PI-037 - QUANTITATIVE CLINICAL PHARMACOLOGY SUPPORTS TOTALITY OF EVIDENCE, DATA INTEGRATION AND DOSE SELECTION PROPOSAL OF A NEW MOLECULAR ENTITY WITH NO SINGLE AGENT ACTIVITY DEVELOPED IN COMBINATION: CASE STUDY OF ENGLUMAFUSP ALFA

C. JAMOIS¹, K. KORFI², S. HERTER², S. WILSON³, S. KRISHNAN⁴, Z. JIANG⁴, M. WASMER⁵, I. PRIETO⁶, H. HINTON⁷, W. DRIESSEN¹, G. KAZANTZIDIS⁸, D. SAHIN⁸, A. TAGAWA⁸, N. DIMIER⁹, K. LECHNER⁵; ¹Pharma Research and Early Development, Roche Innovation Center Basel, PHARMA RESEARCH AND EARLY DEVELOPMENT, ROCHE INNOVATION CENTER BASEL, SWITZERLAND, ²Pharma Research and Early Development, Roche Innovation Center Zurich, Pharma Research and Early Development, Roche Innovation Center Zurich, Switzerland, ³Pharma Research and Early Development, Roche Innovation Center Welwyn, Pharma Research and Early Development, Roche Innovation Center Welwyn, United Kingdom, ⁴Pharma Research and Early Development, Roche Innovation Center Basel, Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland, Switzerland, ⁵Pharma Research and Early Development, Roche Innovation Center Penzberg, Pharma Research and Early Development, Roche Innovation Center Penzberg, Germany, ⁶Pharma Development, Roche Innovation Center Welwyn, Pharma Development, Roche Innovation Center Welwyn, UK, ⁷Pharma Development, Roche Innovation Center Basel, Pharma Development, Roche Innovation Center Basel, Basel, ⁸Pharma Development, Roche Innovation Center Basel, Pharma Development, Roche Innovation Center Basel, Switzerland, ⁹Pharma Research and Early Development, Roche Innovation Center Welwyn, Pharma Research and Early Development, Roche Innovation Center Welwyn, UK.

Background: Englumafusp alfa (englu), an antibody-like fusion protein binding to CD19 on B cells and 4-1BB on immune cells, tested in combination with glofitamab (glofit, COLUMVI®) in a phase I dose escalation (DE) study (NCT04077723) exhibits no single agent activity, but delivers a strong costimulatory signal.
Earlier and better characterization of the dose that maximizes patient benefit risk (BR) is critical for oncology. In absence of dose/exposure response (DER), we leveraged the totality of evidence to enable the selection of doses for further evaluation.

Methods: Hundred twenty-two patients (pts) with pharmacokinetic (PK) and 99 pts with biomarkers (PD) treated with englu doses ranging from 0.36 mg to 75 mg were included for this analysis.
Preclinical and clinical data (efficacy, safety, PK, PKPD, biomarkers) were integrated to characterize DER relationships.
Population PK, logistic regression modeling, and graphical exploration were used to assess PK properties, the correlation between probability of response and exposure (EXP). Average concentrations at steady-state (Cav,ss) and risk of EXP overlap between pts were compared among the different doses tested.

Results: Englu clinical PK was characterized by target mediated drug disposition with body weight effect on clearance and volume parameters.
The combination with glofit was well tolerated, with no additive or synergistic safety signals and no relationship between dose and toxicity. Efficacy was observed at all doses with no relationship to englu EXP .
A PD response in line with the mode of action (MoA) of 4-1BB costimulators was observed, showing a trend towards an inverse bell-shaped relationship between MoA-related PD markers (peripheral PD1+ CD8+ Temra cells, soluble CD25).
Clinical data and absence of DER do not support the choice of a single dose, therefore given the totality of data and use of In Silico quantitative approaches, an optimal dose range in line with an expected bell-shaped dose response curve was identified (Figure 1, Figure 2).

Conclusion: Two doses maximizing the proportion of pts with EXP within the in vivo efficacious and the optimal PD response ranges and with distinct Cav,ss were selected for randomization in combination with glofit, to ultimately identify the one maximizing pts’ benefit risk.