BCMA-targeted CAR-T shows ‘outstanding responses’ in advanced multiple myeloma
Idecabtagene vicleucel induced responses in nearly three-quarters of patients with relapsed or refractory multiple myeloma, according to initial results of the phase 2 KarMMa trial presented during the ASCO20 Virtual Scientific Program.
Higher doses of the investigational, autologous chimeric antigen receptor T-cell therapy led to increased response rates, results showed.
“The response rates with idecabtagene vicleucel were extremely clinically meaningful,” Nikhil C. Munshi, MD, associate professor of medical oncology at Dana-Farber Cancer Institute, told Healio. “For these patients to show deep and durable responses of this magnitude is quite impressive.”
Idecabtagene vicleucel (bb2121; bluebird bio, Bristol-Myers Squibb) targets the B-cell maturation antigen expressed on the surface of cancer cells.
A total of 128 patients (median age 61 years; range, 33-78; 59% men) in the pivotal KarMMa trial received idecabtagene vicleucel at one of three dose levels. Patients had received a median six (range, 3-16) previous therapies, and 84% were triple-refractory to common treatments, including an immunomodulatory agent, proteasome inhibitor and anti-CD38 antibody. Most patients (88%) received bridging therapy.
Overall response rate served as the primary endpoint. Secondary endpoints included complete response rate, duration of response, PFS and OS.
Median follow-up was 13.3 months across all dose levels, with data cutoff on Jan. 14.
Results showed an ORR of 73% (95% CI, 65.8-81.1) and a complete response rate of 33% (95% CI, 24.7-40.9). Median time to complete response was 2.8 months (range, 1-11.8).
Twenty percent of patients had very good partial responses and 21% had partial responses to therapy.
To put the results into perspective, Munshi said the typical ORR is 25% to 30% with currently available therapies for advanced multiple myeloma.
“This means that [idecabtagene vicleucel] has led to outstanding responses that far exceed anything else we have tried before in this group of patients,” he said.
Median duration of response was 10.7 months (95% CI, 9-11.3).
Survival data showed median PFS of 8.8 months (95% CI, 5.6-11.6) and median OS of 19.4 months (95% CI, 18.2 to not estimable) among all patients treated with idecabtagene vicleucel.
Both ORR and PFS increased substantially with higher doses of treatment. ORRs ranged from 50% with the lowest dose (150 × 106 CAR T cells/kg) to 82% with the highest dose (450 × 106 CAR T cells/kg). PFS ranged from a median 2.8 months (95% CI, 1 to not estimable) with the lowest dose to a median 12.1 months (95% CI, 8.8-12.3) with the highest dose.
Researchers deemed the highest dose of idecabtagene vicleucel to be the optimal dose.
The safety analysis showed most patients (84%) experienced cytokine release syndrome (CRS), but fewer than 6% had grade 3 or higher CRS.
Twenty-three patients (18%) developed neurotoxicity after infusion, with less than 6% experiencing grade 3 or higher neurotoxicity.
CAR T-cell persistence appeared durable, with infused cells detected in 59% of patients at 6 months and 36% at 12 months.
Munshi noted that patients who had complete responses to therapy tended to have more durable responses, as well. He added that patients who responded to therapy had a significantly higher number of CAR T cells in their circulation that those who did not respond.
The manufacturers submitted a biologics license application for idecabtagene vicleucel to the FDA, which responded with a refusal to file letter requesting more information regarding the Chemistry, Manufacturing and Control module of the application.
Nevertheless, Munshi said he is confident idecabtagene vicleucel will achieve FDA approval for patients with relapsed or refractory multiple myeloma.
“The clinical data is not the issue with the study,” he told Healio. “This treatment has a very good chance of being approved because it is showing outstanding response rates in this patient population.”
Perspective
Back to TopThis study by Munshi and colleagues met its endpoints of ORR and complete response. At median follow up of 13.3 months across all target dose levels, nearly three-fourths of patients achieved response, with one-third achieving complete response.
More impressively, responses were deep, with 26% of patients who achieved complete response and 39% of patients with very good partial responses or better achieving minimal residual disease negativity, defined as less than 10-5 nucleated cells using next-generation sequencing. Best responses were seen at a dose of 450 × 106 cells, with an ORR of 82%. About half of those who achieved very good partial responses or better at this dose level also achieved minimal residual disease negativity.
Median duration of response and PFS across all dose levels were 10.7 and 8.8 months, respectively, which are comparable to those of other agents used for the treatment of relapsed or refractory multiple myeloma.
Duration of response, PFS and depth of response increased with idecabtagene vicleucel dose, with the best responses seen at the dose of 450 × 106 cells. Patients who achieved deeper responses had longer PFS.
Data for OS were immature at the time of presentation.
Idecabtagene vicleucel was efficacious irrespective of age, cytogenetic risk profile, tumor burden, BCMA expression and presence of extramedullary disease. Researchers observed efficacy even among patients with triple- and penta-refractory disease and those who received bridging therapy with no response, making it an attractive salvage treatment option for this hard-to-treat population.
The toxicity profile for idecabtagene vicleucel is manageable, with CRS experienced by a majority (84%) of the patients. Although incidence increased with the dose of the cell product, most patients had grade 1 or grade 2 CRS, with very few experiencing grade 3 or higher CRS, even at higher dose levels. CRS was short-lived for most patients and resolved with the use of tocilizumab (Actemra, Genentech) or corticosteroids.
Neurotoxicity, which occurred infrequently, was mostly grade 1 or grade 2 and resolved without intervention. No grade 4 or grade 5 events occurred. Cytopenias were very common, mostly grade 3 or higher and unrelated to the dose but probably related to poor bone marrow reserve from extensive prior treatment and/or tumor burden. Many patients had delayed cell recovery, and infections were very common at all dose levels.
Five patients died within 2 months of treatment with idecabtagene vicleucel, including three treatment-related deaths.
Idecabtagene vicleucel seems to be a safe and efficacious CAR T-cell therapy option for patients with heavily pretreated relapsed or refractory multiple myeloma. Close monitoring for infection and aggressive management is warranted given the high risk for cytopenias and reported infection-related deaths.
Large phase 3 studies will provide more data on efficacy and safety outcomes. A phase 1 clinical trial (KarMMa-4 study) is investigating idecabtagene vicleucel as consolidation after induction therapy among patients with high-risk, newly diagnosed multiple myeloma. Clinical trials like these can inform us regarding whether use of idecabtagene vicleucel earlier in the treatment algorithm can lead to better outcomes in terms of response, survival and adverse events. Also, trials comparing idecabtagene vicleucel to other salvage therapy regimens for myeloma, including autologous stem cell transplantation, are warranted.
Collapse
Munshi NC, et al. Abstract 8503. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
