055: First-in-Human Population PKPD Modelling & Simulation of CUE-101: Preliminary Results

Statement of Purpose, Innovation or Hypothesis: Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen complex, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of attenuated human interleukin-2 to activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers. CUE-101 continues to demonstrate safety, tolerability, and meaningful clinical benefit in patients with HPV16+ R/M HNSCC. In this study, preliminary Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) data from study CUE-101-01 were used to generate a population PKPD model for CUE-101.

Description of Methods & Materials: A population pharmacokinetic (PPK) model was developed using CUE-101 drug concentrations. CUE-101 was administered as an IV infusion with doses ranging from 0.06-8 mg/kg to 49 patients as monotherapy, and in combination with 200 mg pembrolizumab. Body weight was assumed as a covariate on all PK parameters except duration of infusion.The predictive performance of the final PK model was evaluated using posterior predictive checks, where mean dose-normalized AUC and Cmax values were calculated from the observed data and then compared to simulated mean exposures generated from the model. Multiple candidate PD markers were evaluated as potential biomarkers of drug response as a function of CUE-101 total exposure (AUC). AUC for each patient versus the highest observed post-dose PD value (corrected for baseline) was used to assess the drug exposure-response relationship. The equation for the Emax model is:PD response=(AUCi*Emax)/(AUCi+EC50) where AUCi is the individual area under the curve, Emax is the maximum estimated response, and EC50 is the estimated AUC that produces half of the response. NONMEM7.5. and R4.2.1 were used for modelling and statistical/graphical analyses, respectively.

Data & Results: A 3-compartment PPK model provided the best fit for the CUE-101 concentration data. No major systematic discrepancies between simulated and observed AUCs were apparent, and AUC increased proportionally with CUE-101 dose. A direct relationship was observed between PD response and AUC, and the maximum PD response to CUE-101 plateaued at exposures associated with the 4 mg/kg dose level. Additional simulations suggest that fixed doses of CUE-101 would result in similar exposures as weight-based doses.

Interpretation, Conclusion or Significance: CUE-101 drug concentrations were best described by a 3-compartment PPK model that can be used to predict AUC reasonably well. Preliminary PD biomarker assessments from CUE-101 monotherapy treated subject samples support that CUE-101 elicits dose- and exposure-dependent PD effects that are consistent with reported IL-2 pharmacology and also supportive of the preferential effect of CUE-101 on E7 specific T cells. The observed results support that the PD effect of CUE-101 appeared to level off at exposures associated with the 4 mg/kg dose, suggesting that the 4 mg/kg CUE-101 dose results in a maximum PD effect. Additional model-based simulations will further inform selection of doses of CUE-101 for study in Phase 2. Furthermore, as the first Immuno-STAT to enter clinical development, these CUE-101 datasets will also inform studies with future clinical candidates from this platform, including the ongoing study of CUE-102 in Wilms’ Tumor-1 positive tumors.

Disclosures: The authors serve as consultants for the pharmaceutical industry and as scientists in the pharmaceutical industry.

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Additional Information/Authors: Abdulaziz Nanah, Janak Wedagedera, Archana Patil, Padma Ahilaveni, Apollina Goel, Steven N. Quayle, Matteo Levisetti, Michael J. Fossler