Exposure-efficacy analysis for Elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) from the Phase 1 first-in-patient study (MagnetisMM-1)
Objectives: Elranatamab (PF-06863135) is a humanized heterodimeric bispecific molecule that targets B-cell maturation antigen (BCMA) on multiple myeloma cells and CD3 on T cells. Exposure and efficacy data were analyzed to guide the selection of recommended dose for expansion (RDE) in phase 1 and the Recommended Phase 2 Dose (RP2D).
Methods: The concentration-time data and clinical response of elranatamab from the dose escalation part of the Phase 1 ?rst-in-patient study (MagnetisMM-1, Study C1071001) were analyzed. The dose range encompassed by SC escalation was 80-1000 µg/kg weekly (QW), and clinical responses were observed starting from 215 μg/kg SC. Logistic regression was performed to assess the relationship between observed total elranatamab exposure (i.e., both soluble BCMA-bound or unbound elranatamab) and objective response rate (ORR based on IMWG criteria), as well as other covariates (e.g., baseline soluble BCMA). Free elranatamab exposure, predicted by a mechanism-based PK model was analyzed to further explore the relationship between sBCMA and clinical response. Upon completion of the expansion, the exposure-efficacy analysis was updated to verify the RDE selection.
Results: In dose escalation, efficacy appeared to be associated with total elranatamab exposure and plasma sBCMA supporting sBCMA acts as a potential decoy for BCMA-targeted agents. Logistic regression based on total exposure demonstrated that 1000 µg/kg QW is more likely to achieve superior efficacy in patients with high baseline sBCMA compared to lower doses. Furthermore, the predicted free PK profiles in the therapeutic dose range (≥215 μg/kg) are generally higher in responders compared with non-responders. The PK model also suggests 1000 µg/kg is more likely to achieve higher free PK exposure across different sBCMA ranges than lower doses. To maximize the potential for response by overcoming the sBCMA effect, a dose of 1000 µg/kg (or its equivalent fixed dose of 76 mg) was subsequently implemented in expansion cohorts as the selected RDE (full dose). Experience from the dose expansion cohort showed no clear correlation between baseline sBCMA and efficacy at this dose level, suggesting that the RP2D can achieve clinical benefit in RRMM patients with high baseline sBCMA. Meanwhile, 1000 µg/kg (76 mg) QW demonstrated a manageable safety profile similar to that observed in lower efficacious doses.
Conclusions: This integrated exposure-efficacy analysis evaluated the impact of baseline sBCMA and provided the rationale for selecting 1000 µg/kg (or its equivalent fixed dose of 76 mg) QW for further clinical development.
Author(s)
- Sibo Jiang, Pfizer, Inc. (Presenting Author)
- Jennifer E. Hibma, Pfizer, Inc. (CoAuthor)
- Hoi-Kei Lon, Pfizer, Inc. (CoAuthor)
- Edward M. Chan, Pfizer, Inc. (CoAuthor)
- Athanasia Skoura , Pfizer, Inc. (CoAuthor)
- Diane Wang, Pfizer, Inc. (CoAuthor)
- Mohamed Elmeliegy, Pfizer, Inc. (CoAuthor)
- Donghua Yin, Pfizer, Inc. (CoAuthor)