162: Pharmacokinetics of DYP688 in Patients With Metastatic Uveal Melanoma & Other GNAQ/11 Mutant Melanomas

Statement of Purpose, Innovation or Hypothesis: DYP688 is a first-in-class PMEL17- “targeted-targeted” antibody drug conjugate (ADC) for GNAQ/11 mutant melanomas, investigated in an ongoing phase I dose-escalation first-in-human study. Upon binding to PMEL17, DYP688 is rapidly internalized and processed to liberate SDZ475 (payload) that inhibits Gq/11 oncogenic signaling, resulting in cell-cycle arrest and cell death. One of the key characteristics of DYP688 identified in nonclinical studies is the inactivation of the payload in the systemic circulation while still attached to the antibody backbone. Comprehensive quantitative evaluations performed allowed characterization of the clinical pharmacokinetics of DYP688 and its main biotransformation products, considering payload instability, in this phase I study.

Description of Methods & Materials: Pharmacokinetics of DYP688 was evaluated in this Phase I, first-in-human, open-label, multicenter, single-arm study in patients with metastatic uveal melanoma (MUM) and other GNAQ/11 mutant melanomas. The primary objectives of this study were to evaluate safety and tolerability, and to determine the recommended dose(s) for future studies¹. The secondary objectives were to evaluate pharmacokinetics, immunogenicity, and antitumor activity (NCT05415072) ¹. Intensive PK sampling was collected over a two-week interval after first dose and on cycle 3 (Day 1 to Day 15). Bioanalytical methods were used for quantification of total antibody in serum (ligand binding assay), active and inactive conjugated payload in plasma (papain-release assay followed by liquid chromatography/mass spectrometry [LC/MS]) and free payload in blood (LC/MS). DYP688 pharmacokinetic parameters were computed using non-compartmental analysis methods.

Data & Results: PK parameters were calculated for 32 patients treated with DYP688 intravenous infusion at 4 (n=5), 8 (n=11), 12 (n=10), and 16 (n=6) mg/kg biweekly (q2w). DYP688 demonstrated nearly dose proportional increase in total monoclonal antibody, active conjugated payload, and inactive conjugated payload exposures with low to moderate intersubject variability. The mean terminal half-life of the conjugated active payload was 48.9 hours, and the total antibody effective half-life was 8.8 days. At 12 mg/kg, steady-state mean (coefficient of variation [CV%]) AUC(0-336h) for total antibody in serum was 51,800 h*mcg/mL (16.8%), and the mean (CV%) AUC(0-336h) for conjugated active payload and conjugated inactive payload in plasma were 166,000 h*ng/mL (21.0%) and 95,900 (20.0%) h*ng/mL, respectively. Free payload steady state mean (CV%) AUC(0-336h) and Cmax in blood were 1750 (14.9%) h*ng/mL and 6.9 (16.0%) h*ng/ml, respectively, at 12 mg/kg. There was low systemic accumulation of total antibody and conjugated inactive payload, and no accumulation of active conjugated payload. A trend in the dose-exposure-response relationship was observed.

Interpretation, Conclusion or Significance: Comprehensive pharmacokinetic and quantitative analyses, along with robust bioanalytical methods allowed characterization of the pharmacokinetics of DYP688 and its main biotransformation products in humans. DYP688 demonstrated nearly dose proportional exposure of total antibody, conjugated active payload, and conjugated inactive payload. Clinical pharmacokinetic analyses confirmed payload inactivation in humans. Pharmacokinetic results are consistent with and support the observed clinical activity.

Disclosures: All authors are employees of Novartis and eligible to receive stocks.

Citations/References: 1. Carlino M, et al. A Phase I/II Study of DYP688, an Antibody Drug Conjugate Delivering a Direct Gq/11 Inhibitor in Patients with Metastatic Uveal Melanoma (MUM) and Other GNAQ/11 Mutant Melanomas. Oral Presentation [Late Breaking Abstract] at: 20^th International Congress of the Society for Melanoma Research; November 6-9, 2023; Philadelphia, PA, United States.

Additional Information/Authors: None.