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Exploratory biomarker findings from regorafenib plus toripalimab in patients with refractory metastatic colorectal cancer (REGOTORI study)
Background
REGOTORI study is a phase 1b/2 clinical trial for MSI-L/MSS/pMMR refractory metastatic colorectal cancer (mCRC). Our group previously reported that regorafenib plus toripalimab as later line therapy can improve efficacy and survival of refractory mCRC patients (REGOTORI study). In this study, we did exploratory research on tumor and plasma samples to provide potential biomarkers that may affect the efficacy and survival of combination therapy.
Methods
Forty-two patients with MSI-L/MSS/pMMR refractory mCRC were enrolled in the REGOTORI study. Before treatment, FFPE tumor tissue samples from patients were subjected to whole-exome sequencing (WES), 520 genes panel and multiplex immunohistochemistry (mIHC) testing, respectively. Before treatment and every evaluation point, peripheral blood samples from patients were examined by 520 genes panel. Somatic mutations, tumor mutation burden (TMB), blood-based intratumor heterogeneity (bITH), high allele frequency blood-based tumor mutation burden (HAF-bTMB) and high allele frequency blood-based intratumor heterogeneity (HAF-bITH) were evaluated accordingly.
Results
Overall survival (OS) was significantly worse in patients with higher bITH (p = 0.008), circulating tumor DNA (ctDNA) max AF (p = 0.014), HAF-bTMB (p = 0.032) and HAF-bITH (p = 0.014). Besides, dynamic change of ctDNA concentration seems related to the response of combination treatment. In addition, patients with SMAD4 mutation had no response in combination therapy (0/6) and had worse progressive-free survival (PFS) (p < 0.001) and OS (p = 0.011) than those with SMAD4 wild type; patients with PIK3CA mutation had worse OS (p = 0.01). Further, mIHC show that patients had longer PFS with higher stroma rate of CD3+ (p = 0.007), CD3+ CD8+ (p = 0.016), CD3+ CD8- (p = 0.007) and PD1+ CD3+ (p = 0.007). However, we found WES-TMB was not related to PFS (p = 0.718) or OS (p = 0.647) in this cohort.
Conclusions
These results suggest that selective markers of tumor microenvironment could be predictive biomarkers in refractory mCRC patients who received the combination treatment of regorafenib and toriplalimab. Besides, somatic mutation in SMAD4/PIK3CA and the level of bITH, HAF-bITH, ctDNA max AF and HAF-bTMB could be prognostic factors of these patients. Further analyses are needed for larger treatment cohorts.
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (81930065, 82173128); Science and Technology Program of Guangdong (2019B020227002); Science and Technology Program of Guangzhou (201904020046).
Disclosures
All authors have declared no conflicts of interest.
