Gilead's KTE-X19 Demonstrates 93% Overall Response Rate in Relapsed/Refractory Mantle Cell Lymphoma

Recently, data from the registrational Phase II ZUMA-2 clinical trial (NCT02601313), which evaluated Gilead’s chimeric antigen receptor T-cell (CAR-T) therapy KTE-X19 in adult patients with relapsed or refractory mantle cell lymphoma (R/R MCL), were published online in the New England Journal of Medicine (NEJM), a leading international medical journal. The article is titled “KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma.”

KTE-X19, developed by Kite Pharma, a Gilead Sciences subsidiary specializing in cell therapy, is undergoing priority review by the U.S. Food and Drug Administration (FDA) for its Biologics License Application (BLA) for the treatment of relapsed or refractory mantle cell lymphoma (R/R MCL), with a Prescription Drug User Fee Act (PDUFA) target action date of August 10, 2020. Additionally, the Marketing Authorization Application (MAA) for KTE-X19 in the treatment of R/R MCL is under review by the European Medicines Agency (EMA). In the United States and the European Union, KTE-X19 had previously been granted Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) status, respectively.

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma (NHL) that originates from cells in the “mantle zone” of lymph nodes and typically affects men over the age of 60. If approved, KTE-X19 would become the first CAR-T cell therapy for the treatment of MCL, and Kite would become the first biopharmaceutical company with multiple commercialized CAR-T therapies.

KTE-X19 is an investigational, autologous, anti-CD19 CAR T-cell therapy that utilizes the XLP manufacturing process, including T-cell selection and lymphocyte enrichment. Lymphocyte enrichment is a necessary step for certain B-cell malignancies with evidence of circulating lymphoblasts. KTE-X19 is currently undergoing Phase I/II clinical trials for the treatment of acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL).

ZUMA-2 is a single-arm, multicenter, open-label study conducted in adult patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) whose disease was refractory to or relapsed after five prior lines of therapy, including anthracycline- or bendamustine-based chemotherapy regimens, anti-CD20 monoclonal antibodies, and the BTK inhibitors ibrutinib or acalabrutinib. The objective of the study was to evaluate the efficacy (n=60) and safety (n=68) of a single infusion of KTE-X19.

A total of 74 patients were enrolled in the study. KTE-X19 was manufactured for 71 patients, and 68 patients received a single infusion. Results showed that, based on assessments by the Independent Radiologic Review Committee (IRRC), with a median follow-up of 12.3 months (range: 7.0–32.3), among the 60 patients included in the primary efficacy analysis, the objective response rate (ORR) was 93% (n=56/60; 95% CI: 84–98) and the complete response rate (CR) was 67% (n=40/60; 95% CI: 53–78). The intent-to-treat (ITT) analysis, which included all 74 patients, yielded an ORR of 85% (n=63/74) and a CR of 59% (n=44/74). With a median follow-up of 12.3 months (range: 7.0–32.3), 57% (34 patients) of the 60 patients included in the primary efficacy analysis remained in response. At 12 months, the estimated progression-free survival (PFS) rate was 61%, and the overall survival (OS) rate was 83%.

Regarding safety, common grade ≥3 adverse events were cytopenia (occurring in 94% of patients) and infection (occurring in 32% of patients). Grade ≥3 cytokine release syndrome (CRS) and neurological events occurred in 15% and 31% of patients, respectively; there were no patient deaths. Two cases of grade 5 infectious adverse events occurred.

The above results indicate that KTE-X19 induced durable remission in most patients with relapsed/refractory mantle cell lymphoma (R/R MCL), and the severe and life-threatening toxicities observed in the study were consistent with those reported for other CAR-T cell therapies.

In recent years, despite some progress, patients with relapsed/refractory mantle cell lymphoma (MCL) who no longer respond to their current treatment regimens face a severe lack of effective therapeutic options. Based on the encouraging results of KTE-X19, this therapy will bring an innovative CAR-T treatment option to the population of patients with R/R MCL.

T-cell therapy is a highly promising treatment modality, with Kite being a leading company in this field. In late August 2017, Gilead Sciences acquired Kite for $12 billion to enter this sector. In October 2017, Kite’s first CAR-T cell therapy, Yescarta (axicabtagene ciloleucel, KTE-C19), received approval from the U.S. FDA, becoming the first CAR-T therapy approved globally for the treatment of diffuse large B-cell lymphoma (DLBCL). It was also the second CAR-T therapy to be approved and launched on the market, following Novartis’ Kymriah (tisagenlecleucel-T, CTL019).

FKC876 (Yijililunse Injection): The First CAR-T Cell Therapy Under Review in China

Both Yescarta and Kymriah work by genetically modifying a patient’s own T cells to express chimeric antigen receptors (CARs) that target the CD19 antigen. CD19 is an antigenic protein expressed on the surface of various hematologic tumor cells, including B-cell lymphoma and leukemia cells. The engineered T cells are then infused back into the patient, where they recognize and attack CD19-expressing tumor cells as well as other B cells.

In China, Fosun Kite Biotechnology Co., Ltd. (FOSUN Kite) is advancing the development of FKC876 (proposed name: Yijililuncel Injection). In mid-March this year, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) included the New Drug Application (NDA) for FKC876 in the priority review program. The application is for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.

FKC876 is an anti-CD19 autologous CAR-T cell therapy product, for which Fosun Kite has licensed the Yescarta technology from Kite Pharma and obtained authorization for localized production in China. Yescarta was approved by the U.S. Food and Drug Administration (FDA) on October 18, 2017, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. It was the first CAR-T cell therapy approved by the U.S. FDA for a specific type of non-Hodgkin lymphoma. On August 27, 2018, Yescarta became one of the first CAR-T cell therapies approved for marketing and clinical use in Europe, indicated for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL). Notably, FKC876 is the first CAR-T cell therapy product being commercialized by Fosun Kite in China, and it is also the first CAR-T cell therapy product for which the National Medical Products Administration (NMPA) has formally accepted a marketing application. As a novel cancer treatment modality, FKC876 offers new hope and opportunities for Chinese patients with relapsed or refractory large B-cell lymphoma who have experienced disease recurrence or progression after two or more lines of systemic therapy.

Original Source: KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle Cell Lymphoma

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