Liso-cel Induces Statistically Significant Responses in R/R Follicular Lymphoma and Mantle Cell Lymphoma

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Lisocabtagene maraleucel (Breyanzi; liso-cel) elicited statistically significant and clinically meaningful responses in patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma (MCL), meeting the primary end point of the phase 2 TRANSCEND FL (NCT04245839) and phase 1 TRANSCEND NHL 001 (NCT02631044) trials, respectively.¹

The CAR T-cell therapy was also reported to induce high complete response (CR) rates in both populations, meeting a key secondary end point of the trials. Notably, no new safety signals were observed with liso-cel in either study.

A full evaluation of the trial data is planned, according to Bristol Myers Squibb.

“For people living with relapsed or refractory follicular lymphoma or MCL, there are limited treatment options that provide deep and durable responses, especially for [those] with high-risk disease,” Anne Kerber, senior vice president and head of Cell Therapy Development at Bristol Myers Squibb, stated in a press release. “…We believe these data further confirm [liso-cel’s] best-in-class and best-in-disease profile and underscore the significant progress we are making in bringing the promise of our differentiated CAR T-cell therapy, [liso-cel], to more patients.”

TRANSCEND FL

The open-label, global, multicenter, single-arm, phase 2 trial enrolled patients with relapsed or refractory follicular lymphoma that was grade 1, 2, or 3a; or those with marginal zone lymphoma.² To be eligible for enrollment, patients must have previously received at least 1 prior systemic treatment that includes an anti-CD20 agent or an alkylating agent. They also needed to have an ECOG performance status of 0 or 1, as well as acceptable organ function.

Notably, they could not have evidence, or a history, of diffuse large B-cell lymphoma and follicular lymphoma, or of transformed follicular lymphoma; they also could not have duodenal-type disease. Other key exclusion criteria included: a history of another primary malignancy that was not in remission for 2 years or longer, previous CAR T-cell or cell therapy, active hepatitis B or C virus, or active autoimmune disease in need of immunosuppressive treatment.

The trial was conducted in compliance with the International Council of Harminsation of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice, and in accordance with other applicable regulatory requirements.

TRANSCEND FL was comprised of the following periods: pretreatment, treatment, and posttreatment. In the first period, participants underwent screening, received leukapheresis, and were evaluated before receiving study treatment. During the treatment period, they received lymphodepleting chemotherapy in the form of fludarabine at 30 mg/m2 daily for day 3 days plus cyclophosphamide at 300 mg/m2 daily for 3 days. Two to 7 days after this treatment was completed, patients were administered liso-cel at a target dose of 100 x 106 CAR+ viable T cells. The posttreatment period will entail follow-up assessments of disease status and safety that will continue for 5 years.

In addition to ORR serving as the primary end point of the research, and CR rate serving as an important secondary end point, other end points of interest include duration of response (DOR), progression-free survival (PFS), overall survival, safety, pharmacokinetics, and quality of life.

TRANSCEND NHL 001

The open-label, multicenter, phase 1 TRANSCEND NHL 001 trial enrolled patients with relapsed/refractory B-cell NHL, including DLBCL, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma grade 3B, and MCL.^3,4

Patients needed to be at least 18 years of age; have received at least 2 prior lines of systemic therapy, including a prior anti-CD20 agent and an anthracycline and subsequently relapsed; and an ECOG performance status of 0 or 1. Patients were allowed to have previously undergone autologous or allogeneic hematopoietic stem cell transplant.

Participants underwent leukapheresis and subsequent bridging chemotherapy was permitted per the discretion of the treating physician. Lymphodepletion chemotherapy, comprised of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2, was given for 3 days once the CAR T-cell product was available and the patient was determined to be eligible for infusion.

Two to 7 days following the lymphodepleting regimen, liso-cel was given as 2 sequential infusions of CD8+ and CD4+ CAR T cells at one of the target dose levels of 50 x 106 CAR+ T cells, 100 x 106 CAR+ T cells, and 150 x 106 CAR+ T cells.

The primary outcome measures for this trial are treatment-related toxicities, dose-limiting toxicities, and ORR.¹ Secondary measures include CR rate, DOR, and PFS.

Findings presented at the 2021 ASH Annual Meeting showed that at 2 years of follow-up, liso-cel elicited an ORR of 73% in the cohort of patients with relapsed/refractory large B-cell lymphoma (n = 257), with a CR rate of 53%.⁵ The median DOR was 23.1 months (95% CI, 8.6-not reached). Moreover, the median PFS and OS was 6.8 months (95% CI, 3.2-12.7) and 27.3 months (95% CI, 16.2-45.6), respectively.

The probabilities of continued response, PFS, and OS at 24 months were 49.5% (95% CI, 41.4%-57.0%), 40.6% (95% CI, 34.0%-47.2%), and 50.5% (95% CI, 44.1%-56.5%), respectively.

The most frequently experienced grade 3 or higher adverse effects comprised neutropenia (60%), anemia (37%), thrombocytopenia (27%), reduced appetite (3%), hypotension (3%), cytokine release syndrome (2%), fatigue (1%), nausea (1%), headache (1%), diarrhea (<1%), dizziness (<1%), and vomiting (<1%).

The pharmaceutical company will be working with the study investigators to present detailed information from TRANSCEND FL and TRANSCEND NHL 001 at upcoming medical meetings, as well as to discuss the data with health authorities.¹

References

1. Bristol Myers Squibb’s TRANSCEND FL and TRANSCEND NHL 001 studies of Breyanzi (lisocabtagene maraleucel) in relapsed or refractory follicular lymphoma and mantle cell lymphoma meet primary endpoint of overall response rate. News release. Bristol Myers Squibb. May 1, 2023. Accessed May 1, 2023. https://news.bms.com/news/corporate-financial/2023/
2. A study to evaluate the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL) (TRANSCEND NHL). ClinicalTrials.gov. Updated April 19, 2023. Accessed May 1, 2023. https://clinicaltrials.gov/ct2/show/NCT04245839
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0
4. Study evaluating the safety and pharmacokinetics of JCAR017 in B-cell non-Hodgkin lymphoma (TRANSCEND NHL 001). ClinicalTrials.gov. Updated March 3, 2023. Accessed May 1, 2023. https://www.clinicaltrials.gov/ct2/show/NCT02631044
5. Abramson JS, Palomba ML, Gordon LI, et al. Two-year follow-up of Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed or refractory (R/R) large B-cell lymphomas (LBCL). Blood. 2021;138(suppl 1):2840. doi:10.1182/blood-2021-148948