FDA Approves Less Toxic Liso-Cel in R/R Large B-Cell Lymphoma

SAP Partners | <b>City of Hope</b>

A CAR T-cell therapy that promises fewer side effects, and possibly lower hospital costs, wins approval after lengthy delays.

After delays that proved costly to investors, FDA today approved lisocabtagene maraleucel (liso-cel), the chimeric antigen receptor (CAR) T-cell therapy from Juno Therapeutics/Bristol Myers Squibb, that promises to offer the life-saving potential of the first generation of gene therapy with fewer toxic effects.

To be sold as Breyanzi, liso-cel was approved for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have not responded to at 2 other treatments. The CAR T-cell therapy is not indicated for patients with primary central nervous system lymphoma.

“Today’s approval represents another milestone in the rapidly progressing field of gene therapy by providing an additional treatment option for adults with certain types of cancer affecting the blood, bone marrow, and lymph nodes,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in statement. “Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens.”

Liso-cel’s original target date for approval was mid-August of 2020, which then moved November 16, 2020. But that date came and went with no word from FDA—only reports that regulators had not visited a manufacturing facility where the CARs would be made. When the inspection finally occurred in early December, regulators found issues and BMS said it responded quickly. But no word came from FDA, and investors who held $6.4 billion in contingent value rights that were tied to BMS’ purchase of Celgene saw their payment evaporate when the calendar year ended without the approval.

DLBCL is newly diagnosed in about 25,000 people a year and represents the most common type of non-Hodgkin lymphoma in adults. When DLBCL is aggressive and does not respond to treatment, patients may quickly find themselves with few options.

Like the first 2 approved CAR T-cell therapies, treatment with liso-cel involves a process in which a patients own T-cells are collected and then modified to include a new gene that allows the T-cells to hunt down and kill the cancer cells. The customized T-cells are then infused back into the patient. In a trial of 250 patients with refractory or relapsed LBCL, the complete remission rate after treatment was 54%.

In an earlier interview with The American Journal of Managed Care®, Tanya Siddiqi, MD, of City of Hope, explained that liso-cel involves a different manufacturing process that has led to reduced toxicity in clinical trials. The process results in precise, equal numbers of CAR cells that are CD4+ and CD8+, while other treatments can have varying ratios of CD4+ and CD8+ cells. “The thought is, the researchers and the drug manufacturer feel that this helps to have an expectation of what expansion you will have of these cells in the body,” Siddiqi said.

As a result, patients in clinical trials experienced less toxicity from cytokine release syndrome (CRS), which occurs as the T-cells mount their charge against the lymphoma, and fewer effects from hyperinflammation or neurotoxicity.

“We've just seen fewer severe adverse events so much so that at some [cancer] centers across the country, we’ve been able to give liso-cel CAR T-cells to patients in the clinic or outpatient setting rather than having to admit them to the hospital, depending on the patient's situation,” Siddiqi said.

“This means fewer days of inpatient hospitalization for these patients, so it may be less costly overall. I don’t think the efficacy is necessarily different—meaning that it seems to work as well as the other FDA-approved products already commercially available,” she said. “I think it might be a very good option for older patients, maybe patients who are bit more frail, or younger patients who just don't want to be admitted to the hospital—they just want to try to do it in the outpatient setting.

At a time when some hospitals are overwhelmed with patients due to coronavirus disease 2019 (COVID-19), the option to treat DLBCL in an outpatient setting could be a plus.

“As we see new products emerge, if there's no direction that they should be given in a hospital, I think that will encourage the use of these therapies in the outpatient setting. The COVID pandemic, as we all know, has been a driver to push care away from the hospital and into the clinic,” Ajeet Gajra, MD, FACP, vice president at Cardinal Health, told AJMC® last month.

Patients who are treated with liso-cel are still at risk of severe adverse events, so the approval will come with a boxed warning for CRS, a risk evaluation and mitigation strategy, and a post-marketing study of long-term effects. Health care facilities offering liso-cel must receive a special certification. Other possible adverse events include hypersensitivity reactions, serious infections, low blood cell counts and a weakened immune system. Typically, adverse events with liso-cel occur within the first 7-14 days but some do occur later.