REPORTING FROM ASH 2017
ATLANTA (FRONTLINE MEDICAL NEWS) – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
The current analysis includes 21 patients and an additional 5 months of follow-up, and showed an overall response rate of 94%, according to James N. Kochenderfer, MD , who presented the updated dose escalation data at the annual meeting of the American Society of Hematology.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial ) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
