| Background:How to break through immune resistance in patients with proficient mismatch repair(p MMR)/microsatellite stable(MSS)advanced colorectal cancer is a current research hotspot.Preclinical studies have shown synergistic effects of immune checkpoint inhibitors in combination with Immune checkpoint inhibitors in colorectal cancer models,but efficacy in clinical trials has been mixed.This is a observational studies to explore the efficacy,quality of life and safety of regorafenib tablets in combination with programmed cell death receptor-1(PD-1)inhibitors compared to regorafenib tablets monotherapy as third-line and above for the treatment of patients with p MMR/MSS advanced colorectal cancer,and to analyse prognostic factors,screen the beneficiary population and guide clinical individualised treatment.Methods:This study initially reviewed 1356 colorectal cancer patients diagnosed at Huaihe Hospital of Henan University,Kaifeng Cancer Hospital and First Affiliated Hospital of Henan University from June 2019 to September 2022.46 patients with p MMR/MSS m CRC were finally included in the study after screening by inclusion and exclusion criteria.All patients were divided into treatment and control groups,with the treatment group applying regorafenib tablets combined with PD-1 inhibitors and the control group applying regorafenib tablets alone.In the treatment group,regorafenib were administered orally at 80-160mg once daily on days 1-21,repeated every 28 days,in combination with intravenous Pembrolizumab Injection 200mg or Sintilimab Injection 200mg or Camrelizumab Injection 200mg on day 1,repeated every 3 weeks;Nivolumab Injection 240mg or Toripalimab Injection 3mg/kg on day 1,repeated every 2 weeks.The control group received oral regorafenib 80-160mg once daily on days 1-21,repeated every 28 days.Patients were assessed for tumour every 8 weeks,using RECIST 1.1 as the assessment criteria.The primary endpoint was progression-free survival(PFS)and the secondary endpoints were objective response rate(ORR),disease control rate(DCR),Quality of life scores(QLQ-C30)before and after 8 weeks of treatment,and the difference in Adverse Event(AE)between the two groups.Statistical analysis was performed using SPSS25.0 software;counting data were expressed as number of cases and composition ratio,and the chi-square test was used for comparison between groups.The mean and standard deviation were used for measurement data,and the rank sum test was used for comparison of quality of life scores;the Kaplan-Meier method was used to plot PFS survival curves,and the Log-rank method was used for statistical tests between groups.Statistical descriptive analysis of adverse events and abnormal laboratory tests was performed according to the Common Terminology Criteria for Adverse Events version 5.0(CTCAE 5.0).Cox proportional risk regression models were used to explore prognostic factors.P<0.05 indicates a statistically significant difference.Results:The clinical characteristics of the patients in the treatment and control groups were similar.In the treatment group,2 patients(11.0%)had partial response,10 patients(55.6%)had stable disease,of which liver metastases accounted for 50%(5/10),and 6 patients(33.3%)had progressive disease.The ORR was not statistically different between the treatment and control groups(11.1%vs.4.0%,P=0.562),and the DCR was 66.7%in the treatment group and 44.0%in the control group.The DCR in the treatment group was 66.7%compared to 44.0%in the control group,with no statistical difference(P=0.216).The median PFS was 4.1months(95%CI,3.468-4.731)in the treatment group and 2.9 months(95%CI,1.316-4.484)in the control group,a statistically significant difference(P=0.031).Subgroup analysis showed that patients with clinical characteristics such as male,age≥60 years,left hemicolectomy,third-line treatment,no previous cetuximab and ECOG score 0-1 were at lower risk of disease progression or death with regorafenib combined with PD-1 inhibitor than with regorafenib alone.The QLQ-C30 showed an improvement in physical and emotional functioning in the treatment group compared to the control group.There were adverse effects associated with fatigue,poor mood,nausea and vomiting after treatment,with no statistically significant difference in nausea and vomiting compared to the control group,and pain was significantly better than before.Overall quality of life improved compared to patients in the control group.The incidence of adverse reactions and adverse events were not statistically different between the two groups(P>0.05).The incidence of adverse reactions adverse reactions in patients in the treatment group was 70.0%(14/20)and included hand-foot syndrome(20.0%),hepatic insufficiency(15.0%),fatigue(15.0%),loss of appetite(15.0%),hypothyroidism(15.0%),hypertension(10.0%),granulocytopenia(10.0%),interstitial pneumonia(10.0%),and peripheral nerve injury(10.0%).The incidence of adverse reactions in patients in the control group was 65.4%(17/26),including hepatic insufficiency(19.2%),loss of appetite(15.4%),hand-foot syndrome(11.5%),hypertension(11.5%),fatigue(11.5%)and granulocytopenia(11.5%).One case(5.0%)of Grade 3-4 adverse reactions occurred in the treatment group,namely hand-foot syndrome,which resolved after discontinuation of the drug and use of glucocorticoids.The adverse effects were reduced by lowering the dose of Regorafenib tablets and symptomatic treatment.The incidence of adverse reactions was higher for patients aged≥60 years compared to those aged<60 years(X~2=4.514,P=0.034).Age and treatment method were statistically significant in the Cox risk proportion model.The risk of disease progression or death was 0.389 times higher in patients aged<60 years than in patients aged≥60 years,and 0.402 times higher in patients applying regorafenib in combination with PD-1 inhibitors than in patients applying regorafenib alone.Conclusions:1.Regorafenib in combination with PD-1 inhibitors showed good efficacy in patients with advanced colorectal cancer of the p MMR/MSS,improving quality of life and with manageable toxic effects.Prospective studies with larger samples are expected to confirm its efficacy and safety,and to explore efficacy predictive biomarkers for immunotherapy to predict the population of benefit and guide individualised treatment. |
