Plasma arginine as a candidate predictive biomarker for response to immune checkpoint inhibition (ICI) in metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.

person Lucy Xiaolu Ma Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada info_outline Lucy Xiaolu Ma, Jonathan M. Loree, Derek J. Jonker, Hagen Fritz Kennecke, Scott R. Berry, Felix Couture, Chaudhary E. Ahmad, John R. Goffin, Petr Kavan, Mohammed Harb, Bruce Colwell, Setareh Samimi, Benoit Samson, Tahir Abbas, Nathalie Aucoin, Francine Aubin, Sheryl L. Koski, Dongsheng Tu, Christopher J. O'Callaghan, Eric X Chen

Authors person Lucy Xiaolu Ma Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada info_outline Lucy Xiaolu Ma, Jonathan M. Loree, Derek J. Jonker, Hagen Fritz Kennecke, Scott R. Berry, Felix Couture, Chaudhary E. Ahmad, John R. Goffin, Petr Kavan, Mohammed Harb, Bruce Colwell, Setareh Samimi, Benoit Samson, Tahir Abbas, Nathalie Aucoin, Francine Aubin, Sheryl L. Koski, Dongsheng Tu, Christopher J. O'Callaghan, Eric X Chen Organizations Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, BCCA, Vancouver Cancer Centre, Vancouver, BC, Canada, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada, Providence Cancer Institute, Portland, OR, Queen's University, Kingston, ON, Canada, CHU de Québec, l'Hôtel-Dieu de Québec, Quebec, QC, Canada, Eastern Health, St John's, NF, Canada, Juravinski Cancer Inst, Hamilton, ON, Canada, Jewish General Hospital-Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada, The Moncton City Hospital, Moncton, NB, Canada, Dalhousie University, Halifax, NS, Canada, Hospital Sacré-Coeur de Montréal, Montreal, QC, Canada, Hopital Charles-LeMoyne, St-Julie, QC, Canada, Saskatchewan Cancer Agency, Saskatoon, SK, Canada, Cite de la Sante, Laval, QC, Canada, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada, Cross Cancer Institute, Edmonton, AB, Canada, Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada, Princess Margaret Cancer Centre, Toronto, ON, Canada Abstract Disclosures Research Funding Other The Canadian Cancer Trials Group (CCTG) is funded by the Canadian Cancer Society., AstraZeneca provided durvalumab and tremelimumab and contributed partial funding for the CO.26 trial Background: Nutritional stress is one of the mechanisms used by tumour cells to evade the immune system. Arginine (ARG), an amino acid involved in several cellular functions including immunomodulation, is important in regulating T-lymphocyte cell activity and the anti-tumour response. ARG deficiency in the tumour microenvironment has been shown to impair T-cell response while ARG supplementation may promote anti-tumour immune activity. In this exploratory post-hoc analysis of the Phase II CO.26 trial (NCT02870920), we investigated the role of plasma ARG in predicting response to ICI in patients (pts) with refractory mCRC. Methods: CO.26 was a phase II trial which randomized pts with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from blood samples pre-treatment using HPLC-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying pts into ARG-high (≥10650 ng/ml) versus ARG-low ( < 10650 ng/ml) groups. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard models were used to analyze prognostic and predictive impacts of ARG on PFS and OS. Results: Of 180 pts enrolled in CO.26, 162 pts (N = 115 treated with D+T and 47 BSC) had pre-treatment blood samples for baseline ARG analysis. There were no significant differences in baseline characteristics between pts included in this analysis and the total study pts, or between ARG-high and ARG-low pts. In pts treated with D+T, ARG-high was associated with more favourable prognosis (ARG-high median OS 7.62 months vs. ARG-low 5.49 months, multivariable hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.40-0.91, p = 0.016). In ARG-high pts, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.61 months BSC; HR 0.61, 95% CI 0.37-0.99, p = 0.04). In ARG-low pts there was no OS benefit with D+T (median OS 5.49 months D+T vs 4.27 months BSC; HR 0.84, 95% CI 0.50-1.41, p = 0.51. Interaction p = 0.037). Baseline ARG values had no association with PFS or disease control rate. Conclusions: Baseline plasma ARG was prognostic in pts with mCRC treated with D+T, and high ARG was predictive of improved OS with ICI. Prospective studies should be done to validate ARG as a biomarker identifying mCRC pts likely to derive benefit from ICI. Therapeutic approaches targeting the ARG pathway should be investigated in future studies.

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