefore, the more a patient is repeatedly exposed to anticancer therapy, the more the fitness of the patient's T cells, which serve as the material for CAR-T, or the patient's own T cells that should attack cancer cells when dual-specific antibodies are administered, inevitably decreases.

Considering this, T-cell–based immunotherapy should ideally be introduced earlier, when immune function is still relatively preserved. Applying CAR-T therapy under normal immune conditions can yield better treatment outcomes, offering advantages in terms of long-term patient prognosis and quality of life.

Reimbursement decisions should also consider treatment outcomes rather than focusing solely on drug prices. Patients who responded well in the ZUMA-1 and ZUMA-7 studies were able to return to daily life and resume economic activity. Given the unique disease course and therapeutic innovation in DLBCL, reimbursement decisions should proceed more quickly.

Q. With the emergence of various new drugs like bispecific antibodies and early-stage CAR-T cell therapy, treatment options have broadened. Specifically, what are the criteria for patient groups where early-stage CAR-T therapy is deemed more urgent and suitable than conventional standard therapy?

[Professor Choi] Patients at the second-line treatment stage, particularly cases where patients relapse within 12 months after first-line therapy. Through large-scale clinical trials, only Yescarta demonstrated effective results in patients who relapse or become refractory within 12 months after first-line treatment. It is the sole option with an approved indication for this patient group. Bispecific antibodies currently lack prospective evidence focused specifically on this patient population.

However, CAR-T is not an immediately available treatment, requiring turnaround time (TAT).

Should evidence for bispecific antibodies accumulate in the future, making both options available, clinicians will need to carefully consider treatment strategies. A cautious approach is warranted, weighing CAR-T's TAT against the biological aggressiveness of DLBCL in the relapse patient population and the rationale for bispecific antibodies in this setting.

Q: What insights do you believe the global experience accumulated with Yescarta could provide for the domestic treatment environment?

[Executive Director Tony Lee] The approval of Yescarta as a third-line therapy in Korea is a significant advancement, which can serve as a starting point that can open new treatment opportunities for both patients and healthcare providers. As experience with Yescarta accumulates in the third-line setting, we expect Korean healthcare providers' understanding of the drug's efficacy and characteristics to deepen.

In addition, real-world data (RWD) continue to accumulate globally, and this evidence may support future discussions on second-line reimbursement in Korea. Given that approval and reimbursement have already been granted in several countries, we anticipate that discussions in Korea will also proceed based on an evaluation of the drug's clinical value.

Q. How do you expect the DLBCL treatment landscape to evolve?

[Professor Choi] About 70% of DLBCL patients can expect cure, but the remaining 30% fall into a high-risk group. Future research will likely focus on more precise identification of high-risk patients and tailored treatment strategies based on risk level.

In particular, we anticipate a shift where T-cell-based immunotherapies, such as CAR-T, move to earlier treatment lines and are introduced earlier for high-risk patients.