Pharmacokinetics of biologics in gastric cancer

Abstract

Gastric cancer (GC) remains one of the leading causes of cancer death worldwide despite improvements in therapeutic options. Several biologics have been investigated in patients with GC, including those approved in other solid tumors; however, the success rate of the pivotal trials that investigated these biologic molecules in GC remains low. Elevation in total clearance and a decrease in systemic pharmacokinetic (PK) exposure in GC compared with other indications have been observed in these biologics across different pathways. Achieving optimal exposure for patients with GC is an important factor in balancing risk and optimizing therapeutic benefit and thus maximizing chance of positive outcomes for pivotal trials. Therefore, in this review, we summarize the PK disposition of several molecules (e.g., anti-HER2, anti-VEGF, and anti-PD1) evaluated in GC and showed a consistent trend of lower drug exposure as compared to other solid tumors. We hypothesize that two possible mechanisms: (1) hyper-catabolism of endogenous and exogenous proteins due to cancer cachexia; and (2) gastric protein leakage due to local inflammation at the gastrointestinal tract may explain or partially explain the increase of clearance in patients with GC. Last, the potential implications of such findings on dose selection to optimize the benefit: risk profile for biologics in GC are also discussed.

FIGURE 1

Clinical pharmacology considerations for dose selection in patients with gastric cancer. E‐R, exposure‐response; PK, pharmacokinetic