Liso-Cel Meets Primary End Point of Event-Free Survival Improvement in Phase 3 Trial

Data from the phase 3 TRANSFORM trial (NCT03575351) of the chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) as second-line therapy for patients with relapsed/refractory large B-cell lymphoma (LBCL) resulted in a statistically significant improvement in the primary end point of event-free survival versus therapy with the standard-of-care comparator arm, according to the company responsible for developing the agent, Bristol Myers Squibb.

Additionally, toxicity profile observed with liso-cel was consistent with the safety data reported in the TRANSCEND NHL 001 trial (NCT02631044) which led to the FDA approving the CD19-directed therapy for patients with certain types of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), following 2 or more prior therapies.

“We ambitiously designed the TRANSFORM trial to evaluate Breyanzi’s potential in the second-line setting for patients with relapsed or refractory large B-cell lymphoma against the standard of care regimen of high-dose chemotherapy and autologous stem cell transplant,” Noah Berkowitz, MD, PhD, senior vice president of Hematology and Cell Therapy Development at Bristol Myers Squibb, said in a press release. “These positive interim results build on our commitment to bring CAR T-cell therapies into earlier lines and highlight the potential of Breyanzi to transform the treatment paradigm for this difficult-to-treat disease, possibly supplanting the need for patients to undergo current aggressive treatment regimens.”

These data represent the first time a treatment for relapsed/refractory LBCL has demonstrated benefit over high-dose chemotherapy and hematopoietic stem cell transplant (HSCT).

The ongoing trial aims to recruit 182 to patients to received either standard salvage therapy with physician’s choice rituximab (Ritxuan)–based combination, BEAM (carmustine, etoposide, cytarabine, and melphalan) high-dose chemotherapy, and HSCT or liso-cel. Patients receiving the CAR T-cell therapy are treated with lymphodepleting chemotherapy of intravenous fludarabine 30 mg/m2 plus intravenous cyclophosphamide at 300 mg/m2 for 3 days concurrently followed by liso-cel infusion.

To be eligible for enrollment, patients must have an ECOG performance status of 0 or 1 and either histologically proven DLBCL, de novo or transformed non-Hodgkin lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, primary mediastinal (thymic) large B-cell lymphoma, T-cell/histiocyte-rich LBCL, or grade IIIB follicular lymphoma. Patient’s disease must be refractory or relapsed to frontline CD20-antibody therapy and anthracycline-containing therapy within 12 months.

In the TRANSCEND NHL 001 trial,2 efficacy by response rate in 186 patients showed that liso-cel was capable of inducing a 73% (95% CI, 66.8%-78.0%) objective response rate (ORR), of which 53% (95% CI, 46.8%-59.4%) were complete responses. At the time of data cutoff, the duration of response had not been reached with rates at 6 and 12 months of 60.4% (95% CI, 52.6%-67.3%) and 54.7% (95% CI, 46.7%-62.0%), respectively.

The most common grade 3 or higher adverse effects were neutropenia (60%), anemia (37%), and thrombocytopenia (27%). Cytokine release syndrome (CRS) occurred in 42% of patients, with only 2% of patients having grade 3 or worse CRS. Neurologic events occurred at rates of 30% and 10%, respectively. Nine patients (6%) had dose-limiting toxicities. Safety information for liso-cel includes a Boxed Warning for CRS and neurotoxicity.

Overall, safety and activity of liso-cel did not appear to be dose dependent, and the recommended target dose based on the data was 100 × 106 CAR-positive T-cells.

Results regarding the primary end point will be evaluated and shared at an upcoming medical conference as well as with regulatory authorities.

References

1. Bristol Myers Squibb announces positive topline results from Phase 3 TRANSFORM trial evaluating breyanzi (lisocabtagene maraleucel) versus chemotherapy followed by stem cell transplant in second-line relapsed or refractory large b-cell lymphoma. News release. Bristol Myers Squibb. June 10, 2021. June 10, 2021. https://bit.ly/355XG2n

2. 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