CLINICAL DEVELOPMENT IN ONCOLOGY


“Even if there’s a 0.1% chance of developing a second cancer, I would say that getting the myeloma in remission is a far bigger threat”


Moreover, Banerjee points to a population- wide Medicare data analysis that was conducted before the era of CAR-T therapies, which found that patients who had B-cell lymphomas had a five-times higher risk of secondary T-cell lymphomas compared to the general population. While some of that is due to treatment, transdifferentiation—where the B-cell lymphoma itself starts to behave as if it is a T-cell lymphoma—could also contribute to it, he adds.


While the underlying mechanisms are not


well understood, the same risk factors that put an individual at risk of one type of blood cancer could put them at risk of a second kind of blood cancer later, says Banerjee.


The benefits outweigh the risks “Even if all 22 cases of T-cell malignancies currently being investigated by the FDA are CAR transgene positive, and in every one of them, there was a determinative link of causality, even then, the risk is many, many, many times lower than the chemotherapy that these patients would have ordinarily received,” says Levine. As recently as five years ago, the life


expectancy of triple class refractory multiple myeloma patients was one year or less, says Banerjee. “Even if there’s a 0.1% chance of developing a second cancer, I would say that getting the myeloma in remission is a far bigger threat,” Banerjee adds. This risk-benefit calculation can be trickier in


lymphoma, where CAR-T therapies like Kymriah are approved. “There, therapies are considered to be curative for up to 50% of patients, depending on the specific study,” says Banerjee. Calling it “a balancing act”, he goes on to say


24 | Clinical Trials in Oncology


that the same principle of considering available alternatives that are used in multiple myeloma is applicable here. “There are some bispecific antibodies, but they have their toxicities along with the inconvenience of indefinite clinic visits,” he says. “Patients can be offered a hematopoietic stem cell transplant, but autologous transplants also carry a risk of secondary cancers and so forth.” In a commentary on this subject published in


Nature Medicine, Levine states that the T-cell malignancy reports should be investigated, but existing data suggests a low risk compared with other cancer treatments. Levine goes on to say that this is also the consensus of various organizations like the International Society for Cell Gene Therapy, the American Society for Transplantation and Cellular Therapy, and others. When asked for a comment, an ASH spokesperson said the organization was unable to take a stance on CAR-T therapies at this time.


Changes going forwards Currently, CAR-T cell therapies are approved as a fourth-line or later treatment, but multiple companies are seeking their approval as an earlier line of therapy. Levine and Banerjee believe that the investigation of CAR-T therapies as an earlier line treatment may help to prove or disprove the hypothesis of a causal relationship between T-cell malignancies and CAR-T therapies. “CAR-T cell therapies are relatively new treatments and have room to grow. So even if they take a hit in, let’s say, the fifth line of therapy sales in multiple myeloma, they still have room to grow in other diseases, and there’s going to be more approvals,” says Sakis Paliouras, associate director for oncology research and analysis at GlobalData. One potential effect could be on investments in other immuno-oncology modalities, and other CAR-T technologies like in vivo CAR-T cells or those that can bypass or minimize the risk for T-cell malignancies, Paliouras adds. Although research into the causal


relationship between CAR-T therapies and T-cell malignancies is ongoing, the CAR-T cell therapy market is expected to grow. Banerjee proposes that identifying and validating risk factors could help tailor therapies for patients with high secondary cancer risks, while not denying them access to CAR-T therapies.


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