Artemin and immune checkpoint inhibitor (ICI) efficacy in metastatic colorectal cancer (mCRC): A correlative analysis of the Canadian Cancer Trials Group (CCTG) CO.26 trial.
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3587 Background: ICIs have limited efficacy in microsatellite stable (MSS) mCRC. The mechanisms of resistance to ICI remain incompletely understood. Recent findings suggest that erythyroid progenitor cells (EPCs) in the tumour microenvironment can exert immunosuppressive properties and promote tumour progression through the secretion of artemin, a neurotrophic factor. We conducted this post-hoc analysis of the Phase II CCTG CO.26 trial (NCT02870920) to investigate the relationship between artemin and ICI treatment outcomes in MSS mCRC. Methods: The CO.26 trial randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) and best supportive care (BSC) compared to BSC alone in a 2:1 fashion. Serum artemin concentrations were determined from pre-treatment and serial on-treatment blood samples. The median artemin value (1.051ng/ml) was used to stratify pts into high versus low artemin 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 artemin on PFS and OS. Results: Of 180 pts enrolled in CO.26, blood samples were available for 161 pts (N= 114 D+T, 47 BSC) at baseline, 94 at week 8 and 69 at progression. In the BSC arm, OS was lower for pts with high artemin at baseline compared to low pts (mOS 3.17 vs. 5.65 months, HR 1.74 [0.94-3.25], p=0.080). In artemin high pts, D+T improved OS compared to BSC (mOS 6.44 vs. 3.17 months, HR 0.54 [0.33-0.91] p=0.020). There was no difference in OS between D+T and BSC arms in artemin low pts (mOS 6.64 vs. 5.65 months, HR 0.87 [0.53-1.43], p=0.58, multivariable p-interaction=0.061). In the D+T arm, pts with progressive disease had significant increases in artemin levels at week 8 compared to baseline (p=0.026), while there was no significant change in week 8 artemin levels in pts with stable disease (p=0.14). Conclusions: High baseline artemin may be a poor prognostic marker in MSS mCRC and increase in artemin level during treatment can be indicative of progressive disease. High baseline artemin may predict benefit from ICI treatment. Studies are warranted to better understand and explore targeting the EPC-artemin axis to enhance efficacy of ICI in MSS mCRC.
