Serum kynurenine-to-tryptophan ratio and long-term outcomes after PD-1/PD-L1 blockade: Results from a prospective cohort study in advanced non-small cell lung cancer

Background Long-term clinical benefit from drugs targeting the programmed cell death protein 1/ligand 1 axis (anti-PD-1/PD-L1s) remains limited. Thus, identifying biomarkers of their durable efficacy is crucial. Objectives We assessed whether a serum kynurenine-to-tryptophan ratio (KYN/TRP), a surrogate of systemic indoleamine-2,3-dioxygenase 1 (IDO1) function, predicts long-term benefits of anti-PD-1/PD-L1 therapy in non-small cell lung cancer. Design Prospective observational cohort study reported in accordance with the STROBE guidelines. Methods A total of 103 patients were evaluated. Blood was collected at baseline and at the end of cycles 1, 2, 3, and 4. The concentrations of TRP, KYN, and other metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) and correlated with treatment outcomes. Results In the pembrolizumab cohort, the on-treatment KYN/TRP ratios were lower in patients with durable benefits. A low KYN/TRP ratio (≤0.0619) at the end of the fourth cycle has been associated with ≥12-month benefits (OR=20.43, p=0.008), later progression (HR=0.300, p=0.006), and death (HR=0.299, p=0.013) in multivariable analyses. No such observations were noted in the atezolizumab group. Conclusions A low KYN/TRP ratio around the third month of treatment has been identified as an exploratory biomarker candidate of long-term benefits of immunotherapy, but not in all patients. Given between-cohort differences (e.g., in smoking status), further studies are warranted to explore the determinants of the observed discrepancies.