Abstract 5198: Non-invasive biomarkers of ECM turnover are prognostic for combinations of checkpoint inhibition immunotherapy in solid tumors
Authors: Bistrup Caroline N. , de Lima Vinicius Araujo Barbosa , Jensen Christina , Karsdal Morten A. , Svane Inge Marie , Lassen Ulrik , Willumsen Nicholas 
Published: March 2024

Abstract
Background: Immune checkpoint inhibitors (ICIs) are investigated in many different combinations (Table 1). As only a fraction of patients responds to ICIs, prognostic biomarkers are needed to assess the likelihood of benefit. High collagen turnover in the tumor microenvironment are closely related to response to ICIs and survival outcomes. In this study, we explored the clinical utility of non-invasive biomarkers of type I collagen (reC1M), type III collagen (PRO-C3), type IV collagen (C4M), type XIX collagen (PRO-C19), type XX collagen (PRO-C20), TGF-β activity in metastatic cancer patients treated with ICIs.
Methods: PRO-C3, PRO-C19, PRO-C20, TGF-β, reC1M and C4M were measured with ELISAs in pre-treatment serum from 33 patients with metastatic disease in a basket trial comprising 14 different tumor types, treated with 8 different checkpoint inhibition regimens (Table 1). The association between biomarker levels and overall survival (OS) outcome was evaluated by Kaplan-Meier analysis and Cox regression analysis after dichotomizing patients at the 75th percentile (Q4).
Results: When evaluating the combined group of cancer patients, high levels (Q4) of PRO-C3 (HR=3.00, 95%CI=1.21-7.44, p=0.018), PRO-C19 (HR=2.49, 95%CI=1.04-5.99, p=0.041), PRO-C20 (HR=2.49, 95%CI=1.04-5.99, p=0.041), TGF-β (HR=2.52, 95%CI=1.05-6.04, p=0.039), reC1M (HR=2.79, 95%CI=1.16-6.67, p=0.021) and C4M (HR=2.52, 95%CI=1.05-6.04, p=0.039) were all associated with poor OS compared to low levels (Q1-Q3). The median OS was 4.7-6.1 months in biomarker-high patients compared to 8.7-11.4 in biomarker-low patients.
Conclusion: Across a diverse cohort of metastatic cancer patients treated with different checkpoint inhibition regimens, non-invasive biomarkers associated with tumor fibrosis and collagen turnover (PRO-C3, PRO-C19, PRO-C20, TGF-β, reC1M and C4M) could identify cancer patients with poor prognosis.
Table 1. Cancer type Number of patients Treatment Esophageal 1 Nivolumab (Nivo) +Anti-LAG3 Breast 2 Carboplatine+Gemciabine+Pembrolizumab (Pembro) Ovarian 4 Atezolizumab+BET inhibitor Parotid 1 Nivo Gastric 2 Nivo+Anti-LAG3 or Atezolizumab+CD40-agonist Bladder 3 Pembro Colorectal 5 Nivo, Pembro, Atezolizumab++bispecific antibody targeting CEA and CD3 or Atezolizumab+CD40-agonist Hepatocellular carcinoma 3 Nivo+Anti-LAG3 Colorectal 1 Atezolizumab+bispecific antibody targeting CEA and CD3 Mesothelioma 2 Pembro or Atezolizumab+CD40-agonist Neuroendocrine tumor 1 Pembro non-small cell 5 Nivo, Pembro or ipilumumab+Nivolumab Pancreas 1 Atezolizumab+CD40-agonist Unknown primary 2 Atezolizumab++bispecific antibody targeting CEA and CD3 or Pembro
Citation Format: Caroline N. Bistrup, Vinicius Araujo Barbosa de Lima, Christina Jensen, Morten A. Karsdal, Inge Marie Svane, Ulrik Lassen, Nicholas Willumsen. Non-invasive biomarkers of ECM turnover are prognostic for combinations of checkpoint inhibition immunotherapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5198.