Association of Baseline and Postinfusion Biomarkers with Safety and Efficacy Endpoints in Patients Treated with Orvacabtagene Autoleucel (orva-cel; JCARH125) in the Phase 1/2 Evolve Study (NCT03430011)
Authors: Piasecki Julia , Devries Todd , Radhakrishnan Aditya , Li Yan , Heipel Mark , Fox Brian A. , Beckett Valeria , Cota Stirner Mariana , Conte Kristin , Doerr Thomas , Mailankody Sham , Wong Sandy W. , McCarthy Philip L. 
Published: November 2020

Background: Orva-cel, a B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy, has shown promising preliminary efficacy and a favorable safety profile in patients with relapsed/refractory multiple myeloma in the ongoing phase 1/2 EVOLVE study (NCT03430011). Patients enrolled in the trial were heavily pretreated (median of 6 prior lines of therapy) and refractory to their last regimen per International Myeloma Working Group criteria. Five orva-cel dose levels (50, 150, 300, 450, and 600 × 106 CAR+ T cells) have been evaluated in 115 patients as of May 1, 2020. Here, we present the serum soluble BCMA (sBCMA) results and levels of immune-related serum factors associated with study safety and efficacy endpoints.
Methods: Baseline and postinfusion levels of sBCMA (preinfusion through disease progression) and 39 immune-related serum factors (preinfusion through Day 29) were quantitated in serum by immunoassay (MesoScale Discovery, Rockville, MD). Linear regression models were used to evaluate the effect of orva-cel dose on biomarkers. Logistic regression models were used to evaluate the association between biomarkers and binary clinical response and safety endpoints. All patients with ≥1-month follow-up were included in the safety analyses (n = 115); all patients with ≥3-months potential follow-up were included in the efficacy analyses (n = 102). For assessment of sBCMA levels at nadir, only patients with sampling at Day 75 or later were considered (n = 91).
Results & Conclusions: Baseline sBCMA levels (median [range], 480 [3.4-5126.5] ng/mL) correlated with established clinical measures of tumor burden, including percentage of malignant plasma cells in the bone marrow, paraprotein levels, and serum free light chain concentrations. Baseline sBCMA levels also correlated with laboratory measures predictive of prognosis, including β2-microglobulin, lactate dehydrogenase, and ferritin levels. As high tumor burden and high levels of these laboratory measures are both associated with poorer outcomes and increased frequency of adverse events (AEs), baseline sBCMA may provide a useful composite marker of disease burden and prognostic indicators. Patients with higher baseline sBCMA levels were more likely to experience AEs, including cytokine release syndrome (CRS) and neurological events (NEs) (P &lt; 0.05). Overall response rate (ORR) was not influenced by baseline sBCMA levels, indicating that circulating sBCMA did not interfere with the ability of orva-cel to bind to and kill tumor cells expressing BCMA such that patients achieved at least a short-term response. Despite a similar ORR, patients with high baseline sBCMA levels were less likely to have an ongoing response at Month 6 (P &lt; 0.05). These associations between baseline sBCMA levels and safety and efficacy endpoints appeared to hold within each dose level cohort, despite lacking power to detect a statistical difference.
sBCMA levels decreased after orva-cel infusion in all responding patients (n = 86), with nadir reached within 2-3 months (median [range] time to minimum concentration, 2.8 [0.4-17.9] months). A dose effect was observed, with a 34% decrease in sBCMA nadir, on average, for every 150 × 106 CAR+ T cell dose increase (P &lt; 0.05). sBCMA levels at nadir were associated with ORR, complete response rate, and Month 6 response rate (P &lt; 0.05). sBCMA concentrations within the first month postinfusion allowed for stratification of Month 6 responders vs nonresponders. The significance of this stratification increased from Days 4-5 through Month 2, indicating that sBCMA may serve as an important early biomarker of durable response.
Baseline levels of immune-related serum factors did not correlate with safety or efficacy endpoints in the current data set. A subset of serum factors characteristic of CAR T cell activation increased after orva-cel infusion; the peak levels of some biomarkers were associated with the orva-cel dose, including interleukin (IL)-2 and IL-6. Peak postinfusion levels of several inflammatory factors were associated with CRS (eg, IL-6 and IL-8) and NE (eg, tumor necrosis factor-α) grades (P &lt; 0.05). Correlative analysis is ongoing, and updated results will be presented.

Disclosures
Piasecki: Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Devries:Bristol-Myers Squibb Company: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Radhakrishnan:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Li:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Heipel:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Fox:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Beckett:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Cota Stirner:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Conte:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Doerr:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Mailankody:PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Physician Education Resource: Honoraria. Wong:Fortis: Research Funding; Amgen: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Research Funding; Roche: Research Funding; GSK: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. McCarthy:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Karyopharm: Consultancy, Honoraria; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board.