The US Food and Drug Administration (FDA) is currently investigating a cancer risk associated with CAR T-cell therapies, specifically related to T-cell malignancies.
The malignancies, including CAR-positive lymphoma, have been reported in patients treated with BCMA- or CD19-directed autologous CAR T-cell immunotherapies.
The FDA said it is investigating the identified risk of developing the T-cell malignancies as secondary cancers with serious outcomes, including hospitalization and death, and also looking at the need for regulatory action.
In a statement outlining its investigation, the FDA said it received reports of the T-cell malignancies from clinical trials and post-marketing safety monitoring.
The FDA’s concern extends to all six FDA-approved CAR T-cell therapies of this kind, which include Bristol Myers Squibb’s (BMS) Abecma (idecabtagene vicleucel) and Breyanzi (lisocabtagene maraleucel); Johnson & Johnson and Legend Biotech’s jointly developed Carvykti (ciltacabtagene autoleucel); Novartis’ Kymriah (tisagenlecleucel); and Gilead Science’s Tecartus (brexucabtagene autoleucel) and Yescarta (axicabtagene ciloleucel).
The BCMA-targeting Abecma and Carvykti are approved for the treatment of multiple myeloma while the others are for lymphomas such as large B-cell lymphoma and follicular lymphoma. Kymriah and Tecartus are also approved for acute lymphoblastic leukemia (ALL).
Across the six CAR T-cell therapies that have been used in the treatment of about 34,400 patients worldwide, the FDA identified 19 cases of T-cell malignancies after treatment.
Despite the concerns, the FDA maintains that the overall benefits of the therapies outweigh the potential risks for their approved uses.
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The risk of secondary malignancies is already included as a class warning on the labels of the approved products. Depending on the findings of the FDA’s probe, the agency could require the risk to be included in a black-box warning, which is the highest safety alert level on a drug label.
CAR T-cell therapies, which have been transformative in several blood cancers, involve extracting a patient’s own T cells, genetically modifying them with a chimeric antigen receptor (CAR) targeting specific proteins on cancer cells and then reinfusing them into the body. The currently approved therapies target CD19 and BCMA, which are expressed in cancers like B-cell lymphoma and multiple myeloma.
Secondary Cancer Risk Associated with CAR T-Cell Therapies
The concern around the therapies arises from the viral integrating vectors (lentiviral or retroviral) used in them to deliver cell and gene therapies. The vectors can potentially cause cancer by inserting genetic material into a patient’s genome, particularly near cancer-related DNA sequences or suppressors.
Thus far, the risk of secondary cancer associated with CAR T-cell therapies has largely been theoretical, and analysts at William Blair said the risk of T-cell lymphoma has been low in clinical trials. However, the FDA’s investigation has now revealed actual reports of T-cell malignancies linked to the therapies.
As part of the initial approvals, the FDA has required manufacturers of the CAR T-cell therapies to conduct 15-year, long-term safety studies. These studies are intended to assess the long-term risk of secondary malignancies following treatment. This requirement stems from past instances where cancer cases and patient deaths led the FDA to halt clinical trials of cell and gene therapies.
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Company Responses
The companies involved have responded to the FDA’s investigation. Gilead Sciences expressed confidence in the safety of its therapies, Tecartus and Yescarta, reporting no evidence of a causal link between the treatments and the development of new malignancies.
Novartis and BMS echoed similar sentiments regarding their respective therapies.
In a statement, Novartis said Kymriah has been used in more than 10,000 patients with “no evidence to date that would change our confidence in Kymriah’s benefit/risk profile.” The company noted that “As part of our continuous safety monitoring, Novartis has not identified a causal relationship between Kymriah and secondary malignancies. We are fully committed to patient safety and will continue to work with the US Food and Drug Administration.”
A BMS spokesperson said its two therapies, Abecma and Breyanzi, have been administered in 4,700 patients and the company “has not observed any CAR-positive T-cell malignancy cases.”
Carvykti maker Legend Biotech noted that T-cell malignancies could occur in multiple myeloma patients even without CAR T-cell treatments, as they usually receive treatments such as chemotherapy before receiving CAR T-cell therapy. The company said other treatments like alkylating chemotherapy agents, immunomodulatory drugs and autologous stem cell transplantation are associated with an increased risk of secondary cancer. Legend’s Carvykti partner Johnson & Johnson shared post-treatment surveillance data with the FDA and is cooperating with the investigation. A Johnson & Johnson spokesperson said Carvykti has been used in 2,000 patients so far with a favorable risk-benefit profile.
The FDA said patients and clinical trial participants receiving the therapies should be monitored life-long for new malignancies.
The approvals of cell and gene therapies often face hiccups as the FDA has had to halt clinical trials of some therapies in the past due to concerns of cancer and deaths associated with the treatments.
The benefits of CAR T-cell therapies have been truly stellar in B-cell lymphomas and multiple myeloma. This includes Carvykti’s 74 percent benefit in delaying tumor progression or death compared to standard therapy in multiple myeloma, and Yescarta’s 60.2 percent reduction of the risk of disease progression compared to standard of care in large B-cell lymphoma.
Currently, Yescarta is the world’s best-selling CAR T-cell therapy, having reached $1.13 billion in sales in the first three quarters of 2023.
BMS and 2seventy bio’s application for moving their CAR T-cell therapy Abecma into earlier treatment is set to be reviewed at the FDA’s oncology drugs advisory committee. The FDA had initially set a decision date for December 16 but announced two weeks ago that it would be moving it pending the advisory committee meeting. Industry analysts say the meeting could be key in getting a sense of the FDA’s CAR T-cell investigation.
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