NICE Recommends Tisagenlecleucel for Relapsed/Refractory DLBCL

Meindert Boysen

Meindert Boysen

The UK’s National Institute for Health and Care Excellence has authorized the use of the CAR T-cell therapy tisagenlecleucel (Kymriah) for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received ≥2 lines of chemotherapy.¹ The treatment will be made available through the Cancer Drugs Fund.

“Recommending another revolutionary CAR T-cell therapy for adults with lymphoma represents a step forward for personalized medicine,” said Meindert Boysen, director of the Centre for Health Technology Evaluation of NICE, in a press release. “We are pleased that patients are set to benefit from such an innovative therapy so rapidly because of joint working between NICE, NHS England and the company.”

“CAR T-cell therapy is expensive, however the treatment is specific to each individual and could be a potential cure for some, although it is early days,” Boysen said in the press release. “Our recommendation for tisagenlecleucel on the Cancer Drugs Fund means people can benefit while more data is collected.”

The list price for the CD19-targeted CAR T-cell therapy is £282,000 and it is given as a single intravenous infusion. However, Novartis, the manufacturer of tisagenlecleucel, has agreed to offer the treatment at a confidential discounted price. Moreover, it is estimated that 200 patients will be eligible for the treatment each year in the United Kingdom.

The FDA approved tisagenlecleucel in May 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma, including DLBCL, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma, following ≥2 lines of systemic therapy.

The approval was based on data from the phase II JULIET study, in which tisagenlecleucel reached an overall response rate (ORR) of 50% (95% CI, 38%-62%) in adult patients with relapsed/refractory DLBCL.² The complete response (CR) rate was 32% and the partial response (PR) rate was 18%; moreover, the median duration of response had not been reached.

Updated results from the JULIET trial presented at the 2018 ASH Annual Meeting confirmed that tisagenlecleucel continued to demonstrate durable ORRs with a median of 19 months of follow-up for patients with relapsed/refractory DLBCL.³

The ORR was 54% (95% CI, 41%-62%) with the CD19-targeted CAR T-cell therapy; the CR rate was 40%, and the remainder of patients had a PR. The median duration of response was not yet reach at the time of the analysis, but 54% of those who initially had a PR had converted to a CR.

At the May 21, 2018, data cutoff, 167 patients were enrolled in the study, of whom 115 had received treatment with a single dose of tisagenlecleucel at a median of 3.0 x 10⁸ CAR-positive T cells. Ninety percent of patients who were enrolled had received bridging therapy and 93% had received lymphodepleting chemotherapy prior to infusion of the CAR T cells. The median time from infusion to data cutoff was 19.3 months.

Moreover, the median age of enrolled patients was 56 years (range, 22-76), and 23% were 65 or older. At baseline, 77% of patients had stage III/IV DLBCL and 17% had double or triple hit disease. More than half of patients (55%) had the germinal center subtype, with 43% having activated B-cell DLBCL. Nearly half of patients (49%) underwent a prior stem cell transplant and 51% had received ≥3 prior therapies.

Additional updated results showed that the 6-month relapse-free survival rate was 66% (95% CI, 51%-78%), which remained consistent at 64% at both the 12- and 18-month data analyses (95% CI, 48%-76%). The median overall survival (OS) for all infused patients was 11.1 months but was not reached for those who achieved a CR to tisagenlecleucel. The 12-month OS rate was 48% (95% Ci, 38%-57%) and the 18-month OS rate was 43% (95% CI, 33%-53%).

Regarding safety, no new deaths were reported since the prior assessment, and adverse events (AEs) remained consistent. Overall, 57% of patients experienced cytokine release syndrome (CRS) of any grade in the study; 14% had a grade 3 event and 9% had a grade 4 event. The rate of neurological AEs was 20%, with 7% grade 3 and 4% grade 4.

The grading system used for these events likely resulted in an overestimation, as the University of Pennsylvania criteria were used and not the Lee criteria. Further studies are ongoing to uncover the true rates of AEs.

Other AEs of interest included prolonged cytopenias, which occurred in 45% of patients, and infection, which was present in 37% of patients. Additionally, 15% of patients experienced febrile neutropenia and 2% had tumor lysis syndrome.

The final draft guidance follows 2 prior NICE CAR T-cell therapy recommendations: tisagenlecleucel for patients up to age 25 with relapsed or refractory B-cell acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for the treatment of adult patients with DLBCL and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies.

References

1. NICE recommends another revolutionary CAR T-cell therapy for adults with lymphoma. NICE. Published February 1, 2019. https://bit.ly/2DNOwuJ. Accessed February 1, 2019.
2. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 577.
3. Schuster SJ, Bishop MR, Tam C, et al. Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel. In: Proceedings from the 2018 ASH Annual Meeting, December 1-4, 2018; San Diego, CA. Abstract 1684.