Adding crenigacestat, a γ-secretase inhibitor (GSI), to anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy was found to produce deep and durable responses, and the results suggest enhanced efficacy of the approach, according to preliminary results of a phase I trial in patients with multiple myeloma (MM). The results were published in Lancet Oncology.
“There has been much interest in methods to improve efficacy of CAR T-cell therapy in MM, and our approach, to increase BCMA antigen density, was shown to be both safe and feasible in this phase I safety and dose-finding trial,” said lead author Andrew J. Cowan, MD, of Fred Hutchinson Cancer Center and the University of Washington in Seattle. “These increases in BCMA density were associated with more prolonged responses.”
Treating patients with relapsed or refractory (R/R) MM remains a challenge. Recently, immune effector cell-activating therapies, CAR T cells targeting BCMA, an antigen expressed on MM cells, have been approved by the U.S. Food and Drug Administration, including idecabtagene vicleucel and ciltacabtagene autoleucel. Yet, despite overall response rates of 70% and greater in clinical trials, in the long term, many patients treated with anti-BCMA CAR T cells tend to relapse.
In preclinical xenograft mouse models, researchers previously showed that GSIs could increase the expression of the BCMA antigen and suggested that increased BCMA density may augment responses to BCMA-targeted CAR T cells in patients with MM, potentially reducing disease relapse and overcoming resistance to these cellular therapies.
In the current phase I trial, the researchers enrolled 18 patients with R/R MM, with a median age of 64.5 years. Seventeen participants were white, and one patient was Black. Seven (39%) patients had previously received anti-BCMA drugs.
Patients were first treated with three 25 mg doses of oral crenigacestat every other day. Patients then underwent a bone marrow biopsy sample to assess the BCMA density on the plasma cell surface as compared with density at screening. Subsequently, patients went through a lymphodepleting chemotherapy protocol and were infused with FCARH143, a fully human BCMA CAR T-cell therapy, manufactured by the Fred Hutchinson Therapeutic Products Program, using autologous T cells collected via leukapheresis.
Seventeen patients had to be admitted to the hospital, with a median hospital stay of 11 days. Grade 3-4 cytokine release syndrome occurred in five (28%) participants, and two (11%) experienced grade 3-4 immune effector cell-associated neurotoxicity. The most common non-hematologic grade 3 or higher adverse events were hypophosphataemia (78%), fatigue (61%), hypocalcaemia (50%), and hypertension (39%).
Nine (50%) of the 18 participants received all preplanned doses of crenigacestat. BCMA antibody binding capacity increased by a median of 12.2 times (range = 9.8-30.5) in all but one participant after treatment with crenigacestat and prior to CAR T-cell infusion.
The overall response rate was 89% (n=16). Eight patients (44%) had a stringent complete response rate of 44%. After 36 months of follow-up, the median duration of response was 14.4 months, with a median progression-free survival of 11.0 months. The median overall survival was 42.0 months.
“In this heavily pretreated population of patients with MM, we saw surprisingly durable responses and an acceptable safety profile,” noted Dr. Cowan. “Whether GSI plus BCMA CAR T-cell combinations are superior to BCMA CAR T cells alone or whether the safety profile will remain manageable in larger clinical trials needs to be tested in larger, randomized trials.
“We are eager to continue exploring this combination strategy for patients with R/R MM in more advanced phase trials,” he concluded.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Cowan AJ, Pont MJ, Sather BD et al. γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial. Lancet Oncol. 2023;24(7):811–822.
