Orvacabtagene autoleucel CAR-T shows ‘promising efficacy’ for advanced multiple myeloma
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A novel chimeric antigen receptor T-cell therapy showed high response rates among patients with relapsed or refractory multiple myeloma, according to updated results of the EVOLVE trial presented during the ASCO20 Virtual Scientific Program.
Orvacabtagene autoleucel (Juno Therapeutics, Bristol-Myers Squibb) — an autologous, B-cell maturation antigen (BCMA)-directed CAR T-cell therapy often referred to as orva-cel — also demonstrated an acceptable safety profile during phase 1 of the trial.
“BCMA has emerged as a promising treatment target in myeloma, and orva-cel is novel CAR T-cell therapy with an optimized manufacturing process that enriches for a central memory phenotype and could lead to more persistent, and hopefully more effective, treatment in this setting,” Sham Mailankody, MBBS, medical oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “Initial data from the ongoing EVOLVE study have demonstrated promising efficacy with orva-cel treatment in patients with relapsed or refractory multiple myeloma.”
Mailankody reported updated results from phase 1 of the study, designed to determine safety and recommended phase 2 dosing of orva-cel among patients with relapsed or refractory multiple myeloma. The latest results included 62 patients (median age, 61 years; range, 33-77; 58% men) who received higher dose levels of orva-cel.
Patients had three or more previous lines of therapy (median, 6; range, 3-18) that included a proteasome inhibitor immunomodulatory drug and an anti-CD38 monoclonal antibody. Nearly all (94%) had a previous autologous hematopoietic stem cell transplant, and 63% had bridging chemotherapy. Median time from diagnosis was 7 years (range, 2-24).
Patients received orva-cel dosed at 300 × 106 CAR T cells (n = 19), 450 × 106 CAR T cells (n = 19) or 600 × 106 CAR T cells (n = 24) after lymphodepletion chemotherapy with fludarabine and cyclophosphamide.
Safety results showed the most frequent treatment-related hematologic adverse events included neutropenia (90%), thrombocytopenia (52%) and anemia (50%). All cases of neutropenia were grade 3 or higher.
Grade 3 or higher infections occurred in 13% of patients.
Eighty-nine percent of patients developed cytokine release syndrome (CRS), but only two patients (3%) had grade 3 or higher CRS. Median time to onset of CRS was 2 days (range, 1-4), with median time to resolution of 4 days (range, 1-10).
Thirteen percent of patients had some form of neurotoxicity, including two patients (3%) with grade 3 or higher neurotoxicity. Median time to onset of neurotoxicity was 4 days (range, 1-6), with median time to resolution of 4 days (range, 1-10).
Two patients died within 90 days of orva-cel infusion — one who received the 300 × 106 CAR T-cell dose and one who received the 450 × 106 cell dose.
“CAR-T therapies have some fairly unique side effects, but the management of these toxicities has evolved in the last several years, leading to early intervention to minimize serious and prolonged toxicities,” Mailankody told Healio. “The toxicities noted in this trial are comparable to prior reports, including the rates of serious (grade 3 or higher) CRS and neurologic events.”
Efficacy results showed an overall response rate of 92%, with a very good or better partial response rate of 68%. Thirty-six percent of patients had a complete response to therapy.
Response rates appeared comparable among the three doses. However, all three patients who had a partial response or better at the 600 × 106 cell dose were minimal residual disease negative, compared with 84% of patients across all three dose levels.
“The median follow-up is different for the different dose levels, so additional follow-up is needed to determine if higher doses provide more durable responses,” Mailankody said.
Median PFS had not yet been reached for the 450 × 106 cell dose group (median follow-up, 8.8 months) or for the 600 × 106 cell dose group (median follow-up, 2.3 months) and was 9.3 months for the 300 × 106 cell dose group (median follow-up, 9.5 months).
Mailankody said currently approved treatments for patients with relapsed or refractory multiple myeloma who have had three or more previous lines of therapy confer ORRs of 30% to 40% and median OS of about 6 months to 12 months.
“The response rates noted in the trial are clinically meaningful,” Mailankody told Healio.
He reiterated that longer follow-up for PFS and OS is needed, especially for the recommended phase 2 dose of 600 × 106 cells.
“There are several other BCMA CAR T-cell therapies in development, and results of two other trials were also presented at ASCO,” he added. “The responses rates in all of these trials have been high, and it is premature to compare them at this time.”
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