Nutritional deprivation serves as a strategy for cancer cells to avoid detection by the immune system. Arginine (ARG), an amino acid with important roles in immune regulation, influences T-cell function and the body's defense against tumors. Low levels of ARG within the tumor surroundings can hinder T-cell effectiveness, while increasing ARG availability might boost anti-cancer immune responses.In this exploratory follow-up analysis of the randomized phase II CO.26 study, researchers assessed whether blood levels of ARG could help forecast treatment outcomes with immune checkpoint inhibitors (ICI) in individuals with microsatellite-stable metastatic colorectal cancer (mCRC) that no longer responds to standard therapies.The CO.26 study randomized patients with treatment-refractory metastatic colorectal cancer to receive either the combination of durvalumab and tremelimumab (D+T) or best supportive care (BSC). Baseline plasma arginine (ARG) concentrations were quantified from pre-treatment blood samples using high-performance liquid chromatography with tandem mass spectrometry. Patients were divided into two groups—ARG-high (≥10,700 ng/mL) and ARG-low (<10,700 ng/mL)—based on the median ARG level. Survival outcomes were evaluated using the Kaplan-Meier approach, with differences between groups assessed by the log-rank test. Additionally, Cox proportional hazards models were applied to determine the prognostic and predictive value of ARG for overall survival.Of the 180 patients enrolled in CO.26, 161 had available pre-treatment plasma samples for arginine (ARG) assessment, including 114 receiving durvalumab plus tremelimumab (D+T) and 47 receiving best supportive care (BSC). The patients analyzed were representative of the overall trial population, with no meaningful differences in baseline characteristics between ARG-high and ARG-low groups. In the BSC cohort, median overall survival (OS) was slightly shorter in ARG-high patients (3.09 months) compared to ARG-low patients (4.27 months; HR 0.89, 95% CI 0.49–1.65; p=0.72). Among patients treated with D+T, ARG-high individuals had a longer median OS of 7.62 months versus 5.27 months for ARG-low patients (HR 0.68, 95% CI 0.48–1.0; p=0.048). Importantly, D+T conferred a significant survival benefit in the ARG-high subgroup relative to BSC (7.62 vs 3.09 months; HR 0.61, 95% CI 0.37–0.99; p=0.047; adjusted interaction p=0.042), whereas no such benefit was observed in ARG-low patients (5.27 vs 4.27 months; HR 0.87, 95% CI 0.52–1.46; p=0.61).Elevated baseline plasma arginine (ARG) was associated with longer overall survival in metastatic colorectal cancer patients receiving D+T. These findings warrant further studies to confirm ARG as a predictive biomarker. Additionally, interventions aimed at modulating the ARG pathway could potentially enhance the efficacy of immune checkpoint inhibitors.
