A Phase I Study of RO7297089, a B-Cell Maturation Antigen (BCMA)-CD16a Bispecific Antibody in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Plesner Torben , Harrison Simon J , Quach Hang , Lee Cindy H. , Bryant Adam , Vangsted Annette Juul , Estell Jane , Delforge Michel , Offner Fritz , Twomey Patrick , Choeurng Voleak , Li Junyi , Hendricks Robert , Sumiyoshi Teiko , Miller Karen , Choi Eunpi , Schjesvold Fredrik H. 
Published: November 2021

Abstract
Background: RO7297089 is a bispecific tetravalent antibody targeting BCMA (Genentech licensed from Affimed GMBH), which is highly expressed on MM cells and CD16a, which is expressed on innate immune cells including natural killer (NK) cells, macrophages, and monocyte subsets. Here we report findings from a Phase I dose-escalation study of RO7297089 in patients with RRMM (GO41582, Study registration NCT04434469).

Methods: All patients had RRMM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bispecific antibodies, and therapies targeting BCMA was permitted. Patients received RO7297089 as weekly IV infusions in 14-day cycles with dose escalation guided by a model implementing the Bayesian continuous reassessment method with overdose control. In Arm A the first dose was given over a single-day infusion, and in Arm B the first dose was divided over two consecutive days. Dose limiting toxicities (DLT) were assessed from Cycle 1. Study objectives included safety, pharmacokinetics (PK), and biologic activity as assessed by the IMWG Uniform Response Criteria.

Results: As of 30 April 2021, 21 patients received RO7297089 at 5 dose levels (60 mg [n=3], 180 mg [n=5], 360 mg [n=4], 1080 mg [n=6], and 1850 mg [n=3]). Median age was 63 years (range 41-76) and median number of prior lines of therapy was 8 (range 2-11). Patients received a median of 8 doses (range 2-42) of RO7297089; 5 patients had prior BCMA-targeted therapy. The most common AEs were anemia (n=11), infusion related reaction (IRR; n=10), back pain (n=5), ALT increased (n=4), and thrombocytopenia (n=4). Eleven (52%) patients had ≥1 treatment-related adverse event (AE) which included IRR (n=9), C-reactive protein increase (n=3), ALT increase (n=3), AST increase (n=2), and thrombocytopenia (n=2). Grade ≥ 3 AEs included anemia (n=9), and platelet count decreased (n=5). Related Grade ≥ 3 AEs were ALT increase and AST increase and lymphocyte count decreased (both n=1). No DLTs or dose-dependent toxicities were reported. Fifteen patients discontinued study treatment due to disease progression (n=12), clinical relapse (n=2), and symptomatic deterioration (n=1). Four deaths were reported in the AE follow-up period, all due to disease progression. Thirteen IRR events (1 Grade 1, 12 Grade 2) were observed in 10 patients (48%). IRR was most common in Cycle 1 (12 events in 10 patients) and was uncommon in subsequent cycles (1 patient). Symptoms of IRR occurring in &gt;1 patient included fever, rigors/chills, and dyspnea. To mitigate IRRs, additional measures were implemented from the 180 mg dose level including steroid premedication and slow infusion for the first dose. Dividing the first dose over 2 days (Arm B) was also implemented from the 1080 mg dose level for improved convenience. Preliminary PK assessments demonstrated a more than dose proportional increase in the exposure of RO7297089 with increasing dose levels from 60-1080 mg, suggesting non-linear PK and target-mediated drug disposition, with a trend of approaching linear PK at doses higher than 1080 mg. The estimated half-life was supportive of weekly dosing. Preliminary observation showed 1/18 patients with treatment-induced anti-drug antibodies, which did not appear to impact PK. BCMA expression was detected in the bone marrow in all patients regardless of prior BCMA-targeted therapy. Levels of total soluble BCMA and soluble CD16a increased immediately after the first dose as expected suggesting engagement and stabilization of soluble factors by RO7297089. Of the 18 response-evaluable patients, 1 patient experienced a partial response (1080 mg cohort) per IMWG criteria. Ten patients had stable disease as their best response at dose levels of 60 mg (1/3 patients), 180 mg (2/5 patients), 360 mg (3/4 patients), 1080 mg (4/6 patients). One patient who started at the 60 mg dose and gradually escalated to the 1080 mg dose has been on treatment for 9.5 months with stable disease at the time of the clinical cut-off date.

Conclusions: Treatment with RO7297089 was well-tolerated at the dose levels tested, although infusion reactions necessitated long infusion duration for the first dose. Modest activity has been observed to date with doses up to 1080 mg. There were no DLTs and a recommended phase 2 dose has not been identified. The latest clinical, biomarker, and PK data will be presented including data from higher dose level cohorts.

Disclosures
Plesner: AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; Takeda: Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding; Janssen: Other: Advisor, Research Funding. Harrison: Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Takeda: 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, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee: BMS: Other: Advisor, Research Funding; Janssen: Other: Advisor; Amgen: Other: Advisor. Bryant: Sandoz: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria. Estell: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Delforge: Bristol Myers Squibb: 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. Twomey: Genentech: Current Employment. Choeurng: Genentech: Current Employment. Li: Genentech: Current Employment. Hendricks: Genentech: Current Employment. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Miller: Genentech: Current Employment. Choi: Genentech: Current Employment. Schjesvold: Schain: Honoraria; AbbVie: Honoraria; Adaptive Biotechnologies: Consultancy; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Sanofi: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria; Bayer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria.

OffLabel Disclosure:
RO7297089 is a Bâ€'Cell maturation antigen (BCMA)-CD16a bispecific antibody intended for use if approved in patients with relapsed/refractory multiple myeloma