First CAR T Cells Approved in Europe

Nick Mulcahy

August 27, 2018

UPDATED with added information about both CAR T-cell products August 28, 2018 //The European Commission (EC) has approved tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Gilead), both of which use the patient's own T cells to fight cancer, for hematologic cancer indications, the companies announced this week.

Both agents are engineered cell therapies that are considered paradigm changing.

The pair become the first chimeric antigen receptor (CAR) T-cell products to become available in Europe.

Tisagenlecleucel is approved for the treatment of B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients up to 25 years of age whose disease is refractory, or who are in relapse post transplant, or who are in second or later relapse. It is also approved for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Axicabtagene ciloleucel is approved as a treatment for adult patients with relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.

The drug has already been approved for both sets of indications in the United States.

Novartis expects to launch its product in Europe initially for the pediatric ALL indication.

The company also said that the treatment's availability in each country will depend on multiple factors, including the certification of qualified treatment centers as well as the completion of national reimbursement procedures.

The European approval of tisagenlecleucel is based on the clinical trials JULIET and ELIANA, which included patients from eight European countries. These are the only global registration studies to date of a T-cell therapy that uses CAR technology, the company noted.

"Bringing Kymriah to patients in the EU advances the treatment paradigm in an unprecedented way and delivers a lifesaving therapy to young patients with ALL who have not been successfully treated with existing therapies, and who have limited options left," Peter Bader, MD, of the University Hospital for Children and Adolescents in Frankfurt/Main, Germany, commented in a statement. Bader was an investigator in the ELIANA trial.

The benefits of tisagenlecleucel are its ability to achieve remission of significant duration in patients with ALL and to achieve an objective response of significant duration in patients with DLBCL, according to the review panel from the European Medicines Agency (EMA).

The EMA listed the most common side effects in patients with ALL as being cytokine release syndrome, infections, hypogammaglobulinaemia, pyrexia, and decreased appetite. The most common side effects in patients with DLBCL are cytokine release syndrome, infections, pyrexia, diarrhea, nausea, hypotension and fatigue.

Tisagenlecleucel should be administered in a qualified treatment center by professionals trained in the administration and management of patients treated with the drug.

Detailed recommendations for the use of this product will be described in the summary of product characteristics, which will made available in all official European Union languages now that the marketing authorization has been granted.

Tisagenlecleucel Clinical Trial Data

Data from the international JULIET trial with tisagenlecleucel were presented at the 2017 American Society of Hematology meeting in December and included details on 81 patients with relapsed and refractory DLBCL who were treated at various centers in several countries.

For 46 patients with at least 6 months of follow-up, the overall response rate was 37%; 30% of those patients achieved a complete response, and 7% achieved a partial response.

Most patients who are in remission at 3 months stay in remission, said study investigator Stephen Schuster, MD, from the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, at the time.

"While we don't completely understand why these remissions are so durable, it's exciting and will change how this disease is treated when conventional therapies fail," he said.

"About a third of patients who fail all current therapies, even transplant, could now have a form of therapy that may offer them durable remissions," he added. "We are going to be able to offer patients who don't respond to standard therapies a form of therapy that may, after a single treatment, relieve symptoms and save lives."

An update to an interim analysis of the open-label, multicenter, single-arm phase 2 ELIANA trial was presented at the 2017 European Hematology Association annual meeting.

Among the 63 evaluable patients, 52 achieved complete remission (CR) or CR with incomplete blood count recovery within 3 months of infusion. All of these patients achieved minimal residual disease-negative status in the bone marrow. The probability of being relapse free 6 months after remission was 75%; the probability of survival was 89% at 6 months and 79% at 12 months.

Tisagenlecleucel was developed collaboratively by the University of Pennsylvania and Novartis. The first clinical trial was conducted at the Children’s Hospital of Philadelphia (CHOP).

"Six years ago, when we treated the first child, Emily Whitehead, with this experimental therapy, these patient populations had exhausted all the treatments we had to offer. There was nothing left for us to offer," said Stephan Grupp, MD, PhD, director of the Cancer Immunotherapy Program, section chief of cell therapy and transplant at CHOP, and professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

The CHOP has now treated more than 250 children, more than any other center in the world.

"In a remarkably short period of time we've ushered in a brand new field of medicine," Grupp commented in a statement. "We couldn't be more pleased the CAR T-cell treatment we first gave Emily has not only saved her life, but has been proven effective in more blood cancers, and may completely change the outcomes of these diseases in patients in Europe and around the world."

Axicabtagene Ciloleucel Clinical Trial Data

The approval of axicabtagene ciloleucel is supported by data from the single-arm ZUMA-1 trial.

In that trial, 72% of patients (n = 73/101) who received a single infusion of axicabtagene ciloleucel responded to therapy, with 51% (n = 52/101) achieving a complete response. The median follow-up was 15.1 months. At 1 year, 60% of patients were alive; the median overall survival had not been reached.

In ZUMA-1, 12% of patients experienced cytokine release syndrome (CRS) of grade 3 or higher, and 31% experienced neurologic toxicities of grade 3 or higher. However, almost all (98%) the patients recovered from CRS and/or neurologic adverse reactions.

The most common grade ≥3 adverse reactions include encephalopathy, unspecified pathogen infection, cytokine release syndrome, bacterial infection, aphasia, viral infection, delirium, hypotension, and hypertension.

"Axicabtagene ciloleucel is a new and exciting way of treating cancer that offers a new option to patients with DLBCL and PMBCL in Europe," said Gilles Salles, MD, of the South Lyon Hospital Complex in France, in a company press statement. "Many patients with these aggressive forms of non-Hodgkin lymphoma who have not responded to or failed commonly available treatment options have a very poor prognosis, and there is an urgent need for new therapies."

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick.

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