What is the role of immunotherapy, such as pembrolizumab (generic name), in treating patients with advanced cholangiocarcinoma, particularly those with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR)?

What Immunotherapy Does in Cholangiocarcinoma

Immunotherapy in cholangiocarcinoma works by blocking immune checkpoint proteins (PD-1/PD-L1) to restore the immune system's ability to recognize and destroy cancer cells, with pembrolizumab and durvalumab demonstrating significant clinical benefit particularly in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors. 1

Mechanism of Action

Immunotherapy agents like pembrolizumab function as humanized IgG4 monoclonal antibodies that bind to PD-1 receptors on T-cells with high affinity, preventing interaction with PD-L1 and PD-L2 ligands on tumor cells 2. This blockade removes the "brakes" on the immune system, allowing T-cells to recognize tumor neoantigens and mount an effective anti-tumor response 3. In cholangiocarcinoma, which often arises in the context of chronic inflammation, this mechanism is particularly relevant as these tumors can exploit immune checkpoint pathways to evade immune surveillance 3.

Clinical Efficacy by Molecular Subtype

MSI-H/dMMR Cholangiocarcinoma (Strong Evidence)

Pembrolizumab achieves an objective response rate of 40.9% with complete responses in 21% of MSI-H/dMMR cholangiocarcinoma patients who progressed after first-line chemotherapy, with median progression-free survival of 4.2 months and median overall survival of 24.3 months. 1

• The FDA and EMA have approved pembrolizumab specifically for MSI-H/dMMR solid tumors including biliary tract cancers based on this tumor-agnostic efficacy 1, 2
• Immune checkpoint blockade should be considered a therapeutic option for patients with intrahepatic cholangiocarcinoma and dMMR/MSI-H who have progressed on first-line chemotherapy and have not received durvalumab in first-line 1
• Case reports demonstrate pathological complete responses after pembrolizumab treatment in MSI-H perihilar cholangiocarcinoma, with dramatic tumor downsizing enabling conversion surgery 4

Unselected Advanced Cholangiocarcinoma (First-Line)

Gemcitabine plus cisplatin combined with durvalumab or pembrolizumab represents the standard of care for first-line treatment of unresectable or metastatic cholangiocarcinoma, achieving a hazard ratio of 0.76 (95% CI 0.64-0.91) and median overall survival of 12.9 months. 5, 2

• This combination is FDA-approved for locally advanced unresectable or metastatic biliary tract cancer regardless of biomarker status 2
• The addition of immunotherapy to chemotherapy transforms the treatment paradigm beyond traditional cytotoxic approaches alone 1

Treatment Algorithm

First-Line Setting

1. For all patients with unresectable/metastatic cholangiocarcinoma: Initiate gemcitabine plus cisplatin combined with durvalumab or pembrolizumab 5, 2
2. Do not delay treatment waiting for further disease progression, as early treatment correlates with improved outcomes 5

Second-Line Setting (After Chemotherapy Progression)

1. Test for MSI/MMR status using PCR or immunohistochemistry if not previously performed 1, 2
2. If MSI-H/dMMR: Pembrolizumab or dostarlimab monotherapy (strong recommendation) 1
3. If microsatellite stable: Consider targeted therapy based on molecular profiling (FGFR2 inhibitors for fusions, ivosidenib for IDH1 mutations) 1

After Single-Agent Immunotherapy Progression

• Sequential dual-agent immunotherapy with ipilimumab plus nivolumab can produce objective responses even in patients without MSI-H or high tumor mutational burden who progressed on pembrolizumab 6

Critical Pitfalls to Avoid

Do not assume MSI status remains static throughout treatment. Tumor heterogeneity and immunotherapy itself can induce shifts from microsatellite stable (MSS) to MSI-H status, particularly in metastatic sites 7. Retesting metastases or recurrent disease is warranted when considering immunotherapy options 7.

Avoid treating patients with ECOG performance status >2, as they derive no benefit and experience increased toxicity 5. Patients must have adequate organ function and WHO/ECOG performance status 0-2 to be eligible 5.

Do not overlook the 29.4% primary progressive disease rate with first-line pembrolizumab monotherapy in the KEYNOTE-177 trial 1. For patients requiring rapid tumor downstaging for resection or with poor prognostic features, first-line chemotherapy with immunotherapy may be preferable to immunotherapy alone 1.

Recognize discordant MSI testing results. Among tumors testing MSI-H/dMMR by local testing, only 56.7% were confirmed MSI-H by FoundationOne CDx and 62.1% were confirmed dMMR by VENTANA MMR RxDx Panel 2. Consider confirmatory testing with FDA-approved assays when feasible 2.

Integration with Other Modalities

Stereotactic body radiation therapy (SBRT) can be combined with systemic chemotherapy-immunotherapy, particularly for oligometastatic sites during first-line treatment 5. SBRT dosing of 30-50 Gy in 3-5 fractions is recommended for unique intrahepatic lesions <5 cm when surgical resection is not possible 5.

Quality of Life Considerations

Quality of life should be the primary focus with survival as a secondary endpoint, as achieving stable disease correlates with improved length and quality of life 5. Pembrolizumab demonstrates a favorable safety profile compared to chemotherapy, with grade 3-4 treatment-related adverse events occurring in only 9-18% of patients versus 49.4% with chemotherapy 8. Common immune-related adverse events include pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions, which require active monitoring 9, 8.