Intravenous and Subcutaneous Administration of RG6234, a Novel GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Biomarker Results from a Phase I Study

Background: RG6234 is a GPRC5DxCD3 T-cell engaging bispecific antibody with a novel 2:1 format. GPRC5D is overexpressed on multiple myeloma (MM) cells and concurrent binding of RG6234 to GPRC5D on tumor cells and CD3 on T cells results in immunological synapse formation and potent T-cell directed tumor cell killing (Eckmann et al. ASH 2022). An ongoing Phase I study (NCT04557150) is investigating the safety, clinical activity, pharmacodynamics (PD), and pharmacokinetics of intravenous (IV) and subcutaneous (SC) administration of RG6234 in patients with RRMM. Clinical activity was observed in both dose escalations (overall response rate [ORR] IV: 71.4%; ORR SC: 60.4%) (Carlo-Stella et al. ASH 2022). Here, we report clinical biomarker data comparing the PD effects of IV and SC administration and confirming the mechanism of action and potency of RG6234 when given by both administration routes.

Methods: Exploratory biomarker analyses included dose-escalation data from 50 patients who received IV doses ranging from 6–10000μg and 46 patients who received SC doses ranging from 30–7200μg. In both cohorts, RG6234 administration was initiated with step-up dosing, reaching the target dose 2 weeks after the initial step dose. Peripheral biomarkers were evaluated using whole blood flow cytometry (IV, n=33; SC, n=40), plasma cytokines (IV, n=50; SC, n=46) and sBCMA (IV, n=36; SC, n=27) Protein Simple ELLA. MM cells were assessed at baseline and on-treatment by bone marrow (BM) aspirate flow cytometry and by BM biopsy CD138/CD8 immunohistochemistry. The data cut-off for the current analysis was June 8, 2022. Updated data will be presented.

Results: RG6234 induced rapid PD changes at all tested doses. With IV administration, cytokines (IFNγ, TNFa, CXCL10, IL6, IL10, IL2, IL8) peaked at 4 to 24 hours after the first infusion and cytokine peaks diminished significantly with subsequent administrations. SC administration resulted in a delayed cytokine release that peaked at 24 to 72 hours after the first injection and was 2.2–24.2-fold lower than with IV dosing. Cytokine peaks were comparably low after each SC step-up administration. After SC dosing, T-cell margination was delayed by 20 hours and recovery to 50% of baseline levels took on average 56 hours longer than with IV dosing. Analysis of paired baseline and on-treatment BM biopsies (IV, n=19; SC, n=8) revealed a comparable degree of T-cell recruitment towards the tumor with IV and SC dosing (2.3- and 1.6-fold increase, respectively, in CD8 T-cell density in responders at the end of Cycle 1). Both IV and SC administration induced rapid depletion of MM cells in responding patients, as demonstrated by a decrease in plasma sBCMA 8 days after the initial administration (median 24.9% [n=27] and 26.2% [n=18] reduction from baseline, respectively). By Cycle 3 Day 1, median decreases from baseline in plasma sBCMA among responders were 91.8% (n=24) after IV administration and 95.6% (n=12) after SC administration. Moreover, at the end of Cycle 1, the majority of patients (15/16 [93.8%] in the IV group and 14/15 [93.3%] in the SC group) had <1% MM cells in BM based on flow cytometry. GPRC5D expression was detected at baseline in almost all patients with evaluable BM aspirate (44/45, median of 94.7% GPRC5D+ MM cells).

Conclusions: Biomarker analysis indicates that RG6234 leads to T-cell engagement in the BM of patients with RRMM and demonstrates rapid and effective T-cell mediated anti-myeloma activity irrespective of the route of administration. Cytokine release, T-cell activation followed by BM infiltration, and MM cell depletion are early PD changes after IV and SC administration and precede clinical responses. Compared with IV dosing, SC administration reduces peak cytokine levels in Cycle 1, suggesting a more subtle immune activation and a potential safety benefit for patients.