Background Nutritional stress is a mechanism that allows tumor cells to evade the immune system. Arginine (ARG), an amino acid involved in immunomodulation, aids in regulating T-lymphocyte cell activity and the antitumor response. ARG deficiency in the tumor microenvironment can impair T-cell response while ARG supplementation may promote antitumor immune activity. In this exploratory post hoc analysis of the randomized phase II CO.26 trial, we investigated the role of plasma ARG in predicting response to immune checkpoint inhibitors (ICI) in patients with microsatellite stable refractory metastatic colorectal cancer (mCRC). Methods CO.26 randomized patients with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from pretreatment blood samples using high-performance liquid chromatography-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying patients into ARG-high (≥10 700 ng/mL) versus ARG-low (<10 700 ng/mL) groups. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard models were used to analyze the prognostic and predictive impacts of ARG on OS. Results Of 180 patients enrolled in CO.26, 161 (N=114 treated with D+T and 47 BSC) had pretreatment blood samples for ARG analysis. There were no significant differences in baseline characteristics between patients included in this analysis and the total study patients, or between ARG-high and ARG-low patients. In the BSC arm, the median OS was 3.09 months for ARG-high versus 4.27 months for ARG-low patients (univariable HR 0.89 (0.49–1.65), p=0.72). In the D+T arm, the median OS was 7.62 months for ARG-high versus 5.27 months for ARG-low patients (univariable HR 0.68, (0.48–1.0], p=0.048). In ARG-high patients, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.09 months BSC; HR 0.61 (0.37–0.99), p=0.047; adjusted p=0.042 for interaction). In ARG-low patients there was no OS benefit with D+T (median OS 5.27 months D+T vs 4.27 months BSC; HR 0.87 (0.52–1.46), p=0.61). Conclusion High baseline plasma ARG was predictive of improved OS in patients with mCRC treated with D+T. Further investigations are needed to validate ARG as a biomarker. Therapeutic approaches targeting the ARG pathway may augment ICI activity. Trial registration number NCT02870920.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual’s cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

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