Tomoko Freshwater 1, Miao Zhao 1, Inmaculada C. Sorribes 1, Ann Gramza 1, Andrew Chow 1, Douglas A Levine 1, Vassiliki Karantza 1, Brad Srinivasan 1, Wade Matthew Tokushige 1, Soniya Vaidya 2, Chetan Rathi 2, Wenbo Chen 1
1 Merck Sharp & Dohme LLC (Rahway, United States), 2 Daiichi Sankyo, Inc. (Basking Ridge, United States)
Objectives: Gocatamig (MK-6070), is a DLL3-targeting T-cell engager that redirects T cells to kill DLL3-expressing cancer cells. Gocatamig has shown promising antitumor activities following intravenous infusion as monotherapy in patients with SCLC, NEPC, and other NEN in an ongoing Phase 1 study (NCT04471727). The current recommended dosing regimen consists of a 1 mg priming dose on Cycle 1 Day 1 (C1D1), a 12 mg step up dose on Cycle 1 Day 8 (C1D8), and a 24 mg target dose every two weeks (q2w) starting on Cycle 1 Day 15 (C1D15)[1]. The objectives were to characterize the pharmacokinetics (PK) of gocatamig, assess the exposure-response relationships for clinical efficacy and safety, evaluate cytokine/T-cell dynamics and trimmer (CD3–gocatamig–DLL3) formation using quantitative systems pharmacology (QSP) modeling, and to support dose selection for future clinical trials.
Methods: A popPK model was developed using 3670 observations from 172 participants following target dose levels ranging from 0.015 mg to 36 mg (Data cut-off: Feb/28/2025), and either q1w schedule without priming doses or q1w/q2w/q3w schedule with different priming doses (1/2/3.6 mg).
Exposure-efficacy analyses for ORR and DCR using sigmoidal Emax models were conducted using data from patients receiving gocatamig monotherapy with a 1 mg priming dose on either a q1w or q2w dosing schedule and were performed using multiple PK parameters (e.g., Cmax, AUC, Cavg) over different periods of time, including 1) Cycle 1, 2) Weeks 0 to 6, 3) Weeks 0 to 12, and 4) up to median time of response to accommodate the different cycle length (28 days for q2w, 21 days for q1w).
A pooled tumor-agnostic exposure-safety analysis using a binary logistic regression model was performed for 21 safety endpoints (CRS, ICANS, dysgeusia etc.) based on available monotherapy safety data. PK parameters (e.g., Cmax, Cavg) at steady state and up to median onset of AEs were explored. Covariates’ effects on PK and exposure response relationship were explored via stepwise selection processes.
A mechanistic QSP platform describing interactions among gocatamig, tumor, and immune system was developed and calibrated with preclinical and clinical data and linked to the IO Simulator [2]. The model comprised three compartments (tumor microenvironment with dynamic tumor volume, lymph nodes, and blood). Tumor, stroma and immune cells, as well as multiple cytokines (IL-6, IL-10 etc.,) were included in the model. Tumor microenvironment composition assumptions were derived from WES/WGS and bulk RNA-seq; tumor purity data were obtained from publications [3–7], and immune cell fractions were estimated using CIBERSORTx. The calibrated model supported virtual trials to evaluate the proposed priming dose, step-up and target dose.
Results: PK data showed that serum exposure of gocatamig increased in a dose-proportional manner from 0.015 mg to 36 mg. A two-compartment model with first-order elimination was selected as the final popPK model. None of the covariates evaluated had a clinically meaningful impact on PK exposures. The clearance was estimated to be 0.0254 L/h, and the central volume of distribution was 3.4 L, and the half-life (t½) was 13.5 days, supporting a q2w dosage.
Exposure-response relationships for both ORR and DCR showed a positive trend and reached a plateau at exposures following 24 mg q2w supporting 24 mg q2w as a RP2D in SCLC. In contrast, no significant ER relationship was observed for safety endpoints, except for Grade ≥2 weight loss and Grade ≥2 dysgeusia.
QSP model prediction suggested that 1) the peak of CD4 andCD8 T-cells in the TME appears to plateau around a 1 mg priming dose, indicating that priming doses higher than 1 mg do not further enhance T cell infiltration. 2) the peak cytokine profile attenuated after higher step-up and target dose. 3) trimer concentration saturation occurs around 24 mg q2w.
Conclusions: PopPK, ER and QSP analyses showed that dosages higher than 24 mg q2w were not expected to result in additional benefit given the plateau in efficacy and trimer concentration and were associated with higher incidences of decreased body weight and dysgeusia, while lower dosages result in lower exposures, thus lower efficacy and higher risk of CRS rebound. Therefore, the selection of 1 mg on C1D1 and 12 mg on C1D8 followed by 24 mg q2w was supported by a better benefit risk profile for future clinical development.
References:
References:
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Reference: PAGE 34 (2026) Abstr 12238 [www.page-meeting.org/?abstract=12238]
Poster: Drug/Disease Modelling - Oncology