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UK Panel Initially Rejects CAR T-cell Therapy Due to Cost
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An independent body that offers guidance to improve health and social care in England recommended against the use of axicabtagene ciloleucel, one of two chimeric antigen receptor T-cell therapies already approved in the United States and European Union.
The National Institute for Health and Care Excellence (NICE) issued draft guidance today that said axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) — which received FDA approval last year for treatment of certain B-cell lymphomas — is too expensive to justify its use in England’s National Health Service (NHS).
The list price for axicabtagene ciloleucel in the United States is $373,000. However, the price in the United Kingdom remains confidential.
“[CAR T-cell therapy] is an exciting innovation in very difficult-to-treat cancers, with a promise of cure for some patients,” Meindert Boysen, director of the center for health technology evaluation at NICE, said in a press release.
“We have been working with the companies involved, and with NHS England, with the aim of ensuring that patients in England are among the first to have access to these new treatments in Europe,” Boysen added. “Although promising, there is still much more we need to know about [CAR T-cell therapy]. ... Unfortunately, in this case, we are not able to recommend axicabtagene ciloleucel for use in the NHS in England at the cost per patient set by Kite Pharma.”
NICE did extended a call for “comments and further evidence” that could lead to axicabtagene ciloleucel being made available through NHS. This feedback will be accepted until Sept. 18.
Officials with Gilead Sciences issued the following statement to Cell Therapy Next and Healio.com: "[Axicabtagene ciloleucel] is a new generation of innovative cell therapy that is bringing a new option to patients who, in many cases, have run out of treatment options and literally have months to live. Our priority is to make axicabtagene ciloleucel available to patients in the UK as soon as possible and, as such, we believe we will soon be able to reach an agreement. Cell therapy is a new and advanced technology and, as NICE has identified, there is little available data about the salvage treatment of patients with aggressive forms of non-Hodgkin lymphoma in England. We’re therefore in ongoing discussions with NICE to identify appropriate treatment comparators which can clarify how cell therapy may be made available to patients in the UK."
The FDA approved axicabtagene ciloleucel — a CD19-directed genetically modified autologous T-cell immunotherapy — in October for treatment of adults with relapsed or refractory large B-cell lymphoma who received two or more lines of systemic therapy.
The approval applies to patients with diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
The FDA based its decision in part on data from the ZUMA-1 trial, which included 101 adults with relapsed or refractory large B-cell lymphoma.
Overall, 72% of patients treated with a single infusion responded to therapy, including 51% (95% CI, 41-62) of patients who achieved complete response. At median follow-up of 7.9 months, median duration of response had not been reached (95% CI, 8.1-not estimable) among patients who achieved complete remission.
NICE members noted there are no data to directly compare the regimen with salvage chemotherapy, the standard treatment for patients in the United Kingdom whose disease recurred or did not improve after at least two courses of chemotherapy.
The panel determined cost-effectiveness estimates for axicabtagene ciloleucel compared with salvage chemotherapy exceeded 50,000 English pounds per quality-adjusted life year gained. That is “the upper limit of the specially extended range of cost-effectiveness for cancer treatments,” according to NICE’s draft guidance.
Axicabtagene ciloleucel was the second CAR T-cell therapy to receive FDA approval.
The other — tisagenlecleucel T-suspension (Kymriah, Novartis) — is indicated for the treatment of children and young adults with B-cell acute lymphoblastic leukemia. The approval applies to patients aged up to 25 years with refractory B-cell precursor ALL, as well as those whose disease is in second or later relapse.
Tisagenlecleucel T-suspension is priced at $475,000.
Both axicabtagene ciloleucel and tisagenlecleucel T-suspension received approval from European Union regulators on Monday.
Perspective
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John Sweetenham, MD, FRCP, FACP
The decision by NICE in England to withhold approval of CAR T-cell therapy with axicabtagene ciloleucel for patients with relapsed aggressive B-cell lymphomas is not surprising for two principle reasons. First, the evidence base supporting the use of this therapy is still small, although data are accumulating quite rapidly. Second, NICE has a track record of setting a high bar for new agents and new interventions, and the lack of comparative data for CAR T cells at this time has clearly factored into its decision.
That said, the director of the Centre for Health Technology Evaluation at NICE appears to have cited price as the main reason for its guidance. CAR T-cell therapy, in this context, failed to meet the predetermined threshold for cost-effectiveness required by NICE. Interestingly, the price of this therapy in England has remained confidential, so there is no way of knowing how — or why — the list price might differ from the U.S. price tag of $373000. In the context of the resource limits imposed on the government–funded English National Health Service, however, the quality-adjusted life years gained by this therapy are inevitably limited given the median age of patients with aggressive non-Hodgkin lymphoma.
That said, there is no doubt that axicabtagene ciloleucel is a highly effective therapy for patients in this challenging clinical situation. The ZUMA-1 trial reported an overall response rate of 72% and complete response rate of 51% among patients with relapsed disease. Even though these were, in some respects, a favorable group with regard to median age and proportion of patients with relapsed versus refractory disease, this is still an impressive result — and better than almost anything reported in prior phase 2 studies in this context.
The panel’s comments regarding the lack of comparative data are true, although there is no true standard of care in the clinical setting for those patients not eligible for stem cell transplantation. It is not clear what an appropriate comparator arm of a randomized trial would be in this context. Historical data show that outcomes for these patients is poor. A prospective randomized trial is unlikely to be conducted in this situation, so if historical controls are the only option, these need to be more rigorously conducted than the comparative analysis of ZUMA-1 with the SCHOLAR 1 study reported at this year’s European Society for Medical Oncology Congress.
Since this therapy has been approved by the European Union, my guess is that England will give approval in the coming months. The statements from NICE and from the manufacturer suggest that there will be intense negotiation over the price. Let’s hope for the sake of patients in England who could benefit from this treatment that they are able to reach agreement soon. Let’s also hope that there will be continued and rigorous evaluation of this new therapy to determine its true cost-effectiveness for this challenging population and that — if there is a significant price difference compared with the United States — we have a clear explanation.
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