Abstract
Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated. To investigate the association of liver metastases with response to PD-1/PD-L1-targeting therapy in MSS metastatic colorectal cancer. This single-center retrospective cohort study evaluated clinical responses to PD-1- or PD-L1-targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020. Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1-targeting therapy. Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1-targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P < .001). In addition, median PFS was 5.5 (IQR, 2.0-11.5) months for patients without any prior or current liver involvement at the time of PD-1/PD-L1-targeting treatment initiation. Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition (hazard ratio, 7.00; 95% CI, 3.18-15.42; P < .001). Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors, whereas the presence of liver metastases was associated with resistance. Further prospective studies are needed to investigate PD-1/PD-L1 inhibitors in patients with MSS metastatic colorectal cancer without liver metastases.
Highlights
Microsatellite stable (MSS) colorectal cancers represent 95% of all metastatic colorectal cancer cases and are characterized by low tumor mutation burden (TMB) and low immune infiltration compared with microsatellite instability–high (MSI-H) colorectal tumors.[1]
Patients without liver metastases at the time of PD-1/PD-L1–targeting treatment had a superior median progression-free survival (PFS) compared with patients with liver metastases (4.0 [interquartile range (IQR), 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P < .001)
Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition
Summary
Microsatellite stable (MSS) colorectal cancers represent 95% of all metastatic colorectal cancer cases and are characterized by low tumor mutation burden (TMB) and low immune infiltration compared with microsatellite instability–high (MSI-H) colorectal tumors.[1]. Stable disease occurred in patients without liver metastases at the time of enrollment.[7] the combination of regorafenib plus toripalimab (a PD-1 inhibitor) led to a response rate of 30.0% in patients with MSS colorectal cancer without liver metastases, whereas patients with liver metastases had an inferior response rate of 8.7%.7. The combination of avelumab and regorafenib was investigated in MSS colorectal cancer, with a reported DCR of 53.5%, whereas no objective responses were noted.[8] These data, in summation, suggest a potential clinical benefit to regorafenib plus a PD-1– or PD-L1–targeting agent and suggest a preferential response in patients without hepatic metastatic disease
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