FDA approval of CAR-T for mantle cell lymphoma could be ‘practice changing’
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The FDA approval of brexucabtagene autoleucel represents a major step forward for the treatment of adults with relapsed or refractory mantle cell lymphoma, experts told Healio.
“The approval ... is practice changing,” Henry Chi Hang Fung, MD, FACP, FRCPE, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, told Healio. “It’s a big deal that we now have a new treatment option for patients with an unmet need — that is, refractory disease.”
The FDA granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma/Gilead) in July, making it the third chimeric antigen receptor T-cell therapy approved in the United States for patients with certain hematologic malignancies.
Brexucabtagene autoleucel — which has a U.S. list price of $373,000 for a one-time infusion — targets the CD19 protein on the surface of cancer cells.
The FDA based approval on results of the ongoing pivotal ZUMA-2 trial, which has enrolled 74 patients to date. The latest efficacy results showed 87% of patients responded to one infusion of therapy. Researchers reported a 62% complete response rate at minimum follow-up of 6 months.
“This is an incredibly exciting advancement in the treatment of mantle cell lymphoma, which is historically an incurable lymphoma with relatively short survival when chemotherapy stops working,” Caron Jacobson, MD, medical director of the immune effector cell therapy program at Dana-Farber Cancer Institute and an investigator on the ZUMA-2 trial, told Healio. “The responses seen in the ZUMA-2 trial in very high-risk and heavily pretreated patients with mantle cell lymphoma are phenomenal and — although longer follow-up is needed — many persist beyond the 1-year mark, suggesting that this therapy has the potential to make a substantial impact on the natural history of this disease.”
Safety results of ZUMA-2 showed 18% of patients experienced grade 3 or higher cytokine release syndrome (CRS), whereas 37% had some form of neurotoxicity. The most common grade 3 or higher adverse events included anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, unspecified infection-pathogen, pneumonia, hypocalcemia and lymphopenia.
Brexucabtagene autoleucel will include a boxed warning that outlines risks for CRS and neurotoxicity associated with CAR T-cell therapy.
The FDA also will require Kite Pharma/Gilead to perform a post-approval observational study to determine the long-term safety of brexucabtagene autoleucel.
Hope for a cure
The FDA approved the first two CAR T-cell therapies in 2017. Axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) is indicated for treatment of adults with relapsed or refractory large B-cell lymphoma, and tisagenleleucel (Kymriah, Novartis) is indicated for treatment of certain patients with diffuse large B-cell lymphoma or B-cell acute lymphoblastic leukemia.
These approvals led to an explosion in clinical and preclinical research, and the approval of brexucabtagene autoleucel was highly anticipated.
The response rate for brexucabtagene autoleucel is comparable with that of front-line therapies, Fung said. Further, the greater than 60% complete response rate among patients in ZUMA-2 who had advanced disease is impressive, he said.
Fung told Healio he believes brexucabtagene autoleucel is a safe treatment option.
“Centers that administer these treatments have gained significant experience, and we now know how to properly manage these patients,” he said.
However, Fung said this therapy has more significant adverse effects that noncellular therapy approaches, including hematopoietic stem cell transplantation.
Despite the additional safety risks, “this therapy can lead to potential long-term disease control and is potentially less toxic than HSCT options,” Fung said.
He also acknowledged limitations with brexucabtagene autoleucel. Not all patients will have access to the treatment based on cost or proximity to a certified center to administer the treatment, not to mention the costs of complying with post-infusion Risk Evaluation and Mitigation Strategy monitoring program requirements.
Regardless of risk or limitations, Fung said brexucabtagene autoleucel addresses an unmet need in the treatment of refractory mantle cell lymphoma.
“This is unquestionably a key approval among the treatments available for this disease,” Peter Martin, MD, associate professor of medicine and chief of the lymphoma program at Weill Cornell Medicine and NewYork-Presbyterian, told Healio.
He agreed with Fung that the need for effective therapies for mantle cell lymphoma is significant.
“There have fortunately been several new treatments made available for mantle cell lymphoma over the past decade-plus,” he added. “These treatments have drastically improved our ability to treat patients with mantle cell lymphoma but, unfortunately, they have not improved our ability to cure mantle cell lymphoma.”
The issue with newer therapies is that more patients are experiencing progression after their use, which often results in more aggressive disease, Martin said.
“CAR T-cell therapy is a new approach that works differently and has the possibility to provide more durable responses and possibly even a cure for some patients, which is exciting,” he said.
Nonetheless, Martin said he remains cautious about the curative potential of brexucabtagene autoleucel and insisted that longer follow-up data are needed to determine its potential to induce durable responses.
“Mantle cell lymphoma has repeatedly shown itself to be challenging disease to treat,” Martin said. “The optimist in me believes this could be a cure for mantle cell lymphoma for some patients, so I am hopeful.”
CAR-T for some, but not everyone
Martin is more critical regarding the overall safety profile of CAR T-cell therapies, including brexucabtagene autoleucel. He said the potential for significant morbidity and mortality means the therapy will not be an option for many patients with refractory disease, who instead will opt for safer therapies that at best may delay disease progression for a few years.
“As we learn more about CAR T cells, they will become safer because we will be able to target them toward patients who are less likely to have extreme side effects from the treatment,” Martin said.
With three approved CAR T-cell therapies and counting, Martin emphasized that increased coordination across the cell therapy delivery chain will be required to make this type of treatment feasible for more patients.
“With mantle cell lymphoma, CAR T-cell therapy will require even more planning,” Martin told Healio.
“In the real world, for CAR T cells to have a real impact, clinicians will need to identify high-risk patients early on,” he added. “It will also depend on how well clinicians, community oncologists and academic oncologists collaborate to deliver these therapies. It is this part of the care that is critically underrecognized.”
For more information:
Henry Chi Hang Fung, MD, FACP, FRCPE, can be reached at henry.fung@tuhs.temple.edu.
Caron Jacobson, MD, can be reached at caron_jacobson@dfci.harvard.edu.
Peter Martin, MD, can be reached at pem9019@med.cornell.edu.
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