The European Medicines Agency has validated a Marketing Authorization Application for the CD19-directed CAR T-cell therapy lisocabtagene maraleucel for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma following at least 2 prior therapies.
Stanley Frankel, MD
The European Medicines Agency (EMA) has validated a Marketing Authorization Application (MAA) for the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel) for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma following at least 2 prior therapies.
The application is based on data from the multicenter phase 1 TRANSCEND NHL 001 study, the largest trial in third-line or greater relapsed/refractory large B-cell lymphoma (LBCL), as well as findings from the TRANSCEND WORLD trial. These studies examined patients with relapsed/refractory LBCL, including those with a broad range of histologies and high-risk disease. Notably, some participants received the CAR T-cell product in the outpatient setting.
The validation of the MAA confirms that the submission is sufficiently complete to begin the formal review process, Bristol Myers Squibb, the manufacturer of the drug, stated in a press release.
“With more than 30% of patients diagnosed with DLBCL ultimately relapsing after initial therapy and an expected overall survival (OS) of about 6 months for patients who have had 2 or more prior therapies, there is a need for new treatments,” Stanley Frankel, MD, senior vice president of Cellular Development at Bristol Myers Squibb, stated in the press release. “The EMA’s validation of our application is a critical step toward bringing liso-cel to patients in Europe.”
Results from the TRANSCEND NHL 001 study showed that liso-cell induced an objective response rate of 73% and a complete response (CR) rate of 53%, with a time to CR or partial response occurring at a median of 1 month.
At a median follow-up of 12 months, the median duration of response with the CAR T-cell product had not yet been reached. Additionally, 60.4% of patients remained in response at 6 months; 54.7% remained in response at 1 year.
The median progression-free survival (PFS) was 6.8 months (95% CI, 3.3-14.1), with just under half of the patients, or 44%, remaining free of disease progression. The median OS reported with liso-cel was 21.1 months (95% CI, 13.3-not reached), and more than half of patients (58%) were still alive at 1 year, including 86% of those who achieved CRs.
In the trial, a total of 344 patients with LBCL who had received ≥2 prior lines of therapy underwent leukapheresis, and a total of 269 patients were given the CAR T-cell product at 1 of 3 dose levels. Notably, patients who had high-risk characteristics who had been excluded from previous trials were eligible for enrollment on TRANSCEND NHL 001, including those with secondary central nervous system involvement or those with moderate comorbidities. As such, patients with creatinine clearance as low as 30 mL/min or left ventricular ejection fraction of 40% were eligible to participate. Notably, no lower limit of absolute lymphocyte count was in place with regard to eligibility.
Patients were permitted to receive bridging therapy following leukapheresis per investigator discretion if urgent disease control was required. The CAR T-cell infusion followed 3 days of lymphodepleting therapy comprised of fludarabine and cyclophosphamide.
A total of 25 patients were given nonconforming product that failed to meet all specifications for liso-cel, and as such, were not included in the primary analysis set. In 2 cases, liso-cel could not be manufactured. Additionally, 13 patients who had received CAR T cell infusion were not included in the efficacy analysis either because they did not have positron emission tomography (PET)–positive LBCL prior to liso-cel treatment (n = 4), they did not receive a PET scan following bridging therapy (n = 6), or for other reasons (n = 3). As such, a total of 256 patients were included in the efficacy analysis.
Participants had received a median of 3 prior lines of treatment, and 35% of patients received prior autologous or allogeneic hematopoietic stem cell transplant. Moreover, more than half of patients, or 67%, were refractory to chemotherapy. Notably, 44% had never achieved a CR with previous therapy. Fifty-nine percent of patients received bridging therapy. After comparable safety and analogous safety was noted across all 3 dose levels, all patients who received treatment were pooled for the analysis.
The majority of patients (89%) had high-risk features that are associated with a shortened OS, including high-grade B-cell lymphomas, an ECOG performance status of 2, primary refractory disease, being refractory to second-line or later treatment, no prior autologous stem cell transplant, and no CR achieved with previous treatment.
Of note, responses with the CAR T-cell product proved to be comparable across all patient subgroups, including those with different LBCL histologies and those with high-risk features. PFS benefit observed in patients with double-hit lymphoma or transformed lymphoma from nonfollicular histologies was found to be similar to what was reported in the overall DLBCL population.
Specifically, the median PFS and OS for patients who had a CR had not been reached; 65.1% of patients had been progression free and 85.5% of patients were alive at 12 months.
With regard to safety, liso-cel was found to have a favorable safety profile. Sixty percent of patients experienced grade ≥3 neutropenia with the product. Other grade ≥3 treatment-emergent adverse effects (TEAEs) observed with the treatment included neutropenia anemia (38%) and thrombocytopenia (27%). Any-grade cytokine release syndrome (CRS) occurred in 42% of patients and these events were observed at a median onset of 5 days. Grade ≥3 CRS was reported in 2% of patients.
Liso-cell was previously granted access to the PRIME scheme for the treatment of relapsed/refractory DLBCL, as well as Accelerated Assessment status, which decreases the maximum timeframe to 150 days for the EMA’s Committee for Medicinal Products for Human Use to review the application.
In May 6, 2020, the FDA extended the review period by 3 months for a biologics license application for liso-cel for the treatment of adult patients with relapsed/refractory LBCL following at least 2 prior therapies. Liso-cel was granted a priority review designation in February 2020 based on data from the TRANSCEND NHL 001 study.