JMIR Publications

ABSTRACT

Background:

Colorectal cancer (CRC) is one of the leading cause of cancer-related mortality worldwide. Approximately 13% of CRCs exhibit microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), resulting in high tumor mutational burden and enhanced immunogenicity. These tumors are particularly responsive to programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors. However, despite the durable responses, up to one-third experience disease 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 conducted across PubMed, ProQuest, ScienceDirect, and ClinicalTrials.gov in September - October 2025. Eligible studies included case reports and observational studies involving patients with MSI-H/dMMR CRC who experienced progression after PD-1/PD-L1 blockade and received subsequent chemotherapy, targeted therapy, or combination immunotherapy. The risk of bias was evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports and the Newcastle–Ottawa Scale for cohort studies.

Results:

A total of 504 studies were identified, of which one retrospective cohort study and eight case reports met the inclusion criteria, encompassing 38 patients with MSI-H/dMMR metastatic CRC (mCRC). Post–PD-1/PD-L1 inhibitor treatments included chemotherapy (FOLFOX, FOLFIRI, trifluridine/tipiracil), targeted agents (encorafenib, trastuzumab-based combinations), and immunotherapy rechallenge (nivolumab+ipilimumab or PD-1+anti-angiogenic therapy). 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 Grade 1–2 and manageable.

Conclusions:

Following progression on PD-1/PD-L1 inhibitors, conventional chemotherapy offers modest benefit in MSI-H/dMMR CRC, whereas combination strategies integrating immunotherapy or anti-angiogenic agents show greater and durable efficacy. Prospective studies are needed to define strategies after PD-1/PD-L1 inhibitor failure. Clinical Trial: PROSPERO database (registration number: CRD420251175508)