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The exploration of biomarkers predicting response to immune checkpoint inhibitors in microsatellite stability colorectal cancer can enable more patients to benefit from immunotherapy. Tumor mutational burden (TMB), POLE/POLD1 mutation, CMS classifications, MGMT methylation, and other indicators own the potential and value of predicting response to immune checkpoint inhibitors in microsatellite stability colorectal cancer. In this paper, we reviewed the related research on predictive biomarkers of immune checkpoint inhibitors in microsatellite stability colorectal cancer, provide a reference for the best treatment strategy for microsatellite stability colorectal cancer.
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In recent years, immunotherapy, especially immune checkpoint inhibitors, has shown obvious advantages in prolonging the survival of patients with advanced tumors, and the tumor microenvironment is one of the important factors affecting the efficacy of immunity. Patients with microsatellite-stable colorectal cancer exhibit immune responses in combination with immune checkpoint inhibitor therapy. In-depth exploration of the tumor microenvironment characteristics of microsatellite-stable colorectal cancer and the application of combined immune checkpoint inhibitor therapy can provide new ideas and directions for colorectal cancer immunotherapy.
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OBJECTIVE To evaluate the clinical efficacy and safety of XELOX chemotherapy （oxaliplatin+capecitabine） combined with antiangiogenic agent （apatinib） and immunotherapy （camrelizumab） in patients with inoperable metastatic colorectal cancer （CRC）of microsatellite stable （MSS） type. METHODS Clinical medical records of 40 patients with inoperable metastatic CRC of MSS type treated in Lishui People’s Hospital from January 2020 to January 2021 were retrospectively collected. According to the treatment plan， the patients were divided into control group （20 cases） and observation group （20 cases）. Control group was given XELOX+apatinib regimen， while observation group was given XELOX+apatinib+camrelizumab regimen. Every 3 weeks was a treatment cycle， and the treatment lasted for 2 consecutive cycles. The objective response rate （ORR）， disease control rate （DCR）， progression-free survival （PFS）， overall survival （OS） and adverse events （AEs） were recorded for all patients. RESULTS The ORR and DCR of observation group were 65.0% and 85.0%， respectively； and the ORR and DCR of control group were 35.0% and 75.0%， respectively， with no statistical significance between 2 groups （P＞0.05）. The median PFS of observation group and control groups were 16.0 months and 8.0 months， respectively； and the median OS were 19.0 months and 12.5 months， respectively， with statistical significance between 2 groups （P＜0.05）. Each patient in both groups had at least one AEs， and the incidences of reactive skin capillary hyperplasia and hyperthyroidism in observation group （40.0%， 20.0%） were significantly higher than those in control group （both were 0） （P＜0.05）. The incidence of nausea and vomiting in control group （90%） was significantly higher than observation group （10%） （P＜0.05）. There were 14 cases （70.0%） of patients with grade 3 or above AEs in observation group， and only 5 cases （25.0%） in control group， with statistical significance between 2 groups （P＜0.05）. However， no severe AEs that could not be tolerated or fatal occurred in the two groups， which could be alleviated after drug withdrawal or treatment. CONCLUSIONS The efficacy of XELOX chemotherapy combined with apatinib and camrelizumab in inoperable metastatic CRC patients of MSS type is comparable to that of XELOX chemotherapy combined with apatinib， but it has certain advantages in ORR， PFS and OS， and controllable safety.
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Objective To investigate the clinical efficacy and safety of fruquintinib combined with sintilimab in the treatment of advanced microsatellite stable (MSS) colorectal cancer. Methods A retrospective study of 44 patients with MSS colorectal cancer treated with fruquintinib and sintilimab was conducted.The patients were divided into the fruquintinib alone (n=22) and fruquintinib combined with sintilimab (n=22) groups.The treatment regimen was as follows: The patients in the fruquintinib alone group consumed oral fruquintinib capsules at 5 mg/d once for three consecutive weeks with a one week stop in 28 day cycles.The patients in the fruquintinib combined sintilimab group were injected intravenously with sintilimab (200 mg) once per three weeks, and fruquintinib was used in the same manner as the fruquintinib alone group. Results The objective response rate (ORR) of the fruquintinib alone group was 9.09%, the disease control rate (DCR) of the fruquintinib alone group was 45.45%.The ORR of the fruquintinib combined with sintilimab group was 18.18%, and the DCR was 63.64%.The median PFS of the fruquintinib alone and fruquintinib combined with sintilimab groups were 4.4 months (IQR: 2.1-8.2) and 6.7 months (IQR: 3.9-12.6), respectively (χ2=4.372, P=0.037).Most of the adverse reactions during the treatment of the two groups were grades 1-2.In addition, no significant difference in the incidence of adverse reactions was found between two groups (P > 0.05). Conclusion Compared with fruquintinib alone, fruquintinib combined with sintilimab in the treatment of patients with MSS colorectal cancer after the failure of standard treatment has better clinical efficacy, and adverse drug reactions can be controlled.
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Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.