OBJECTIVES: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) constitutes 95% of patients with mCRC who are inherently resistant to programmed cell death-1 (PD-1) inhibitors in ≥2-line of treatment. Preclinical and clinical data suggest that regorafenib enhances effect of these PD-1 inhibitors by modulating tumor microenvironment, thereby offering a promising treatment strategy for these patients. We reviewed recent real-world (RW) data to examine clinical outcomes of regorafenib + PD-1 (≥3-line) when used in heavily pre-treated MSS-mCRC population.

METHODS: We performed a targeted literature search on PubMed, limited to English language and with a 5-year timeframe (2017-2022). We analyzed key endpoints such as overall survival (OS), progression free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs).

RESULTS: We identified 8 (n=7: China; n=1: United States) retrospective RW studies which included 306 patients with confirmed MSS-mCRC status who were treated with regorafenib + PD-1 (≥3-line). At a median follow-up of 5-12 months, proportion of patients who achieved partial response, progressive disease and stable disease ranged between 5-13%, 13-60% and 29-78%, respectively. In terms of efficacy, median OS, PFS and ORR ranged between 15-17 months, 3-5 months and 8-13%, respectively. As opposed these insights, regorafenib alone (≥3-line) which is recommended in treatment refractory mCRC patients, exhibited a median OS, PFS and ORR of 7 months, 2 months and 1-4%, respectively. Moreover, patients assigned with regorafenib + PD-1 inhibitor (≥3-line) had a treatment duration of 6 to 19 months with incidence of grade ≥3 TRAEs in 13-22% patients.

CONCLUSIONS: Regorafenib + PD-1 inhibitor (≥3-line) is likely to offer a promising treatment option in heavily pre-treated MSS-mCRC population. However, baseline liver metastasis and neutrophil/platelet -lymphocyte ratio should be examined to forecast their response to regorafenib combined with a PD-1 inhibitor. This could also help design of larger prospective studies in patients with MSS-mCRC.