Warning signs for CAR-T after secondary cancer cases

CAR-T black box

CAR-T treatments emerged as a major success for the pharma industry when first approved in 2017, but this has been muddied by concerns over secondary malignancies. Ben Hargreaves uncovers why regulatory action in the US and the EU has come about, and what the next steps are to determine the risk posed to patients.

The development of CAR-T therapies represented a major breakthrough to combat difficult to treat blood cancers. Prior to the treatment’s emergence, patients had few options left to them. By contrast, clinical results showed that patients could be potentially cured or go years without having blood cancers return once treated with the new therapies. At the time of the first CAR-T approval, Novartis’ Kymriah, it was acknowledged that the treatment did pose some risk to patients, such as cytokine release syndrome and increased risk of infections, but that the benefit-risk profile was in the treatment’s favour.

The recent investigation into the safety of CAR-T therapies has brought this profile back into the scope of the FDA, as the agency probed whether the treatments were linked to the development of T-cell cancers. It was revealed that clinical trials and post-marketing adverse events data sources had notified the agency of an increased risk of T-cell malignancies. This arrived after the FDA became aware of 22 cases of T-cell cancers that occurred after treatment with CAR-T therapies. At the beginning of the year, this led the FDA to request a change to safety labelling to include a warning on all approved CAR-T therapies.

Alarm bells

The FDA announced that it would be looking into the issue in November 2023, and had determined that the risk applied to all approved BCMA-directed and CD19-directed CAR-T therapies. Without noting at the time which companies were involved, the agency stated that cell malignancies had occurred in patients treated with ‘several products’ in the class of treatments.

As part of the initial approval process for these treatments, post-marketing requirements ensured that there was a 15-year long-term follow-up to determine any longer term safety signals and risk of secondary malignancies occurring after treatment. With the follow-up carried out, the FDA informed the companies with CAR-T treatments by letter that changes would need to be made to safety-related labelling. The letter stated that the agency had “become aware of the risk of T-cell malignancies, with serious outcomes, including hospitalisation and death, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.”

The letters were sent out to the companies that market CAR-T treatments, and the documents included the stipulation that, within 30 calendar days of the letter, the developers must submit ‘a supplement’ proposing changes to the approved labelling in accordance with the updates requested by the FDA. Within this 30-day period, the companies are also allowed to notify the agency why they do not believe such a change is warranted, along with the reasons for this.

Of the six products that require changes to their labelling, the letter regarding Tecartus (brexucabtagene autoleucel), a CAR-T treatment developed by Kite Pharma and Gilead, was initially removed and then updated days later. The change removed a reference to patients having experienced T-cell malignancies with the product, indicating that, for this product, there has not yet been such a safety signal. However, the FDA still noted that the product would have to provide a label warning that the treatment could still lead to the development of T-cell malignancies.

In Europe, the EMA also started a safety review of CAR-T cell medicines, announced on 12th January. As in the US, there are the same six products approved that will come under review. The agency noted that, at the time of approval, secondary malignancies were considered as an ‘important potential risk’. As part of its action, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) is reviewing evidence, including 23 cases of various types of T-cell lymphoma or leukaemia in the EudraVigilance system, a database of adverse events.

Benefit against risk

Penn Medicine, which completed research behind the first approved CAR-T therapy and helps deliver the treatment to patients, released a statement after the letters were issued to developers. The academic medical centre noted that, of the 449 patients treated at its facility, only one case of an incidental T-cell lymphoma was found, which did not express the CAR gene. Further, the organisation outlined that 16 were diagnosed with a second cancer after receiving CAR-T cell therapy, most of which were solid tumours (12 of 16).

“When this case was identified, we did a detailed analysis and concluded the T-cell lymphoma was not related to the CAR-T cell therapy. As the news of other cases came to light, we knew we should go deeper, to comb through our own data to better understand and help define the risk of any type of secondary cancer in patients who have received CAR-T cell products. What we found was very encouraging and reinforces the overall safety profile for this type of personalised cell therapy,” said Marco Ruella, an assistant professor of Haematology-Oncology and scientific director of the Lymphoma Program, Penn Medicine.

The FDA’s decision not to pull marketing authorisation for the products seems to suggest that, although the secondary malignancies are a cause for concern, the benefit-risk profile for the treatments remains favourable. However, the agency did not rule out the need for potential further regulatory action. In a statement at the time on sending letters to the companies responsible for the approved treatments, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalisation and death, and is evaluating the need for regulatory action.”

A small setback?

The question that will now hang over CAR-T therapies is what will be the impact on both the research and commercial interests of the area. Additional regulatory action or an escalation of secondary malignancy cases could bring serious doubts over the future of the treatment – though, at present, the numbers of cases per patients treated remains low.

For the first approved CAR-T, Kymriah, the treatment has already become an established part of Novartis’ commercial portfolio, after generating revenue of $508 million in revenue for the full-year 2023. However, this represented a drop from the previous year, where it generated $536 million. For Gilead’s Yescarta, the CAR-T product launched not long after Kymriah, sales told a different story, as it generated $1.5 billion in the full year, an increase of 29% on the previous year.

Both results paint a different picture of the current CAR-T market. There is substantial profit to be made – any drug that launches to blockbuster sales will be considered a success – but also one where increasing competition is eroding early leads. The therapeutic area is still a major one for investment, with a number of deals taking place, as oncology specialist companies attempt to make their own mark. With regulatory concerns hanging over the space, there will be increased interest in any further large-scale deals to come in 2024, as well as watchful eyes to see if any further regulatory action is in the pipeline.