BCMA-directed CAR-T induces early, deep responses in advanced multiple myeloma
ORLANDO — An investigational chimeric antigen receptor T-cell therapy that targets the B-cell maturation antigen induced response in 100% of patients with relapsed or refractory multiple myeloma, according to results of the phase 1b/phase 2 CARTITUDE-1 trial presented at ASH Annual Meeting and Exposition.
More than two-thirds of patients in the open-label, multicenter study achieved complete response to the agent, JNJ-4528 (Janssen Pharmaceuticals).
“These patients are heavily pretreated and are usually running out of options,” researcher Deepu Madduri, MD, assistant director of the cellular therapy service within Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, told Healio. “Median OS in this group is less than a year for heavily refractory patients, so we need to come up with new therapies that provide sustained and deep responses.”
The study results were presented on the same day the FDA granted breakthrough therapy designation to JNJ-4528 for the treatment of adults with relapsed or refractory multiple myeloma who received at least three prior lines of therapy.
The JNJ-4528 CAR contains a 4-1BB costimulatory domain and two BCMA-targeting single domain antibodies. It is identical to the CAR used in the LEGEND-2 trial, a phase 1 investigator-initiated study of 74 patients conducted in China that demonstrated the safety and feasibility of the investigational CAR T-cell therapy.
The phase 1b portion of the CARTITUDE-1 trial evaluate the safety of JNJ-4528 and confirm the phase 2 dose as determined by the LEGEND-2 trial. Phase 2 of CARTITUDE evaluated efficacy of JNJ-4528 for patients with heavily pretreated multiple myeloma.
The study included 29 adults (mean age, 60 years; range, 50-75) diagnosed with multiple myeloma per International Myeloma Working Group criteria who had measurable disease. All patients had received at least three prior lines of therapy (median, 5; range, 3-18), and 25 (86%) were triple-refractory to a proteasome inhibitor, immunomodulatory drug and anti-CD38 antibody.
Twenty-five patients (86%) had undergone autologous stem cell transplant.
Study participants underwent apheresis to collect their T cells, and protocol allowed bridging therapy after apheresis.
Lymphodepletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over a 3-day period was given before CAR T-cell infusion. A single infusion of JNJ-4528 at the target dose of 0.75 x 106 cells/kg (target range, 0.5 x 106 to 1 x 106) was given 5 to 7 days after starting the lymphodepletion regimen.
Median follow-up was 6 months (range, 3-14).
All patients achieved response and 69% achieved complete responses, defined as partial responses or better as assessed by an independent review committee. An additional 17% of patients achieved very good partial responses and 14% achieved partial responses.
Twenty-seven patients (93.1%) remained progression free at data cutoff. All patients who could be evaluated for minimal residual disease (MRD) status were MRD-negative.
Twenty-seven patients (93.1%) developed CAR T-cell therapy-related cytokine release syndrome; however, all but two cases were grade 1 or grade 2. Median time to cytokine release syndrome onset was 7 days, with more than 90% occurring between 5 to 9 days after infusion. One patient who had prolonged grade 4 cytokine release syndrome died of treatment-related complications at day 99 after CAR T-cell infusion.
Three patients experienced immune effector cell-associated neurotoxicity syndrome; only one case was grade 3 or higher.
“The phase 1b portion of this study confirmed the phase 2 dose, and the results also show that this is a very safe and tolerable product that gave early and deep responses,” Madduri told Healio. “We were happy to see that the treatment was pretty safe, with not much neurotoxicity.”
More data and more follow-up are necessary to determine how this treatment will compare with currently available therapies for this patient population, said Madduri, noting the phase 2 portion is fully enrolled.
“There are a lot of CAR-Ts in the multiple myeloma space right now, and it’s just a matter of timing before they become approved therapies,” she said.
Madduri’s research group plans to conduct studies to move JNJ-4528 to an earlier line of treatment and assess if patients who failed only one prior therapy can achieve a longer duration of response.
“Sustained and deep responses were why CAR-Ts were created. We initially hoped that CAR-Ts would cure everything, but we have found that a true cure may still be way down the line,” Madduri said. “However, if we can provide patients with a one-time treatment that provides deep, sustained and durable response, then patients won’t have to come into the clinic once a week and can actually live their lives.” – by Drew Amorosi
Madduri D, et al. Abstract 577. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Janssen Pharmaceuticals sponsored this study. Madduri reports consultant roles with AbbVie, Celgene, Foundation Medicine, Janssen Pharmaceuticals and Takeda. Please see the abstract for all other authors’ relevant financial disclosuress.