Chemotherapy Sequential Tislelizumab After Radical Resection in Patients With dMMR/MSI-H or POLE/POLD1 Mutations

Colorectal Adenocarcinoma Clinical Trial

Official title: A Single-arm, Open, Multicenter Phase II Study of Chemotherapy-sequential Tislelizumab Adjuvant Therapy After Radical Resection in Patients With Gastric or Colorectal Adenocarcinoma With dMMR/MSI-H or POLE/POLD1 Mutations

Status Not yet recruiting

Clinical Trial Summary

Objective of this study to evaluate 1-year disease-free survival in patients with dMMR/MSI-H or POLE/POLD1 gene mutations with gastric or esophagus-gastric junctional adenocarcinoma or colorectal adenocarcinoma after chemotherapy-sequential tiralizumab adjuvant radical resection (based on RECIST v1.1 criteria).

Clinical Trial Description

Colorectal cancer and gastric cancer are common malignant tumors of digestive tract. The latest statistical data show that the number of new cases of colorectal cancer and gastric cancer in China ranks second and third among all malignant tumors, and the number of death cases ranks fifth and third. They are one of the main cancers threatening the life and health of Chinese residents, causing serious social burden In recent years, immunotherapy represented by immune check point inhibitors (ICI) has made great progress in the treatment of malignant tumors, among which programmed death receptor 1(pro grammed death) 1,PD-1) antibody is the most widely used.

Microsatellite instablehigh (MSI-H) is highly unstable due to DNA mismatch repairdeficient (dMMR) .The insertion or loss of the base pairs of microsatellite fragments, the change of the length of microsatellite tandem repeats, and the emergence of new microsatellite alleles are one of the mechanisms of tumor occurrence. Deficient mismatch repair (dMMR)/ microsatellite instablehigh (MSI-H) is the first molecular marker discovered to predict the efficacy of ICI treatment for pancancer .The emergence of ICI therapy has brought the dawn for prolonging the survival time of patients with advanced gastrointestinal tumors.Immune checkpoint inhibitors have shown satisfactory results in patients with MSI-H/dMMR from late-stage to first-line therapy.A 2015 study by Le et al.was the first to show that molecular phenotypic metastatic colorectal (mCRC) with mismatch repair defects (dMMR) or high microsatellite instability (MSI-H) can benefit significantly from the immune checkpoint PD-1 inhibitor pembrolizumab. Immune checkpoint inhibitors have made significant progress in the treatment of the posterior line of colorectal cancer.In KEYMAT-016, a pivotal study of MSI-H tumor immunotherapy, multiple tumors of dMMR benefited from PD-1 monoclonal antibody Pbolizumab. For mCRC patients who failed standard therapy, 7 out of 13 dMMR/MSI-H patients received pembrolizumab monotherapy and achieved objective remission (62%) .All patients did not achieve median progression-free time (PFS) and overall survival time (OS), and the KEYNOTE-164 study further investigated dMMR/MSI-H The clinical benefit of pabolizumab in mCRC patients was an objective response rate (ORR) of 32%(median follow-up 12.6 months) and 1-year progression-free survival and overall survival were 41% 76%, respectively, among 63 previously treated patients in KEYMAT-164 Cohort B This study shows that MSI-H CRC patients treated with pabolizumab have sustained anti-tumor effects even after first-line therapy progresses.The KEYNOTE-059 trial, which included patients with metastatic gastric/gastroesophageal junction tumors after second-line chemotherapy failure, showed an ORR of 47%(3/7) in the MSI-H group compared to only 9%(15/167) in the non-MSI-H group.In KEYNOTE 158, the ORR for MSI-H gastric cancer treated with pembrolizumab reached 45.8% (11/24 95% CI: 25.6% ~ 67.2%) .A number of subgroup analyses have shown that MSI-H gastric cancer has advantages over chemotherapy in immunotherapy, and adverse drug reactions are within the acceptable range. A number of PD-1/PD-L1 models have been approved for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors. Immune checkpoint inhibitors not only show surprising efficacy in the posterior treatment of patients with advanced tumors, but also have been confirmed as first-line treatment. CheckMate142、KEYNOTE-177 study explored the efficacy of immunotherapy as first-line treatment of bowel cancer, and both achieved promising OS and PFS results.KEYNOTE-177 MSI-H first-line patients treated with pembrolizumab for advanced colorectal cancer significantly extended median PFS(16.5 months vs.8.2 months) and improved ORR(43.8%vs.33.1%) compared to standard chemotherapy. This study also established the position of immunotherapy in the first-line treatment of MSI-H advanced colorectal cancer, further supporting the gradual push of immunotherapy from the back line treatment to the front line treatment.

However, the role of immunotherapy in the adjuvant treatment of MSI-H/dMMR solid tumors is still uncertain. No matter NCCN guidelines, ESMO guidelines or China's CSCO guidelines, for postoperative adjuvant treatment of people with advantages of immune benefit, observation or chemotherapy is recommended according to the stage and risk factors. Based on the remarkable results achieved in previous studies, the role of immunotherapy in MSI-H/dMMR adjuvant therapy for colon and gastric cancer is worthy of expectation.

tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody, which is currently the only PD-1 antibody modified by Fc segment. It removes the binding ability of FC-γR on the surface of macrophages, does not mediate the cross-linking of immune cells, avoids the ADCP effect to the greatest extent, avoids T cell consumption, and theoretically enhances its anti-tumor activity. RATIONALE 209 study results show that patients with MSI-H metastatic solid tumor who failed standard therapy receiving tislelizumab monotherapy can also achieve an impressive objective response rate (ORR(mCRC :39%; G/GEJC :55.6%), the security is controllable. tislelizumab has been approved by NMPA for the treatment of urothelial carcinoma, non-small cell lung cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, and highly microsatellite unstable solid tumors.

POLE/POLD1 mutations encoding DNA polymerase are involved in the occurrence and development of various tumors, and the mutation rate of POLE/POLD1 is about 7.4% in colorectal cancer and 7.1% in esophageal cancer. Mutations in the gene encoding POLE and POLD1 exonuclide region lead to loss of correction function, which is closely related to tumor hypermutation, TMB elevation, neogenic antigen increase, and increased intra tumor immune cell infiltration. Previous studies have shown that these are closely related to good immune efficacy, which also indicates that POLE/POLD1 mutation is expected to become a molecular marker for predicting the efficacy of ICI, a new pan-cancer species.

In summary,MSI-H/dMMR and POLE/POLD1 mutations are advantageous populations for immunotherapy. The purpose of this study was to explore the efficacy and safety of chemotherapy followed by tislelizumab for adjuvant treatment of gastric or esophago-gastric junctional adenocarcinoma or colorectal adenocarcinoma in patients with radical resection of dMMR/MSI-H or POLE/POLD1 mutations. To provide clinical guidance for MSI-H/dMMR or POLE/POLD1 gene mutated colon and gastric cancer adjuvant therapy modalities ;

Related Conditions & MeSH terms

• Adenocarcinoma
• Colorectal Adenocarcinoma

• NCT number: NCT06118658
• Study type: Interventional
• Source: China Medical University, China
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: November 1, 2023
• Completion date: December 31, 2026