Approval of new CAR-T may have ‘immediate impact’ on treatment of large B-cell lymphoma
The uptake of chimeric antigen receptor T-cell therapy has been sluggish despite its tantalizing promise to provide a cure for a large proportion of patients with advanced large B-cell lymphoma.
What sets apart lisocabtagene maraleucel — the latest CAR T-cell therapy approved by the FDA for certain types of this disease — are its perceived safety advantages, which may increase access to the potentially life-saving therapy.
“The FDA approval of [lisocabtagene maraleucel] marks a giant step forward in CAR T-cell therapy and for effective treatments for [non-Hodgkin lymphoma],” David G. Maloney, MD, PhD, Leonard and Norma Klorfine endowed chair for clinical research and director of cellular immunotherapy at Fred Hutchinson Cancer Research Center, as well as medical director of the Bezos Family Immunotherapy Clinic at Seattle Cancer Care Alliance, said in a press release. “Clinical trials have shown the treatment to be safe and effective and, with the FDA approval, we will be able to make the treatment available to more patients.”
The FDA granted accelerated approval Feb. 5 to lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) — a CD19-directed, genetically modified, autologous CAR T-cell therapy — for adults with relapsed or refractory diffuse large B-cell lymphoma who received two or more lines of systemic therapy. The indication includes DLBCL arising from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma and grade 3 follicular lymphoma. The therapy is not indicated for patients with primary central nervous system lymphoma.
Lisocabtagene maraleucel — commonly known as liso-cel — is the fourth CAR T-cell therapy approved by the FDA, and the third for large B-cell lymphoma.
The FDA previously approved axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead), or axi-cel, for treatment of adults with relapsed or refractory large B-cell lymphoma and tisagenlecleucel (Kymriah, Novartis) for certain types of lymphoma. The agency had twice delayed its decision on liso-cel, most recently because of an inability to conduct a manufacturing site inspection due to COVID-19-related travel restrictions.
Efficacy and safety data
The FDA based approval of liso-cel on data from the TRANSCEND-NHL-001 trial, which included 269 patients (median age, 63 years; interquartile range, 54-70; 65% men) with relapsed or refractory large B-cell lymphoma.
The efficacy analysis, which included 256 patients, showed an objective response rate of 73% (95% CI, 66.8-78) and a complete response rate of 53% (95% CI, 46.8-59.4) after one infusion of liso-cel. Fifty-eight percent of patients remained alive 1 year after therapy.
The safety analysis showed 46% of patients experienced cytokine release syndrome (CRS), but few cases (4%) were grade 3 or greater. In addition, 35% of patients had symptoms of neurotoxicity.
Efficacy results of the FDA-approved CAR T-cell therapies for large B-cell lymphoma are similar despite lack of a comparative study, according to Dennis Cooper, MD, medical oncologist and chief of the blood and marrow transplantation program at Rutgers Cancer Institute of New Jersey. The key difference among the therapies may be liso-cel’s superior safety profile, which has implications for access and affordability given that most patients indicated for the treatment are Medicare beneficiaries.
Liso-cel has a U.S. wholesale list price of $410,300 for a one-time infusion, which is higher than the price of axi-cel and tisagenleceucel, which are both $373,000 for a single infusion when indicated for certain types of lymphoma.
“Despite recent improvements in reimbursement, hospitals can lose a significant amount of money on patients who receive CAR T-cell therapy in the hospital,” Cooper told Healio. “The potential financial losses may inhibit consideration of this therapy.”
However, “given that we’re seeing a better safety profile and lower toxic side effects with liso-cel, we've also been able to deliver it to most of our patients in an outpatient setting,” Maloney said.
Such delivery can have a substantial impact on costs, as reimbursement rates are higher when patients receive CAR T-cell therapy as an outpatient and avoid many of the expenses associated with inpatient care in the week after infusion, Cooper said. Outpatient administration of tisagenlecleucel is possible but rare based on current research data, he said.
“It is likely that the introduction of liso‐cel will have an immediate impact on the venue of treatment, as the median time to CRS was 5 days and appeared to be relatively mild in most cases,” Cooper said. “Liso-cel appears to also represent a potentially curative therapy and the very low incidence of CRS or severe neurologic sequela is striking.”
Why liso-cel is unique
Liso-cel differs from previously approved CD19-directed CAR T cells in its defined composition of genetically modified CD8 and CD4 T cells designed to reduce the variability of these cells within the single dose.
The ratio of CD4 to CD8 cells in the product is constant, unlike the manufactured product for axi-cel or tisagenlecleucel, according to Frederick L. Locke, MD, co-leader of the immune-oncology program and vice-chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center, and member of the Cell Therapy Next Peer Perspective Board. Regardless, Locke added, previous research with axi-cel and tisagenlecleucel has shown that an exact ratio of CD4 and CD8 T cells in a product has no effect on treatment efficacy except in the rare, most extreme cases where the treatment comprised a very small percentage of one of the cell types.
“What we have confirmed is that you need both types of cells, but no association between efficacy and the ratio has been established in clinical trials,” Locke told Healio. “The real advantage of [liso-cel] is its safety profile.”
Liso-cel will include a boxed warning that outlines risks for CRS and neurotoxicity associated with CAR T-cell therapy. The FDA also is requiring the manufacturer to conduct a post-marketing observational study of patients treated with liso-cel to comply with its Risk Evaluation and Mitigation Strategy (REMS) monitoring program.
Bristol Myers Squibb said the therapy has “inpatient or outpatient administration options” and that it will provide liso-cel recipients with “disposable wearable technology” for real-time monitoring immediately after infusion via a smartphone app.
The manufacturer also said it plans to launch an “extensive network of treatment centers,” certified as compliant with REMS, to promote patient access to the therapy.
The long-term impact of liso-cel’s approval is not yet clear, but what is certain is that it provides another treatment option for certain cancer types where few options exist.
“CAR T cell therapy continues to make very important progress, and the FDA’s approval of this therapy for relapsed or refractory large B-cell lymphoma offers hope and optimism to a group of patients whose other treatments have failed them,” Caron Jacobson, MD, MMSc, assistant professor of medicine at Harvard Medical School and medical director of the immune effector cell therapy program at Dana-Farber Cancer Institute, told Healio. “As clinicians, our goal to help patients and improve their quality of life, and I’m encouraged to be able to provide another option for patients with no other effective treatments.”
Locke said he is uncertain whether liso-cel will increase access to CAR T-cell therapy but he welcomed the FDA’s approval of what could prove to be a safer option than what the commercial market currently offers.
He noted that nearly 60% of patients in the TRANSCEND-NHL-001 trial had no symptoms of CRS. Keeping such a large proportion of patients out of the hospital after infusion would provide immense benefits to patients and the health care system.
“Large transplant and CAR-T centers like Moffitt will be equipped to do this, and it could reduce the cost of care, but there needs to be a robust infrastructure in place that can rapidly admit the patient and provide 24-hour care if they become sick outside the hospital,” Locke said. “[Although] some posit that a therapy like this could be given at smaller clinics or in a community setting, I think it is unlikely over the short term. Significant infrastructure is needed to provide CAR T-cell therapy, even in the outpatient setting.”
Locke said the FDA’s approval of liso-cel is unlikely to broaden the pool of those eligible for CAR T-cell therapy, but that it will provide some level of competition for existing commercial CAR-T therapies.
The next step is to evaluate how well it performs in a real-world setting compared with its competitors, he said.
“The data so far suggest that liso-cel will cause lower rates of toxicity — especially severe toxicity — and the major question remains whether there is a trade-off that has an effect of efficacy,” Locke said. "Clinicians will be eager to use this as a standard of care, but only subsequent, well-designed observational studies can answer the question of whether liso-cel is as safe and effective as other CAR-Ts and whether this can be reliably administered in an outpatient setting.”
Breyanzi (prescribing information). Bothell, WA: Bristol Myers Squibb; 2021.
Bristol Myers Squibb. U.S. Food and Drug Administration approves Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel), a new CAR T cell therapy for adults with relapsed or refractory large B-cell lymphoma (press release). Available at: https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-Breyanzi-lisocabtagene-maraleucel-a-New-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Large-B-cell-Lymphoma/default.aspx. Accessed Feb. 7, 2021.
Fred Hutch. Fred Hutch statement regarding the FDA approval of CD19 immunotherapy, lisocabtagene maraleucel. Available at: https://www.fredhutch.org/en/news/releases/2021/02/fred-hutch-statement-regarding-the-fda-approval-of-cd19-immunoth.html. Accessed Feb. 8, 2021.
Kymriah (prescribing information). East Hanover, NJ: Novartis Pharmacueticals Corp.; 2020.
Yescarta (prescribing information). Santa Monica, CA: Kite Pharma, Inc.; 2021.
For more information:
Dennis Cooper, MD, can be reached at firstname.lastname@example.org.
Caron A. Jacobson, MD, can be reached at email@example.com.
Frederick L. Locke, MD, can be reached at firstname.lastname@example.org.
Editor’s Note: On Feb. 12, we updated this story and accompanying infographic to include the most recent safety data from Bristol Myers Squibb and Novartis. The list price for tisagenlecleucel for lymphoma also was corrected. The Editors regret this error.