FDA Approves Second CAR T-Cell Therapy

Roxanne Nelson BSN, RN

October 18, 2017

The US Food and Drug Administration (FDA) has today approved the second T-cell therapy that uses chimeric antigen receptor (CAR) technology.

Axicabtagene ciloleucel (Yescarta, Kite Pharma) has received FDA approval for the treatment of patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.

This comes right on the heels of the FDA's approval of tisagenlecleucel-T (Kymriah, Novartis), the first therapy using CAR technology to enter the marketplace. Indicated for use in pediatric and young adult patients (age 3 to 25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL), the product got the green light on August 30.

The therapy involves engineering of a patient's T cells to express a CAR that will then target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. The cells are then redirected to kill the cancer cells.

As previously reported by Medscape Medical News, CAR T cells have demonstrated dramatic results in clinical trials in patients with relapsed/refractory hematologic cancers, who have limited or lack any therapeutic options. In some cases, one dose of the treatment has eradicated the disease.

"Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer," said FDA Commissioner Scott Gottlieb, MD, in a statement. "This approval demonstrates the continued momentum of this promising new area of medicine and we're committed to supporting and helping expedite the development of these products."

"We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine," noted Dr Gottlieb. "That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies."

High Response Rate

Today's approval is based on data from the ZUMA-1 pivotal trial for axicabtagene ciloleucel, which was conducted in 101 patients with aggressive NHL, in collaboration with the National Cancer Institute. The company released final results in February 2017, https://ir.kitepharma.com/releasedetail.cfm?ReleaseID=1014817 which showed an overall response rate (ORR) in 82% of patients and a complete response (CR) in 54%.

At 6 months, the ORR was maintained in 41% of patients and CR in 36%.

In addition, five of the 101 patients (5%) continue to experience highly significant and durable partial responses (PRs) with minimal abnormalities on positron emission tomography scans. One of these PRs converted to a CR at month 9, the company noted.

"We know as clinicians that patients with aggressive lymphoma who do not respond to their previous treatments have a very poor prognosis," said Frederick L. Locke, MD, the co-lead investigator of the trial and director of Research for the Immune Cell Therapy Program at Moffitt Cancer Center in Tampa, Florida, in a statement, when the final results were released. "In fact, we know from the SCHOLAR-1 study, these patients have only an eight percent chance of achieving a complete response with current therapies.

"Several patients we treated at Moffitt Cancer Center experienced a rapid and durable complete response with this first-of-its kind therapy," Dr Locke pointed out. "The ZUMA-1 study results suggest that axicabtagene ciloleucel could become a new standard of care for patients with refractory aggressive lymphoma."

The manufacturer has not yet announced what this new treatment will cost. Immunotherapies have not only been breaking new ground in innovation but also in cost. Novartis had announced that tisagenlecleucel-T would be priced at $475,000, which may well be testing the boundaries of what insurance companies and patients may be willing to pay, but it has also been pointed out that this is a 'one-off' therapy that is potentially curative. In successful cases, the one-time treatment can eradicate the disease. The nearest parallel is bone marrow transplants, which cost around $800,000 for an allogeneic bone marrow transplant in the United States and around $350,000 for an autologous transplant, although these costs vary considerably.

Risk for Severe Adverse Events

However, on the downside, these therapies can be associated with serious toxicity, and treatment-related deaths have occurred in clinical trials. This risk had led to restricting use of the therapy to specially certified centers.

In clinical trials, CRS has been treated successfully with an interleukin-6 blocker, tocilizumab (Actemra, Genentech), which is already marketed for use in rheumatoid arthritis. The FDA has now expanded its indication to include treatment of CAR T cell–induced severe or life-threatening CRS in patients 2 years of age or older. The agency noted that in clinical trials among patients treated with CAR T cells, 69% of patients had complete resolution of CRS within 2 weeks after one or two doses of tocilizumab.

The risk of these unique acute toxicities, which are uncommon with other cancer therapies, has prompted the development of a framework for systematically dealing with them. Clinicians at the University of Texas MD Anderson Cancer Center in Houston put together the guidance that addresses CRS and CAR T-cell–related encephalopathy syndrome (CRES).

Other severe side effects have also been observed with CAR T-cell therapy. In the ZUMA-1 trial, these included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). Grade 3 or higher CRS was seen in 13% of patients and neurologic events in 28%, but there were no cases of cerebral edema.

Because of the risk for severe adverse events, axicabtagene ciloleucel has been approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA has restricted the use of these agents to specially certified centers. The certification would require that all personnel involved in the prescribing, dispensing, or administering of CAR T cell therapy to be trained to recognize and manage CRS and neurologic events. In addition, patients also must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop.

To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study.

New Option, Cost to Be Addressed

Commenting on the approval, Gwen Nichols, MD, chief medical officer of The Leukemia & Lymphoma Society, noted that patients with relapsed or refractory aggressive NHL have a particularly poor prognosis. "This approval brings a new option to patients who do not respond to standard therapies," she told Medscape Medical News.

"Immunotherapy is dramatically changing the way we approach blood cancer treatment, and we are hopeful that this therapy will ultimately be applicable to patients with other types of cancers as well," she said. "Today's approval is a very significant advance for lymphoma patients and for the cancer community as a whole."

While the manufacturer has not yet divulged the cost of this new product, Dr. Nichols pointed out that in general, blood cancers are costly to treat. "But the cost of many of the exciting new therapies is a financial burden for patients and one of the many aspects of the financial burden of cancer care," she said. "Many patients who are now benefitting from CAR T-cell therapy would clearly not have otherwise have survived.   But innovation is costly so we have to carefully look at value-based cost structures for therapies as well as the overall cost of treating cancer." 

She emphasized that the Leukemia & Lymphoma Society believes that patients should not be solely liable for the increasing cost of cancer care, and that last year, the society received more than 26,000 calls from patients and families – the majority included concerns about financial stress and difficulties accessing treatment.

"We are advocating on behalf of the blood cancer community – we need to take bold action and call on all stakeholders in the cancer ecosystem to ensure that patients are not the only ones who are shouldering the rising cost of care," Dr. Nichols said.

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