English

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Abstrak

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality. Approximately 13% of CRCs are microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR), resulting in high tumor mutational burden and immunogenicity. These tumors are particularly responsive to programmed cell death protein 1 (PD-1) or programmed death-ligand 1 inhibitors (PD-L1). However, despite the durable responses, up to one-third experience progression due to primary or acquired resistance. The optimal management strategy following progression on PD-1/PD-L1 inhibitors remains undefined.

Objective: This systematic review summarizes current and emerging treatment options in this setting.

Methods: A systematic search was performed. Eligible studies included case reports and observational studies of MSI-H/dMMR CRC patients who progressed on PD-1/PD-L1 blockade and received subsequent chemotherapy, targeted therapy, or combination immunotherapy. Risk of bias was assessed using the Joanna Briggs Institute checklist for case reports and the Newcastle–Ottawa Scale for cohort studies.

Results: A total of 504 studies were identified, one retrospective cohort study and eight case reports met inclusion criteria, comprising 38 patients with metastatic MSI-H/dMMR CRC. All studies demonstrated a low risk of bias. The cohort study reported limited efficacy of chemotherapy (ORR 13%, median PFS 2.9 months, OS 7.4 months), whereas combination regimens especially PD-1 with bevacizumab or CTLA-4 blockade yielded durable responses up to 12–36 months. Most adverse events were manageable.

Conclusion: Following progression on PD-1/PD-L1 inhibitors, conventional chemotherapy offers modest benefit, whereas combination strategies integrating immunotherapy or anti-angiogenic agents show greater and durable efficacy. 

Keywords: MSI-H/dMMR colorectal cancer, PD-1/PD-L1 inhibitor, Post–PD-1 progression, Treatment options