What Immunotherapy Does in Stage 4 Cholangiocarcinoma with Low MSI
For your patient with unresectable stage 4 cholangiocarcinoma and low MSI (microsatellite stable/MSS), immunotherapy monotherapy is NOT recommended and should NOT be used, as MSI-low tumors lack the high neoantigen burden required for immune checkpoint inhibitors to work effectively. 1
Understanding Immunotherapy's Mechanism
Immunotherapy works by blocking immune checkpoint proteins (PD-1/PD-L1) that cancer cells exploit to evade immune destruction. 2 However, this mechanism only succeeds when tumors have sufficient neoantigens—mutated proteins that the immune system can recognize as foreign. 3
Why MSI Status Determines Immunotherapy Efficacy
MSI-High/dMMR tumors contain thousands of mutations that encode mutant proteins recognizable by the immune system and upregulate PD-L1, making them highly responsive to PD-1 inhibitors with objective response rates of 40-53%. 4, 3
MSI-Low/MSS tumors (like your patient's) do not respond to single-agent immunotherapy because they lack this high neoantigen burden, with pembrolizumab showing 0% objective response rate (95% CI, 0%-20%) in MSS colorectal cancer. 4
Appropriate Treatment for Your MSI-Low Patient
First-Line Therapy
Gemcitabine plus cisplatin (GemCis) with durvalumab is the standard first-line treatment for unresectable cholangiocarcinoma with good performance status, regardless of MSI status. 1 This combination improved overall survival to 12.8 months versus 11.5 months with chemotherapy alone (HR 0.80; p=0.021) in the TOPAZ-1 trial. 1
Second-Line Options After Progression
For MSI-low cholangiocarcinoma, appropriate second-line treatments include:
- FOLFOX chemotherapy 1
- FGFR inhibitors if FGFR2 fusions/rearrangements are present 1
- Ivosidenib if IDH1 mutations are present 1
- NOT immune checkpoint blockade monotherapy 1
Critical Testing Requirements
Testing for MSI/MMR status should be performed before or during standard treatment using immunohistochemistry (IHC) as the highly recommended method (Grade A recommendation), with PCR or validated NGS as alternatives. 2, 1 This testing is essential because it determines whether immunotherapy will be considered in second-line treatment. 1
When Immunotherapy IS Appropriate in Cholangiocarcinoma
Immune checkpoint blockade should only be considered in cholangiocarcinoma patients with dMMR/MSI-High status who have progressed on first-line chemotherapy (Level 4 evidence, 97% consensus). 1 The international consensus guidelines strongly recommend PD-1/PD-L1 inhibitors for MSI/dMMR tumors with 100% expert agreement. 2
Evidence for MSI-High Disease
- Pembrolizumab achieved 53% objective response rate in dMMR/MSI-H advanced cancers including cholangiocarcinoma, with 21% achieving complete response. 1
- Case reports document dramatic responses in MSI-high cholangiocarcinoma, including resolution of portal vein tumor thrombosis with pembrolizumab. 5
Important Caveats and Pitfalls
Do not assume MSI status remains static throughout treatment. Rare cases document MSI status shifts from MSS to MSI-H after immunotherapy exposure, suggesting tumor heterogeneity and the potential influence of spatial or temporal factors. 6 However, this phenomenon is extremely rare and should not influence initial treatment decisions.
For patients with impaired performance status, gemcitabine monotherapy or gemcitabine plus S-1 may provide comparable efficacy with fewer adverse events, but immunotherapy monotherapy remains inappropriate regardless of performance status in MSI-low disease. 1
Beware of rapid tumor necrosis in MSI-high responders. One case report documented intrahepatic tumor perforation from rapid necrosis after pembrolizumab in MSI-H cholangiocarcinoma, though pathological autopsy confirmed near-complete tumor disappearance. 7
Sequential Immunotherapy Strategy
If your patient's tumor were MSI-high and progressed on single-agent immunotherapy, dual-agent immunotherapy with ipilimumab plus nivolumab could be considered. 8 A case series demonstrated objective responses in advanced cholangiocarcinoma patients who progressed on pembrolizumab, even without high tumor mutation burden. 8