Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab

Clin Cancer Res. 2022 Apr 1;28(7):1363-1371. doi: 10.1158/1078-0432.CCR-21-2662.


Purpose: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti-programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)-tumor growth dynamics (TGD) models.

Patients and methods: Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models.

Results: In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition.

Conclusions: We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination.

Trial registration: NCT02155647.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Carcinoma, Merkel Cell* / drug therapy
  • Carcinoma, Merkel Cell* / pathology
  • Humans
  • Immune Checkpoint Inhibitors
  • Skin Neoplasms* / drug therapy
  • Skin Neoplasms* / pathology
  • Tumor Microenvironment


  • Antibodies, Monoclonal, Humanized
  • Immune Checkpoint Inhibitors
  • avelumab

Associated data