ALBERT

Description: JNJ-4528 is a chimeric antigen receptor T cell (CAR-T) therapy containing two B-cell maturation antigen (BCMA)-targeting single-domain antibodies designed to confer avidity. We present translational data from the phase 1b cohort of an ongoing phase 1b/2 study conducted in the US to explore the safety and efficacy of JNJ-4528 in patients with R/R MM (NCT03548207). Apheresis samples were collected from 25 patients, and T cells were selected and transduced with a lentivirus encoding the BCMA CAR construct. Immune cell composition of both the apheresis samples and transduced cells following expansion ("drug product" [DP]) was evaluated by multiparametric flow cytometry. The median proportion of CAR+ T cells in the DP was 16% (range 6-28%) of total cells, with a median proportion of 12% (range 4-22%) CD4+ CAR+ and 7% (range 3-20%) CD8+ CAR+ T cells. The CD4:CD8 ratio of CAR+ T cells in the DP was variable between patients, with a median of 1.5 (range 0.62-4.40). Significant variability between patients was observed in the composition of the DP regarding T cell subsets (i.e., naïve, Tscm, Tcm, Tem, Teff, Temra) although this profile was comparable in the CAR- and CAR+ T cell subpopulations within each patient. Patients were administered a single infusion of the JNJ-4528 DP at a target dose of 0.75x106 CAR+ T cells/kg (target range 0.5-1.0x106). Of the 21 patients with a postbaseline disease evaluation, the overall response rate was 91% at a median follow-up of 3 months (range 1-10). Among the 15 patients with post-infusion day 28 evaluable bone marrow (BM) samples by next generation flow cytometry and/or next generation sequencing, 10 were minimal residual disease negative at the 10-5 level of sensitivity, 2 at 10-4 level of sensitivity, and 3 had unidentified clones. All patients expressed BCMA in BM tumor cells at baseline, as assessed by flow cytometry, although levels varied among patients. Clinical responses appear independent of BM BCMA expression. Following infusion, CAR+ T cells expanded reaching a peak between 20-87% of the total T cells in blood between days 10-14 post-infusion. The CD4:CD8 ratio and the proportion of T cell memory subsets in the final DP did not correlate with peak CAR+ T cell expansion. Peak CAR+ T cell expansion did not correlate with response. Ten patients had a follow-up of enumeration of CAR+ T cells in blood of at least 8 weeks. In 5 patients, CAR+ T cells decreased to below the limit of quantification (BLOQ) of the flow cytometry assay (5 cells/µl) within 8 weeks (range 2-7) post-infusion. Although preliminary, no difference was observed in the response rate between these patients compared with patients with measurable CAR+ T cells after 8 weeks. A similar trend was observed when expansion and persistence were assessed by measuring transgene levels. While both CD4+ and CD8+ CAR+ T cells expanded in vivo, the CD4:CD8 CAR+ ratio decreased at peak expansion compared with the final DP (from a median of 1.35 to 0.35), indicating a preferential expansion of CD8+ CAR+ T cells in blood. At peak expansion, CD8+ CAR+ T cells showed predominantly a central memory (Tcm) phenotype (CCR7+ CD45RO+; median of 90% [range 29.3-98.5%]). In contrast, CD4+ CAR+ T cells were enriched in effector memory (Tem) cells (CCR7- CD45RO+; median of 87% [range 69.5-98.1%]) at peak expansion. A similar trend in the CD4:CD8 ratio, as well as the T cell memory subset composition, was observed in BM of all 11 patients with evaluable samples at day 28. CD8+ CAR- T cells showed an approximate 50:50 ratio of stem memory (Tscm):Tcm subsets while CD4+ CAR- T cells showed an approximate 50:50 ratio of Tcm:Tem subsets, indicating a differential T cell maturation course for CD4+ and CD8+ CAR+ and CAR- T cells. Expansion of CAR+ T cells correlated with increases in serum cytokines levels (i.e., IL-6, IFNγ, IL-10) which peaked around day 10, coinciding with maximal expansion of CAR+ T cells. Generally, increases in some proinflammatory cytokines (i.e., IL-6) correlated with onset of cytokine release syndrome symptoms (median time to onset of 7 days [range 2-12]). Findings from the ongoing CARTITUDE-1 trial suggest that JNJ-4528 is a differentiated CAR-T cell therapy that is highly active at a relatively low dose, potentially related to a preferential and consistent in vivo expansion of CD8+ CAR+ T cells displaying a central memory phenotype. Disclosures Zudaire: Janssen R&D: Employment, Equity Ownership. Madduri:Foundation Medicine: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Usmani:Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Patents & Royalties, Research Funding; Celgene: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Janssen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Skyline DX: Consultancy; Amgen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Array Biopharma: Patents & Royalties, Research Funding; Sanofi: Patents & Royalties, Research Funding, Speakers Bureau; Takeda: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau. Jakubowiak:Adaptive Biotechnologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Geng:Legend Biotech: Employment, Equity Ownership. Rizvi:Legend Biotech: Employment, Equity Ownership. Nesheiwat:Legend Biotech: Employment, Equity Ownership. Schecter:Janssen R&D, LLC: Employment, Equity Ownership. Goldberg:Janssen R&D: Employment, Equity Ownership. Banerjee:Janssen R&D: Employment, Equity Ownership. Allred:Janssen R&D: Employment, Equity Ownership. Singh:Janssen R&D: Employment, Equity Ownership. Verona:Janssen R&D: Employment, Equity Ownership. McCaffery:Janssen R&D: Employment, Equity Ownership. Jagannath:Celgene Corporation: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Merck & Co.: Consultancy.

Description: Background: Substantial improvements in both progression free survival (PFS) and overall survival (OS) have been observed in patients with multiple myeloma over recent years. Despite these therapeutic advances, multiple myeloma remains incurable, and most patients eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 monoclonal antibodies (mAbs) and others. Understanding the effectiveness of current standards of care in heavily pretreated patients with relapsed and / or refractory multiple myeloma (RRMM) remains an area of unmet need, and there are currently no prospective data reflecting real-world practice in this patient population progressing after PIs, IMiDs and anti-CD38 mAbs. Study design: This prospective multinational efficacy and safety study of real-life current standards of care (real-life SOC) will be conducted in the USA and Europe in approximately 230 adult patients with RRMM who received at least 3 prior lines of therapy or are double refractory to PI & IMiD and have received at least a PI, an IMiD, and CD38 mAbs and with documented progressive disease (PD) since their last line of therapy and have an ECOG score of 0-1. Also, subjects with documented evidence of PD (as above) within the previous 6 months and who are refractory or non-responsive to their most recent line of treatment are eligible. There are no exclusion criteria due to the observational nature of the study. The treatments that these patients receive in real life will be assessed for safety and efficacy over a two-year period. Real-life SOC treatments are defined as the treatment used in local clinical practice by the investigator for adult subjects with RRMM, who meet the eligibility criteria. Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase up to 24 months from day 1, cycle 1 of the treatment. The Follow-up Phase will continue until study completion, which is defined as 24 months after the last subject receives the first dose of real life SOC treatment. Subjects will be treated until disease progression, unacceptable toxicity, or other reasons. The primary objective of the study is to evaluate the overall response rate (ORR) of real-life SOC treatments in participants with RRMM patients. The secondary and exploratory objectives of the study are the further evaluation of the clinical benefit, patient-reported outcomes (PROs), safety and the potential correlation of rate of minimal residual disease (MRD) negativity with duration of response (DOR), PFS and OS. Methods: Demographic and patient characteristics, clinical response parameters, PRO measures, health care resource utilization, and safety data will be descriptively summarized. Due to the observational nature of the study, there is no direct hypothesis being tested. Therefore, the sample size is based on the clinically acceptable precision of the 95% confidence interval for the primary objective of describing ORR under real-life current SOC treatment. For the primary endpoint exact 95% confidence intervals by the Clopper-Pearson method will be calculated. For therapies available to treat participants with RRMM the reported ORR is 30% or less. When the sample size is 230, using the large sample normal approximation, the width of a two-sided 95% confidence interval for the observed proportion will vary from 0.107 to 0.130 for an expected proportion varying from 0.20 to 0.40. Disclosures Moreau: AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Juno: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Goldschmidt:ArtTempi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma: Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Molecular Partners: Research Funding; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. Cavo:Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene: Speakers Bureau; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Gay:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Van De Donk:AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Potamianou:Janssen-Cilag: Employment. Sakabedoyan:Janssen-Cilag: Employment. Strulev:Jansen Pharmaceutica NV: Employment. Nesheiwat:Legend Biotech: Employment, Equity Ownership. Bergmans:Janssen-Cilag: Employment. Rizvi:Legend Biotech: Employment, Equity Ownership. Pilatowicz:Janssen-Cilag: Employment. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding.