The European Commission has granted marketing authorization to the CD19-directed CAR T-cell therapy lisocabtagene maraleucel for use in adult patients with relapsed or refractory diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B following 2 or more lines of systemic treatment.
The European Commission has granted marketing authorization to the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) for use in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B) following 2 or more lines of systemic treatment.1
The authorization is supported by findings from the phase 1 TRANSCEND NHL 001 trial (NCT02631044), in which 73% of 213 patients evaluable for efficacy (95% CI, 67%-78.5%) responded to treatment with liso-cel; this included 53% of patients who experienced a complete response (CR; 95% CI, 47%-60%), meaning they had minimal or no detectable lymphoma after treatment.
In all responders, the median duration of response (DOR) was 20.2 months (95% CI, 8–not reached [NR]) with the CAR T-cell therapy. Among those who experienced a CR with liso-cel, the median DOR was even longer, at 26.1 months (95% CI, 23-NR).
“Advancing cell therapies is a significant part of our commitment to deliver innovative and potentially curative treatments in order to transform the lives of people living with cancer,” Samit Hirawat, MD, chief medical officer of Bristol Myers Squibb, stated in a press release. “[Liso-cel] addresses an ongoing unmet need for patients in Europe battling relapsed or refractory LBCL who have few treatment options that provide long-term remission. The European Commission approval of [liso-cel] is a significant step toward bringing the novel and personalized science of CAR T-cell therapies to more patients around the world.”
TRANSCEND NHL 001 enrolled patients with relapsed/refractory LBCL, including DLBCL, high-grade B-cell lymphoma, PMBCL, and FL3B, who are at least 18 years of age, had an ECOG performance status of 0 to 2, a creatinine clearance level of 30 mL/min/1.73 m2, and a left ventricular ejection fraction of at least 40%.2 Those who previously underwent hematopoietic stem cell transplantation and those with secondary central nervous system (CNS) lymphoma were permitted.
Patients were first screened and then underwent leukapheresis. They were able to receive bridging therapy while the CAR T-cell therapy was being manufactured. When PET-positive disease was reconfirmed, patients were given a lymphodepletion regimen that included fludarabine at 30 mg/m2 and cytarabine at 300 mg/m2 for 3 days.
Liso-cel was then given at 1 of 3 dose levels, 2 to 7 days following lymphodepletion. The first dose level was 50 x 106 CAR-positive T cells, dose level 2 was comprised of 100 x 106 CAR-positive T cells, and dose level 3 was comprised of 150 x 106 CAR-positive T cells.
The primary end points of the trial included adverse effects (AEs) and independent review committee (IRC)–assessed objective response rate (ORR). Secondary end points comprised IRC-assessed CR rate, DOR, progression-free survival (PFS), overall survival (OS), and pharmacokinetics.
A previous analysis of the trial indicated that liso-cel induced an ORR of 73%, which included a CR rate of 53%. Follow-up data from the trial were shared during the 2021 ASH Annual Meeting & Exposition.
The median age among the 270 patients who received the CAR T-cell therapy was 63 years (range, 18-86); 41% of patients were 65 years of age or older and 10% were 75 years of age or older. Ninety-nine percent of patients had an ECOG performance status of 0, 3% had secondary CNS lymphoma, 67% were chemotherapy refractory, and 44% did not achieve a CR.
Patients had received a median number of 3 lines of prior systemic therapy (range, 1-8), 33% previously underwent autologous transplant, 3% previously underwent allogeneic transplant, and 59% received bridging therapy.
At a median follow-up of 19.9 months (range, 0.2-45.2), the median DOR was 23.1 months (95% CI, 8.6-NR), and 49.5% (95% CI, 41.4%-57.0%) were estimated to continue to respond at 2 years. The median IRC-assessed PFS was 6.8 months (95% CI, 3.3-12.7) with the CAR T-cell therapy, and the probability of PFS at 2 years was 40.6% (95% CI, 34.0%-47.2%). The median OS was 27.3 months (95% CI, 16.2-45.6), with a probability of OS at 2 years of 50.5% (95% CI, 44.1%-56.5%).
Safety of the CAR T-cell therapy was analyzed by pooling data from a total of 314 patients with relapsed/refractory LBCL who received the agent at a dose ranging from 44 x 106 CAR-positive viable T cells to 120 x 106 CAR-positive viable T cells spanning the following 4 studies: TRANSCEND NHL 001, TRANSCEND WORLD (NCT03484702), PLATFORM (NCT03310619), and OUTREACH (NCT03744676).
Thirty-nine percent of patients experienced cytokine release syndrome (CRS), 3% of whom experienced a grade 3 or 4 event. The median time to onset of this toxicity was 5 days (range, 1-14), with a median duration of 5 days (range, 1-17).
Twenty-six percent of patients who received the CAR T-cell therapy experienced neurologic toxicities, 10% of whom experienced effects that were grade 3 or 4 in severity. The median time to onset of this effect was 6 days (range, 1-66), and 99% of these effects were reported within the first 8 weeks post infusion. The median duration of these toxicities was 10 days (range, 1-84).
The most common grade 3 or higher toxicities experienced with liso-cel included neutropenia, anemia, thrombocytopenia, leukopenia, infection with an unspecified pathogen, and febrile neutropenia.
In February 2022, the FDA accepted and granted priority review to a supplemental biologics license application seeking the approval of liso-cel for the treatment of adult patients with relapsed or refractory LBCL in whom frontline therapy has failed.3 The application is supported by findings from the phase 3 TRANSFORM trial (NCT03575351), and regulatory agency is expected to decide by June 24, 2022 under the Prescription Drug User Fee Act.