Quantitative Pharmacology for Dose and Regimen Determination of Cevostamab Monotherapy in Relapsed/Refractory Multiple Myeloma

Background: In Phase I clinical trials of T-cell engaging bispecific molecules, the recommended dose and schedule are informed by evaluation of priming dose regimens which mitigate cytokine release syndrome (CRS) risk and target doses that impact the balance between efficacy and non-CRS safety. Having a quantitative pharmacology strategy can complement the clinical dose finding of T-cell engaging bispecifics. Here, we present the quantitative pharmacology strategy to inform the dose and schedule of monotherapy cevostamab, an FcRH5xCD3 bispecific antibody that facilitates T cell-directed killing of myeloma cells, and has shown promising activity and manageable safety in an ongoing Phase I study in patients with relapsed/refractory (R/R) multiple myeloma (MM) (GO39775 [NCT03275103]; Trudel et al. ASH 2021).

Methods: Complementary quantitative pharmacology approaches to characterize and decouple the pharmacological drivers for efficacy and CRS were used to inform the selection of the priming dose(s) (to mitigate CRS) and target dose (to maximize efficacy) of cevostamab recommended phase 2 dose (RP2D) in R/R MM patients. To identify a target dose with maximal benefit-risk profile, a model-guided clinical empirical dose escalation/expansion data, together with real-time population pharmacokinetics-tumor growth inhibition (PopPK-TGI) and exposure-response (E-R) characterizations across a dose range of 0.15mg − 252mg in study GO39775 for the clinically relevant safety and efficacy endpoints was employed. For the priming dose regimen evaluation, logistic regression analysis was performed to characterize the statistical relationship between cevostamab exposure and CRS. Given the time and exposure dependence of CRS, a mechanistic quantitative systems pharmacology (QSP) model was leveraged to identify a suitable priming dose regimen that can mitigate the CRS risk while enabling the delivery of higher target doses that would provide meaningful clinical benefit in patients with R/R MM. Specifically, the QSP model was utilized to evaluate the effect of various priming regimens on the post-dose IL-6 dynamics.

Results: The Sponsor used an integrated framework of clinical evidence and comprehensive modeling and simulation approaches (including QSP, PopPK-TGI, and E-R) for cevostamab across a wide range of doses/schedules in study GO39975. A comprehensive in silico evaluation based on QSP simulations indicated that the 0.3/1.2/3.6mg triple-step priming regimen prior to the target dose falls within the region of lowest post-dose peak IL-6 concentrations suggesting lowered CRS risk for cevostamab. The clinical data, along with the E-R and PopPK-TGI analyses, demonstrate that increasing cevostamab exposure is associated with higher response rates (overall response rate and VGPR+ rate), with the attainment of plateau at the 160mg Q3W dose, implying diminishing gains at doses beyond 160mg Q3W.

Conclusions: The model-guided clinical dose escalation/expansion data together with the quantitative pharmacology strategies and insights support that the 0.3/1.2/3.6mg triple-step priming regimen and the Q3W 160mg target dose provides a favorable benefit-risk for the R/R MM population.

Susilo:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Genentech, Inc.: Patents & Royalties. Dokhaei:Genentech, Inc.: Current Employment. Brooks:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in private company, Current equity holder in publicly-traded company. Vadhavkar:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Liu:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd, Eli Lilly, Regeneron: Current holder of stock options in a privately-held company. Tyagi:F. Hoffmann-La Roche Ltd, Gilead Sciences: Current equity holder in publicly-traded company; CytoKinetics Inc: Ended employment in the past 24 months; Genentech, Inc.: Current Employment. Wong:CTMX, BMRN, UBX: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment; For Henry AHC: Membership on an entity's Board of Directors or advisory committees. Samineni:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company.