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The China National Medical Products Administration’s Center for Drug Evaluation has granted a breakthrough therapy designation to relmacabtagene autoleucel for use in the treatment of patients with mantle cell lymphoma.
The China National Medical Products Administration (NMPA)’s Center for Drug Evaluation has granted a breakthrough therapy designation to relmacabtagene autoleucel (relma-cel; Carteyva) for use in the treatment of patients with mantle cell lymphoma (MCL).1
The designation is supported by data from the phase 2 JWCAR029-005 trial (NCT04718883), which set out to evaluate the safety and efficacy of the autologous CD19-targeted CAR T-cell therapy in adult patients with relapsed or refractory MCL in China.
The study is planned to enroll a total of 59 patients who are either relapsed or refractory to second-line or later regimens. To be eligible for enrollment, patients must have received an anti-CD20 monoclonal antibody, anthracycline- or bendamustine-containing chemotherapy, and a BTK inhibitor.
Moreover, patients need to be at least 18 years of age, have an ECOG performance status of 0 or 1, an expected survival of longer than 12 weeks, acceptable organ function, and adequate vascular access for leukapheresis.2 Those who received prior CD19-targeted therapy need confirmation that their lymphoma lesions still express CD19.
If patients had central nervous system (CNS)–only involvement by malignancy or primary CNS lymphoma, a history of another primary malignancy that has not been in remission for at least 2 years, deep venous thrombosis or pulmonary embolism, uncontrolled infection, acute or chronic graft-vs-host disease, a history of serious cardiovascular disease, or if they previously underwent allo-hematopoietic stem cell transplantation, they were excluded.
Study participants will receive relma-cel at a dose of 1.0 x 108 CAR-positive T cells, and they will be followed for 2 years following the infusion.
The primary objective of the trial is objective response rate, and secondary objectives included complete response (CR) rate, best objective response rate (ORR), best CR rate, adverse effects (AEs), type of AEs, severity of AEs, number of those with laboratory abnormalities, type of laboratory abnormalities, severity of laboratory abnormalities, duration of response (DOR), duration of complete and partial remission, time to response, time to CR, progression-free survival (PFS), and overall survival (OS), among others.
In September 2021, the NMPA approved relma-cel for use in the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) following 2 or more lines of systemic therapy.3 With this decision, relma-cel because the first CAR T-cell therapy to receive regulatory approval as a category 1 biologics product in China.
The approval was based on findings from the single-arm, multicenter phase 2 RELIANCE trial (NCT04089215), which enrolled 59 patients with relapsed/refractory LBCL in whom at least 2 lines of therapy had failed, including a CD20-targeted agent and an anthracycline.4
At a data cutoff date of December 31, 2020, relma-cel elicited a best ORR of 77.6%, with a best CR rate of 51.7% in 58 evaluable patients. Moreover, at a median follow-up of 17.9 months (range, 0.3-25.6), the median PFS with the CAR T-cell therapy was 7.0 months (95% CI, 4.8–not reached [NR]), and the median OS had not yet been reached (95% CI, NR-NR). The 12-month OS rate was 76.8%. The median DOR was also not reached (95% CI, 4.9-NR).
Regarding safety in the 59 patients who received treatment, 5.1% experienced grade 3 or higher cytokine release syndrome and 3.4% experienced grade 3 or higher neurological toxicity. Any-grade CRS was experienced by 47.5% of patients, and any-grade neurologic events were experienced by 20.3% of patients.
The most common grade 3 or higher treatment-related toxicities experienced with relma-cel included neutrophil count decrease (30.5%) and white blood cell decrease (13.6%). No treatment-related deaths were reported.
In a single-arm, open-label, dose-escalation, phase 1 trial (NCT03355859), relma-cel was evaluated in 10 patients with relapsed or refractory B-cell non-Hodgkin lymphomas;5 this included 8 patients with diffuse large B-cell lymphoma and 2 with MALT lymphoma.
All patients had received chemoimmunotherapy as induction treatment and more than 2 lines of salvage treatment. Two patients received bridging chemotherapy following T-cell collection because of rapid progression; this was followed by re-evaluation prior to infusion with the CAR T-cell therapy. Lymphodepletion preconditioning in the form of fludarabine at 25 mg/m2 and cyclophosphamide at 250 mg/m2 on day -4 to -2, followed by relma-cel infusion on day 0.
The CAR T-cell therapy was delivered as a single infusion at different levels; dose level 1 was 2.5 x 107 CAR T cells, dose level 2 was 5.0 x 107 CAR T cells, and dose level 3 was 1.0 x 108 CAR T cells.
Among 6 evaluable patients, 3 of whom had received the agent at dose level 1 and the remaining 3 had received it at dose level 2, the ORR was 100% on day 29; this included 4 CRs and 2 PRs. All patients experienced grade 1 CRS, with the main symptoms being fever, fatigue, and muscle soreness. No difference in CRS was observed between the dose levels. No patients experienced neurotoxicity.
Other AEs included leukopenia (grade 1/2, 16.7%; grade 3/4, 83.3%), hypofibrinogenemia (grade 1, 16.7%) liver dysfunction (grade 1, 33.3%), elevated C-reactive protein (grade 1, 83.3%), ferritin (grade 1/2, 83.3%), or interleukin-6 (grade 1/2, 100%).