Treatment Options After PD-1/PD-L1 Inhibitors in dMMR/MSI-H Colorectal Cancer: A Systematic Review (Preprint)
Bibliographic record
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. CLINICALTRIAL PROSPERO database (registration number: CRD420251175508)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.014 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.006 | 0.006 |
| Bibliometrics | 0.005 | 0.006 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".