On December 5, 2020 Bristol Myers Squibb (NYSE: BMY) and bluebird bio, Inc. (Nasdaq: BLUE) reported updated data evaluating the companies’ investigational B-cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR) T cell therapy, idecabtagene vicleucel (ide-cel), were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, bluebird bio, DEC 5, 2020, View Source [SID1234572220]). The data include longer-term updated results from the original Phase 1 CRB-401 study of ide-cel in relapsed and refractory multiple myeloma (RRMM), including the primary endpoint of safety and exploratory endpoints of progression-free survival (PFS) and overall survival (OS). Analyses of the pivotal registrational KarMMa trial will also be presented at the ASH (Free ASH Whitepaper) meeting, including an analysis of health-related quality of life in patients with RRMM treated with ide-cel, and a subgroup analysis of outcomes for patients with high-risk RRMM. A subgroup analysis of elderly patients with RRMM treated with ide-cel in the KarMMa study were presented today. In addition, data from the ongoing Phase 1 CRB-402 study of bb21217, an investigational BCMA-directed CAR T cell therapy, were presented today at the meeting.
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"Building on our experience in multiple myeloma, Bristol Myers Squibb is dedicated to delivering the promise of CAR T cell therapy to patients with relapsed and refractory multiple myeloma," said Kristen Hege, senior vice president, Early Clinical Development, Hematology/Oncology and Cell Therapy, Bristol Myers Squibb. "Ide-cel and bb21217 are part of our broad cell therapy development program intended to bring transformative therapies to patients in need, and these data from different studies, including the longest follow-up for any anti-BCMA CAR T cell therapy from the original CRB-401 study and important analyses from our pivotal KarMMa trial, further underscore the potential of ide-cel to improve patient outcomes with durable responses and clinical benefits for patients with triple-class exposed multiple myeloma."
"The breadth of data presented at ASH (Free ASH Whitepaper) from across our studies underscores our commitment to the continued innovation of cell therapies for patients with multiple myeloma," said David Davidson, M.D., chief medical officer, bluebird bio. "We are encouraged by the longer-term results from the Phase 1 CRB-401 study, showing consistency with the depth and durability of responses observed in the Phase 2 KarMMa study, and reinforcing the role of ide-cel as an important potential therapeutic option for patients with triple-class exposed multiple myeloma. Additionally, we are pleased to see the updated results from the Phase 1 CRB-402 study, which continue to suggest promising response rates and durability. As had been hoped, early data also suggest that enrichment of bb21217 for memory-like T cells may be associated with sustained response. We look forward to presenting additional data from across our ide-cel and bb21217 development programs in the future as we work to transform the treatment landscape for patients living with this devastating disease."
Updated Results from CRB-401 Study of Ide-cel
In the Phase 1 CRB-401 study, 62 patients with heavily pretreated relapsed and refractory multiple myeloma were treated with ide-cel across dose levels of 50, 150, 450, or 800 × 106 CAR positive T cells (Presentation #131). The primary endpoint was safety, and secondary and exploratory endpoints included response rates, PFS, OS, and minimal residual disease (MRD).
Safety remained consistent with previously reported results from CRB-401. The most frequent adverse events (AEs) were neutropenia (92%), cytokine release syndrome (CRS; 76%), anemia (76%), and thrombocytopenia (74%). The most frequent Grade 3/4 AEs were neutropenia (89%), leukopenia (61%), anemia (57%), and thrombocytopenia (57%). Most CRS events were Grade 1 or 2. Four patients (7%) had Grade 3 CRS; there were no Grade 4 or 5 CRS events reported.1
Among 62 patients treated with ide-cel in this study, the overall response rate (ORR) was 76%, including 24 patients (39%) who achieved a complete response (CR). The median duration of response (DoR) was 10.3 months. Median PFS was 8.8 months and median OS was 34.2 months, with a median follow-up of 14.7 months. Full results from the CRB-401 study will be presented today in an oral presentation (Presentation #131).1
"The CRB-401 study continues to demonstrate the potential of ide-cel to provide deep and durable responses for heavily pre-treated relapsed and refractory multiple myeloma patients," said Yin Lin, M.D., Ph.D., presenting author, associate professor of hematology at Mayo Clinic. "This longer-term data is also important as it reflects a meaningful median duration of response for hard-to-treat patients, further highlighting the importance of ide-cel as a potential innovative treatment for patients with significant unmet treatment needs."
Analyses of Pivotal KarMMa Study: Subgroup Analyses of Ide-cel Outcomes in High-Risk and Elderly Patients and Health-Related Quality of Life
Ide-cel demonstrated deep and durable responses in the pivotal Phase 2 KarMMa study of patients with triple-class exposed relapsed and refractory multiple myeloma. A subgroup analysis was conducted to assess outcomes of treatment with ide-cel across target dose levels of 150 to 450 × 106 CAR positive T cells in patients with poor prognosis, including those with extramedullary disease, high-risk cytogenetics, and high tumor burden.
In the analysis of 128 patients, ide-cel demonstrated deep and durable responses across the majority of subgroups, including those with the highest risk. The ORR and CR rate were ≥65% and ≥20%, respectively, for the majority of high-risk subgroups. Additionally, in the majority of the high-risk subgroups, the median DoR was >9.2 months and the median PFS was >7.5 months. Results will be presented in a poster presentation on Monday, December 7 (Presentation #3234).2
A separate subgroup analysis was conducted to evaluate the outcomes of treatment with ide-cel in elderly patients (Presentation #1367). Multiple myeloma occurs most commonly among the older population, with a median age of 69 at diagnosis. Advanced age has been shown to negatively affect prognosis and limit treatment options.3
Of the 128 patients treated with ide-cel in the KarMMa study, 45 patients (35%) were aged ≥65 years and 20 patients (16%) were aged ≥70 years. Response rates for both age groups were comparable and consistent with the overall ide-cel treated population, across all target dose levels, with ORRs of 84% to 90% and CR rates of 31% to 35%.3
Likewise, median DoR among responders in both age groups (10.7 months in patients aged ≥65 years and 11.0 months in patients aged ≥70 years) was similar to that of the overall ide-cel treated population. Median PFS was 8.6 months (95% CI, 4.9-12.2) in patients aged ≥65 years and 10.2 months (95% CI, 3.1-12.3) in patients aged ≥70 years. Additionally, no new safety signals were observed.3
In an analysis of the impact of ide-cel treatment on health-related quality of life (HRQoL) measures in patients with relapsed and refractory multiple myeloma from the KarMMa study, ide-cel was associated with clinically meaningful QoL benefits without compromising any HRQoL domains (Presentation #437). Patients demonstrated a clinically meaningful improvement in most functioning and symptom scores from baseline to Month 3 through 15, with statistical significance (p<0.05) reached at various time points for different subscales throughout the follow-up period. Full results from the HRQoL analysis will be presented tomorrow, Sunday, December 6, in an oral presentation (Presentation #437).4
Phase 1 CRB-402 Study of bb21217
Updated safety and efficacy results from the ongoing Phase 1 study (CRB-402) of bb21217, an investigational BCMA-directed CAR T cell therapy being studied in patients with relapsed and refractory multiple myeloma, were also presented today in an oral presentation (Presentation #130). bb21217 uses the ide-cel CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention of increasing the in vivo persistence of CAR T cells.
As of the September 1, 2020 cutoff date, 69 patients were treated with bb21217 and updated results include new data following the introduction of a manufacturing process change. The study has completed enrollment and follow-up is ongoing as data continue to mature and the durability of response at the RP2D is assessed.5
About Ide-cel
Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3-ζ chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.
Bristol Myers Squibb and bluebird bio’s broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.
Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between Bristol Myers Squibb and bluebird bio.
Ide-cel is not approved for any indication in any geography.
About bb21217
bb21217 is an investigational BCMA-targeted CAR T cell therapy that uses the ide-cel CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention of increasing the in vivo persistence of CAR T cells. bb21217 is being studied for patients with multiple myeloma in partnership between bluebird bio and Bristol Myers Squibb.
The companies’ clinical development program for bb21217 includes the ongoing Phase 1 CRB-402 study. CRB-402 is the first-in-human study of bb21217 in patients with relapsed and refractory multiple myeloma (RRMM), designed to assess safety, pharmacokinetics, efficacy and duration of effect. CRB-402 is a two-part (dose escalation and dose expansion), open-label, multi-site Phase 1 study of bb21217 in adults with RRMM. A total of 69 patients have been treated with bb21217 and the study has completed enrollment. For more information visit: clinicaltrials.gov using identifier NCT03274219.
bb21217 is not approved for any indication in any geography.
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