medwireNews: Baseline plasma L-arginine levels may predict response to immune checkpoint inhibitors (ICIs) in people with advanced cancers, say French researchers who found that low levels correlated with poorer outcomes.
Antoine Italiano (Gustave Roussy, Villejuif) and colleagues explain that L-arginine metabolism is an “important pathway in regulating immune cell reactivity” and is essential to T-cell activation.
The researchers initially investigated its predictive value using publicly available metabolomics data for 392 patients with advanced renal cell carcinoma who were treated with nivolumab in the CheckMate 025 trial.
Their analysis revealed that L-arginine levels were higher in patients with longer survival, and when the cohort was dichotomized into high and low L-arginine groups, median overall survival (OS) was significantly longer in the high-level group than in the low-level group, at 38.8 versus 24.6 months.
Italiano and team then set out to quantify L-arginine levels using a validated immunoassay on plasma samples from 77 advanced cancer patients treated with ICIs in the molecular profiling BIP study.
In this discovery cohort, the investigators determined that “the most clinically relevant cut off value” for plasma L-arginine was 42.3 μM.
Individuals with L-arginine levels above the cutoff (ARG-high) had a significantly higher clinical benefit rate than those with L-arginine levels below the cutoff (ARG-low), at 40.0% versus 19.2%. They also had significantly longer median progression-free survival (PFS; 12.1 vs 1.9 months) and OS (not reached vs 5.7 months).
The findings were validated in 295 participants of the independent PREMIS cohort. Of these, 81% fell into the ARG-high group.
In line with the discovery cohort findings, patients in the ARG-high group had a significantly higher objective response rate than those in the ARG-low group (30.0 vs 14.3%), longer median PFS (3.8 vs 1.9 months), and longer median OS (13.2 vs 5.0 months).
Finally, the investigators evaluated L-arginine levels, in a third cohort of patients who were enrolled in a phase 1 first-in-human study of the anti-PD1 antibody budigalimab.
In this case, they tested serum samples rather than plasma and found that although median PFS was longer in the ARG-high group than in the ARG-low group, at 1.9 versus 1.7 months, the difference was only marginally significant.
They note, however, that “the cut off value used for this cohort differed from that of the two previous cohorts” and suggest that this was a result of the two different sample types.
Further analysis of paired plasma and serum samples showed that L-arginine levels were significantly lower in plasma than in serum, “confirming that sample type (serum vs. plasma) significantly impacts [L-arginine] level assessment,” the authors write in the Annals of Oncology.
Italiano et al conclude that their “pan-cancer study highlights the importance of baseline [L-arginine] level as a potential predictive biomarker of response to ICI independently of tumor type.”
However, they add: “[I]t is possible that a static cutoff for [L-arginine] levels may not be an optimal approach to identify tumor type-specific responders to ICIs and thus, fine tuning of [L-arginine] levels cutoffs by tumor type may represent an area of future research.”
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