PWII-003 - MINIMAL SAMPLING TO ASSESS MECHANISMS LINKING IMMUNE CHECKPOINT INHIBITOR PHARMACOKINETICS AND OUTCOMES IN CANCER PATIENTS

B. Remaily¹, Y. Guo¹, A. Adeluola², G. Young¹, T. Vu¹, J. Thomas¹, K. Kim¹, Z. Xie¹, G. Mulcahy¹, C. Stanton¹, M. Manna¹, J. Na¹, S. Kulp¹, L. Ganesan¹, C. Coss¹, T. Mace¹, D. Owen¹, M. Phelps¹; ¹The Ohio State University, ²The Ohio State University, Columbus, OH.

Background: Immune Checkpoint Inhibitors (ICIs) are monoclonal antibodies that stimulate anti-tumor effects in the host immune system to kill cancer cells. Durable responses to therapy however are variable with little understanding of the mechanisms behind this variation. Baseline clearance (CL0) of ICIs, independent of dose and drug exposure, is shown to be a strong biomarker of response to ICI therapy with elevated ICI CL0 correlating with worse outcomes. Fc Receptors are well known to play a role in the PK and efficacy of ICIs. Our goal in this study was to evaluate a minimal sampling scheme using pre-dose and within 30 minutes post-dose across 4 consecutive cycles of treatment to estimate baseline and time-varying clearance and to assess underlying mechanisms linking ICI CL0 and Fc Receptors in cancer patients.

Methods: Thus far, 32 patients have been enrolled with either non-small cell lung cancer (NSCLC) or renal cell carcinoma (RCC) and receiving pembrolizumab (carboplatin, paclitaxel, pemetrexed) or nivolumab (+Ipilimumab). ICI concentrations were measured in pre- and post-dose samples collected cycles 1-4, and published nonlinear mixed effect models were used to estimate individual PK parameters. Fc Receptor and other markers were measured by mass cytometry from baseline patient PBMCs, and other clinical laboratory endpoints were included in the analyses.

Results: Pembrolizumab and nivolumab CL0 were estimated at 0.235 (±0.124, n=19) L/Day and 0.358 (±0.228, n=13) L/Day, respectively, which coincides with expected CL0 values in these patient populations. Time-varying clearance estimates also suggest decreasing clearance over time in most patients, which is consistent with expectations, though uncertainty in time-varying clearance estimates is high. There was an observed positive relationship between ICI CL0 and receptor expression of PD-1 and Fc Gamma RI, RII, and RIII on circulating leukocytes. Interestingly we saw no relationship between CL0 and immune cell FcRN expression.

Conclusion: This minimal sampling scheme offers increased access to PK samples while also providing parameter estimations that closely coincided with published values. Additionally, there was an observed relationship between CL0 and circulating leukocyte receptor expression, potentially highlighting a link between ICI CL and response.