© Phil McCarten 2017
James N. Kochenderfer, MD Photo courtesy of ASH
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.