Dose optimization of immune checkpoint inhibitors for gastrointestinal malignancies

Outcomes of patients with gastrointestinal (GI) malignancies have improved substantially since the introduction of immunotherapy, with immune checkpoint inhibitors (ICIs) approved for specific subsets. Two biomarkers (mismatch repair/microsatellite instability status and programmed death-ligand 1 expression) are currently used to guide ICI indications. However, ICIs can be prescribed independently of any biomarker in other scenarios, such as for biliary tract cancer and hepatocarcinoma. Moreover, pharmacokinetics and pharmacodynamics modeling consistently demonstrates wide therapeutic windows, which suggest that a flat dose-response relationship for ICIs is probably excessive. Lastly, as clinical experience with immunotherapy expands, both acute and late toxicities are becoming increasingly relevant. Collectively, these factors create ambiguity regarding the indications of ICIs in GI oncology and raise concerns about increased toxicity and economic sustainability. In this review, we explore potential approaches to optimize immunotherapy for patients with GI cancer, encompassing patient selection, dose adjustment, and cost reduction. We highlight already implemented strategies to address these challenges and present evidence from local health care initiatives demonstrating the feasibility of weight-based dosing. However, we acknowledge important regulatory constraints that would entail the implementation of these changes, as they would require robust new clinical data and formal approval processes before being part of the clinical routine practice.