Immune checkpoint inhibitors (ICIs) have been shown to benefit patients with metastatic colorectal cancer (mCRC) with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) (1, 2). However, PD-1/PDL1 blockade immunotherapy is not effective in pMMR/MSS, which constitutes a large population of patients (3). Ongoing clinical trials are evaluating the efficacy of immunotherapy-based strategies, including chemotherapy, radiotherapy, MEK inhibitors, or other agents in pMMR/MSS mCRC (4). In the REGONIVO study (5), regorafenib combined with nivolumab produced an ORR of 33% (95% CI, 15.6% to 55.3%) in 24 patients with pMMR/MSS refractory mCRC, indicating that anti-angiogenic drugs may enhance the efficacy of immune checkpoint inhibitors. In addition, a single-arm phase II AVETUX trial produced a high ORR of 79.5% in 39 patients, showing the feasibility and early efficacy of avelumab and cetuximab combined with FOLFOX as first-line therapy in RAS/BRAF wildtype MCRC patients (6).

Camrelizumab (SHR-1210) a high-affinity, humanized immunoglobulin and selective IgG4-anti-PD-1 monoclonal antibody, has been approved for the treatment of classical Hodgkin’s lymphoma, advanced hepatic cancer, advanced esophageal cancer, and advanced non-small-cell lung cancer in China (7). Camrelizumab is one of the most widely used anti-PD-1 antibodies for various solid tumors in real-time practice owing to drug accessibility and economic pressure for patients in China. It has shown promising clinical efficacy in several kinds of solid tumors, based on positive efficacy results in clinical trials (8–11), and has also been shown to be effective in MSI-H/dMMR solid tumors (12). The combination of regorafenib and camrelizumab achieved an ORR of 25% in 16 patients with MSS refractory mCRC, indicating the potential benefit of immunotherapy under an appropriately combined therapeutic strategy (13). Hence, we evaluated the efficacy and safety of camrelizumab when added to the first-line XELOX chemotherapy with bevacizumab or regorafenib in patients with metastatic colorectal cancer.

Although recently, rapid development has been made in the field of immunotherapy (14, 15), the first-line standard treatment for metastatic colorectal cancer (mCRC) is 5FU-based chemotherapies, with or without anti-angiogenic agents. ICI monotherapy is efficacious in the treatment of mCRC with dMMR/MSI-H. The role of the combination of PD-1 blockade with VEGF inhibition has been investigated in MSS mCRC. Adding atezolizumab to FP/BEV (standard of care) as first-line maintenance treatment for patients with BRAF wild-type mCRC did not lead to improvement in the outcomes for efficacy (16). However, in the AVETUX trial, avelumab and cetuximab in combination with FOLFOX in patients with previously untreated mCRC produced a high response rate of 79.5%, disease control rate of 92.3% and mPFS of 11.1months in 39 patients with RAS/BRAF wild-type MSS mCRC (6). In this study, a high ORR of 72% and a DCR of 96% were recorded. The mPFS of 11.2 months is as long as that of the AVETUX trial (11.1 months), which is much better than that of bevacizumab plus XELOX chemotherapy (9.4 months) as first-line therapy in patients with mCRC (17). The main factors leading to different efficacies may be that populations in the AVETUX trial included more patients with left-sided tumors (91%) compared to our study (68.8%), and all patients were RAS/BRAF wild-type. Patients with RAS with left-sided mCRC had significantly superior PFS, OS, and ORR compared with patients with right-sided tumors (18), and cetuximab plus FOLFIRI versus bevacizumab as first-line treatment clearly benefitted patients with left-sided tumors (18, 19).

Several studies have suggested that liver metastases are predictive of a lack of benefit from PD-1/PD-L1 inhibitors in MSS mCRC (5, 20). The liver is considered an immunologically-tolerant organ that is characterized by a much higher proportion of immunosuppressive cells (21). In the present study, the difference in patients with liver metastasis was considered not statistically significant compared with those without liver metastasis, probably due to the small sample size.

Recently, in the REGONIVO trial, the combination of regorafenib and nivolumab achieved a robust response rate of 33% in pMMR/MSS refractory mCRC (5). More and more research focused on the regorafenib plus ICIs in MSS refractory mCRC, the current conclusion is controversial due to the small sample size and inconsistency (5, 13, 22–24). In this study, we observed that the mPFS of regorafenib-containing therapies was not as long as that of bevacizumab-containing therapies. Moreover, capecitabine-related hand-foot syndrome (HFS), one of the causes of the switch in three treatments, was in a regorafenib-containing regimen. HFS is a common skin reaction to capecitabine with rates of any grade, of 22%–77% (25). Similarly, regorafenib-associated hand-foot skin reactions occurred at a rate of 61% overall and 20% at grade 3 (26, 27). Regorafenib combined with capecitabine treatment should be used cautiously due to the risk of overlapping skin toxicity. Therefore, this might suggest that as first-line therapy for mCRC, regorafenib may not be a suitable choice for combination with XELOX chemotherapy in future trials.

The combination strategy indicated a potential benefit in terms of ORR and PFS with a acceptable safety profile. Despite its strengths, there are some limitations to consider. First, this is a retrospective pilot study with a small sample size, reflecting its preliminary nature. Second, although antitumor response was observed in mCRC in spite of RAS mutations, a small number of patients had unknown RAS or BRAF status before the beginning of the combination treatment. Besides, the MMR or MSI status of three patients was unknown. Finally, even if the same chemotherapy regimen was adopted, different courses of treatment and varying follow-up intervals may have increased the heterogeneity. Thus, the findings need to be further assessed in a large prospective study.

In conclusion, our study differs from previous immunotherapy study in MSS mCRC based on the study populations and the novel combination regimen. In present study showed the addition of camrelizumab to the first-line XELOX chemotherapy with bevacizumab have demonstrated high response rates, and this immunotherapy combination was practical and helpful in unselected patients with mCRC. Further randomized trials with large sample sizes for this combination strategy are warranted.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Ethics Review Board of the First Hospital of Quanzhou Affiliated to Fujian Medical University, East Road 250, Quanzhou 362000, Fujian Province, China. Written informed consent for participation was not required for this study, in accordance with the national legislation and institutional requirements.

WC, XL, and XH designed the project. HZ, YL, and XH collected patients’ information and wrote the manuscript. WC and XL provided study material or patient. YW evaluated tumor responses. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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