Yescarta DLBCL

Yescarta DLBCL

In the realm of oncology, the treatment of Diffuse Large B-Cell Lymphoma (DLBCL) has witnessed significant advancements over the past decade. Among these innovations, Yescarta (axicabtagene ciloleucel) stands out as a revolutionary therapy for patients with relapsed or refractory (R/R) DLBCL who are ineligible for autologous stem cell transplantation (ASCT). This article delves into the specifics of Yescarta’s approval dates, indications, and its comprehensive profile, including clinical data, safety profile, and its impact on patient outcomes.

Approval Dates and Indications

Yescarta, developed by Kite Pharma and marketed in China by Fosun Pharma (Fosun Kite), has been a game-changer in the treatment of DLBCL. The United States Food and Drug Administration (FDA) approved Yescarta on October 18, 2017, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. In China, the National Medical Products Administration (NMPA) granted approval on June 22, 2021, for the same indication, making it the first CAR-T cell therapy to be approved in the country.

Subsequently, on June 26, 2023, the NMPA approved an additional indication for Yescarta: adult patients with relapsed or refractory large B-cell lymphoma who have failed first-line immunotherapy or relapsed within 12 months after such treatment. This expansion of indications underscores the therapy’s efficacy and versatility in managing DLBCL.

Clinical Data and Efficacy

The ALYCANTE trial, a phase II, open-label study, evaluated the efficacy and safety of Yescarta as a second-line therapy for patients with R/R DLBCL who were ineligible for ASCT. The primary endpoint was the complete metabolic response rate (CMR) at three months post-infusion, as assessed by investigators. Secondary endpoints included objective response rate (ORR) at three months, CMR at six months, best ORR, best CMR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and the incidence, nature, and severity of adverse events.

The trial enrolled 69 patients between March 19, 2021, and May 4, 2022, representing the full analysis set (FAS). Among these, 62 patients received Yescarta infusions between April 26, 2021, and June 16, 2022, and were included in the modified full analysis set (mFAS).

The median age of the enrolled patients was 70 years, with 24.2% being female. The majority (83.9%) had a histological diagnosis of DLBCL, and 54.8% were primary refractory to first-line chemotherapy and immunotherapy. Patients were considered ineligible for HDCT/ASCT due to age ≥65 years (54.8%), high hematopoietic cell transplant-specific comorbidity index (HCT-CI) score ≥3 (32.3%), and/or prior ASCT (3.2%).

The trial results were highly promising. At three months post-infusion, the CMR was 71.0%, and the ORR assessed by investigators was 75.8%. At six months post-infusion, 59.7% of patients remained in CMR. The best ORR and best CMR assessed by investigators were 90.3% and 79.0%, respectively.

At a median follow-up of 12.0 months, the median PFS was 11.8 months, with estimated PFS rates of 67.7% at six months and 48.8% at 12 months. The OS data were not mature, with estimated OS rates of 91.9% at six months and 78.3% at 12 months.

Safety Profile

In terms of safety, Yescarta demonstrated a manageable profile without unexpected toxicities. Among the 62 patients, 95.2% experienced grade 3 or higher adverse events (AEs). The most common grade 3 or higher AEs were neutropenia (66.1%), anemia (38.7%), and thrombocytopenia (38.7%).

Specific AEs related to CAR-T cell toxicity included cytokine release syndrome (CRS) in 93.5% of patients, with 8.1% experiencing grade 3 or higher CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 51.6% of patients, with 14.5% experiencing grade 3 or higher ICANS. Notably, there were no CRS-related deaths or neurological events.

Mechanism of Action

Yescarta is a chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B-cells, including DLBCL cells. The therapy involves collecting a patient’s T-cells through a process called leukapheresis, genetically modifying them to express the CAR protein, and then infusing them back into the patient. These modified T-cells recognize and attack CD19-expressing cancer cells, leading to their destruction.

Patient Selection and Preparation

Patient selection for Yescarta therapy is crucial. Eligible patients are those with R/R DLBCL who have failed at least two lines of systemic therapy and are ineligible for ASCT. Pre-treatment evaluation includes a comprehensive assessment of the patient’s medical history, physical examination, laboratory tests, and imaging studies.

Before receiving Yescatin, patients undergo leukapheresis to collect their T-cells. During this process, blood is removed from the patient’s body, and T-cells are separated and collected. The remaining blood components are returned to the patient. The collected T-cells are then sent to a manufacturing facility, where they are genetically modified and expanded in culture.

Administration and Post-Treatment Monitoring

Yescarta is administered as an intravenous infusion. The infusion process typically takes several hours, and patients are closely monitored for any immediate adverse reactions.

After the infusion, patients are hospitalized for close monitoring for at least several weeks to manage potential side effects such as CRS and ICANS. During this period, patients receive supportive care, including medications to manage fever, pain, and other symptoms.

Long-Term Follow-Up

Patients who receive Yescarta require long-term follow-up to monitor for any late-onset adverse events and to assess the durability of the treatment response. Regular visits to the oncologist, including physical examinations, laboratory tests, and imaging studies, are essential to ensure ongoing disease control and patient well-being.

Impact on Patient Outcomes

The introduction of Yescarta has significantly improved outcomes for patients with R/R DLBCL. The high response rates and durable remissions observed in clinical trials have translated into meaningful improvements in quality of life and survival for many patients. Additionally, the personalized nature of CAR-T cell therapy, with its potential for long-lasting effects, offers hope for patients who have exhausted other treatment options.

Conclusion

In summary, Yescarta has emerged as a transformative therapy for patients with relapsed or refractory DLBCL who are ineligible for ASCT. Its approval in both the United States and China, along with its expanding indications, underscores its efficacy and safety profile. The ALYCANTE trial data demonstrate high response rates and durable remissions, even in a population with poor prognostic factors and comorbidities.

The safety profile of Yescarta, while manageable, requires careful monitoring and management of potential toxicities such as CRS and ICANS. The personalized nature of CAR-T cell therapy, with its potential for long-lasting effects, offers hope for patients who have exhausted other treatment options.

As the field of oncology continues to advance, Yescarta represents a significant milestone in the treatment of DLBCL. Its success not only highlights the potential of CAR-T cell therapy but also paves the way for further innovations in the treatment of hematologic malignancies.