Plasma arginine as a predictive biomarker for outcomes with immune checkpoint inhibition in metastatic colorectal cancer: a correlative analysis of the CCTG CO.26 trial.

Autor:	Ma LX; Princess Margaret Cancer Centre, Toronto, Ontario, Canada lucy.ma@uhn.ca., Titmuss E; BC Cancer - Vancouver, Vancouver, British Columbia, Canada., Loree JM; BC Cancer - Vancouver, Vancouver, British Columbia, Canada., Jonker DJ; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., Kennecke HF; Providence Cancer Center, Portland, Oregon, USA., Berry S; Trillium Health Partners, Mississauga, Ontario, Canada., Couture F; Centre de recherche de l'Hotel-Dieu de Quebec, Quebec, Canada, Canada., Ahmad CE; Eastern Health, St. John's, Newfoundland and Labrador, Canada., Goffin JR; Juravinski Cancer Centre, Hamilton, Ontario, Canada., Kavan P; Segal Cancer Centre, Montreal, Quebec, Canada., Harb M; Moncton Hospital, Moncton, New Brunswick, Canada., Colwell B; Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada., Samimi S; Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada., Samson B; Hopital Charles-Lemoyne, Greenfield Park, Quebec, Canada., Abbas T; Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada., Aucoin N; Hopital de la Cite-de-la-Sante, Laval, Quebec, Canada., Aubin F; Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada., Koski S; Cross Cancer Institute, Edmonton, Alberta, Canada., Tu D; Canadian Cancer Trials Group, Kingston, Ontario, Canada., O'Callaghan C; Canadian Cancer Trials Group, Kingston, Ontario, Canada.; Public Health Sciences, Queen's University, Kingston, New York, Canada., Chen EX; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Dec 04; Vol. 12 (12). Date of Electronic Publication: 2024 Dec 04.
DOI:	10.1136/jitc-2024-010094
Abstrakt:	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. Competing Interests: Competing interests: LM: Consulting or Advisory Role—Eisai, Bristol Myers Squibb. DJ: Consulting or Advisory Role—AstraZeneca. HFK: Honoraria—Exelixis, Natera; Consulting or Advisory Role—TerSera; Speakers' Bureau—Natera; Research Funding—Exelixis (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst). SB: Consulting or Advisory Role—Amgen, Apobiologix, MDBriefCase, Merck, Taiho Oncology. FC: Consulting or Advisory Role—Bristol Myers Squibb, Novartis Canada Pharmaceuticals. JRG: Honoraria—AstraZeneca; Travel, Accommodations, Expenses—AstraZeneca. PK: Consulting or Advisory Role—Amgen, Bristol Myers Squibb, Eisai, Merck, Novartis, Pfizer, Roche Canada, Taiho Pharmaceutical. BS: Honoraria—AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical; Consulting or Advisory Role—AstraZeneca, Bristol Myers Squibb, Pfizer, Taiho Pharmaceutical. FA: Consulting or Advisory Role—Amgen, Bristol Myers Squibb Canada, Incyte, Merck, Pfizer, Taiho Pharmaceutical; Speakers’ Bureau—Amgen, Bristol Myers Squibb Canada, Merck, Pfizer, Taiho Pharmaceutical. Research Funding—Bristol Myers Squibb/Medarex (Inst), GlaxoSmithKline (Inst), Merck (Inst), Novartis (Inst). JML: Consulting or Advisory Role—Advanced Accelerator Applications, Amgen, Bayer, Ipsen, Pfizer, Taiho Pharmaceutical; Research Funding—Amgen (Inst), Ipsen (Inst). EC: Honoraria—AstraZeneca Canada, Bayer, Eisai, GlaxoSmithKline, Ipsen, Merck, Pfizer, Roche; Research Funding—1Globe Health Institute, AstraZeneca/MedImmune, Bristol Myers Squibb, Merck Sharp & Dohme, Mirati Therapeutics, Novartis, NuBiyota, Repare Therapeutics, Roche Canada. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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