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Japan’s Ministry of Health, Labour and Welfare has approved lisocabtagene maraleucel, a CAR T-cell therapy designed to target CD19, for the treatment of patients with relapsed or refractory large B-cell lymphoma, as well as relapsed/refractory follicular lymphoma.
Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved lisocabtagene maraleucel (liso-cel; Breyanzi), a CAR T-cell therapy designed to target CD19, for the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL), as well as relapsed/refractory follicular lymphoma, according to an announcement from Bristol Myers Squibb.1
This regulatory decision was based on safety and efficacy data from the phase 1 TRANSCEND NHL 001 trial (NCT02631044), which examined liso-cel in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL), as well as the phase 2 TRANSCEND WORLD trial (NCT03484702), which looked at the agent in patients with relapsed/refractory B-cell NHL.
“I am pleased that we have received regulatory approval in Japan for Breyanzi, our first CAR T cell therapy, which will allow us to provide a new treatment option for patients fighting relapsed or refractory LBCL and relapsed or refractory follicular lymphoma,” Jean-Christophe Barland, president and CEO of Bristol-Myers Squibb K.K. and Celgene K.K., stated in a press release. “In addition, we are filing an application for a further CAR T-cell therapy to address more unmet medical needs.”
TRANSCEND NHL 001 enrolled a total of 344 patients with relapsed/refractory LBCL.2 To be eligible for enrollment, patients had to have PET-positive relapsed or refractory diffuse LBCL (DLBCL), high-grade B-cell lymphoma with rearrangements in MYC and either BCL2, BCL6, or both, primary mediastinal B-cell lymphoma, or follicular lymphoma. Patients also needed to have previously received at least 2 prior lines of systemic treatment and subsequently relapsed.
Notably, patients who received prior autologous or allogeneic hematopoietic stem cell transplant were permitted, as were those with moderate comorbidities of renal, cardiac, and secondary central nervous system involvement.
All patients underwent leukapheresis, and 269 went on to receive at least 1 dose of liso-cel at 1 of 3 dose levels: 50 × 106, 100 × 106, or 150 × 106. All dose levels were evaluated for dose-limiting toxicities (DLTs) and activity based on complete response (CR) in the dose-finding and -expansion phases of the trial. Notably, those who achieved a CR following treatment with liso-cel and subsequently relapsed were able to receive re-treatment. Additionally, patients were able to receive treatment in the outpatient setting per investigator discretion.
The primary end points for the study included incidence of adverse effects (AEs), probability of DLTs, and objective response rate (ORR). Key secondary end points comprised CR, duration of response, progression-free survival, overall survival, and cellular kinetic variables.
Of the 269 patients who received liso-cel, 65% were male, 42% were 65 years of age or older and 10% were 75 years of age or older. Additionally, 51% of patients had DLBCL not otherwise specified and 29% had DLBCL transformed from indolent lymphomas. Fifty-eight percent of patients had an ECOG performance status of 1, and 26% had received 4 or more prior lines of systemic therapy. Moreover, 67% of participants had chemotherapy-refractory disease.
The median follow-up for overall survival for all patients who underwent leukapheresis was 18.8 months (95% CI, 15.0-19.3), and recommended target dose of liso-cel was established as 100 × 106 CAR T-cells.
Among 133 patients included in the primary efficacy evaluation population, liso-cel elicited an ORR of 74.4% (95% CI, 66.2%-81.6%), which exceeded the protocol-defined threshold ORR of 40%. Additionally, the ORR among 256 patients in the efficacy analysis population who received anti-CD19 CAR T cells was 72.7% (95% CI, 66.8%-78.0%).
In terms of safety, 269 patients treated with liso-cel on this trial were evaluated. AEs occurred in 201 patients, the most common of which were cytokine release syndrome (CRS; 42.0%), fatigue (17.8%), neutropenia (16.4%), anemia (13.8%), headache (13.4%), thrombocytopenia (11.5%), confusion (11.5%), tremor (11.2%), and hypotension (10.4%).
In the TRANSCEND WORLD trial, liso-cel elicited an ORR of 58.8% (95% CI, 40.7%-75.4%), while the ORR among the 10 Japanese subjects enrolled on trial was 70.0% (95% CI, 34.8%-93.3%) as of the data cutoff date of September 2019. As of June 2020 data cutoff, the ORR among 46 patients in the study population was 63.0% (95% CI, 47.5%-76.8%), and 70.0% (95% CI, 34.8%-93.3%) among the 10 Japanese subjects.
In terms of safety, AEs were reported in 42 of the 46 patients enrolled to the study. The most common AEs included neutropenia (52.2%), CRS (41.3%), anemia (39.1%), thrombocytopenia (39.1%), pyrexia (39.1%), leukopenia (23.9%), confusion (15.2%), fatigue (13.0%), and febrile neutropenia (13.0%).
In February 2021, the FDA approved liso-cel for the treatment of adult patients with certain types of LBCL who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment based on data from TRANSCEND NHL 001.