Is immunotherapy contraindicated in a patient with unresectable stage 4 cholangiocarcinoma and low Microsatellite Instability (MSI)?

Immunotherapy in MSI-Low Unresectable Stage 4 Cholangiocarcinoma

Immunotherapy is NOT recommended for patients with unresectable stage 4 cholangiocarcinoma who have low MSI (microsatellite stable/proficient mismatch repair), as immune checkpoint blockade should only be considered for those with dMMR/MSI-H tumors who have progressed on first-line chemotherapy. 1

First-Line Treatment for MSI-Low Disease

For patients with unresectable cholangiocarcinoma and good performance status (ECOG 0-1), the standard first-line treatment is gemcitabine plus cisplatin (GemCis) with the addition of durvalumab where available, regardless of MSI status. 1 This represents a Level 1 evidence recommendation with strong consensus from the 2023 EASL-ILCA guidelines. 1

• Durvalumab added to GemCis significantly improved overall survival (12.8 vs 11.5 months; HR 0.80; p=0.021) in the TOPAZ-1 trial for chemotherapy-naïve advanced biliary tract cancer. 1
• This combination is appropriate for all patients with good performance status, independent of MSI status. 1

Role of Immunotherapy Based on MSI Status

The 2023 EASL-ILCA guidelines explicitly state that immune checkpoint blockade should be considered a therapeutic option ONLY in patients with dMMR/MSI-H cholangiocarcinoma who have progressed on first-line chemotherapy. 1 This is a Level 4 evidence, strong recommendation with 97% consensus. 1

Why MSI Status Matters

• The international consensus guidelines (JSCO-ESMO-ASCO-JSMO-TOS) recommend PD-1/PD-L1 inhibitors strongly for patients with MSI/dMMR tumors (Level III evidence, Grade A recommendation, 100% agreement). 1
• MSI-low/proficient mismatch repair tumors do not respond well to single-agent immunotherapy because they lack the high neoantigen burden that makes MSI-high tumors immunogenic. 1
• A prospective multicenter study showed 53% objective response rate with pembrolizumab in dMMR/MSI-H advanced cancers including cholangiocarcinoma, with 21% achieving complete response. 1

Treatment Algorithm for Your Patient

If MSI-Low (Microsatellite Stable):

1. First-line: GemCis + durvalumab (if available and good performance status) 1
2. Second-line after progression:
   • FOLFOX chemotherapy 1
   • FGFR inhibitors if FGFR2 fusions/rearrangements present 1
   • Ivosidenib if IDH1 mutations present 1
   • NOT immune checkpoint blockade monotherapy 1

If MSI-High (dMMR):

1. First-line: GemCis + durvalumab 1
2. Second-line after progression: Immune checkpoint blockade (pembrolizumab, nivolumab) is a strong therapeutic option 1

Important Caveats

Do not confuse durvalumab in first-line combination therapy with single-agent immunotherapy. Durvalumab is added to chemotherapy upfront for all patients regardless of MSI status, but this is different from using checkpoint inhibitors as monotherapy or primary treatment. 1

Testing for MSI/MMR status is recommended before or during standard treatment of advanced cholangiocarcinoma, as it guides second-line therapy decisions. 1 The international consensus recommends IHC as highly recommended for testing (Grade A), with PCR or validated NGS as alternatives. 1

Rare exceptions exist: Case reports describe responses to dual-agent immunotherapy (ipilimumab + nivolumab) in MSI-low cholangiocarcinoma after progression on multiple therapies, but these are anecdotal and not guideline-supported. 2 One case series showed objective responses in 3 patients without MSI-high or high tumor mutation burden, but this represents experimental sequential therapy, not standard practice. 2

For patients with impaired performance status, gemcitabine monotherapy or gemcitabine plus S-1 may provide comparable efficacy with fewer adverse events compared to combination therapy. 1 Immunotherapy monotherapy is not recommended in this population regardless of MSI status. 1