The efficacy of immune checkpoint inhibitors in biliary tract cancer with KRAS mutation

Abstract

Background: With a 15% incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and is a poor prognostic factor. Immune checkpoint inhibitors (ICIs) as salvage therapy have modest activity in BTC. Objectives: There are limited data on the efficacy of ICIs according to KRAS mutation in BTC. We evaluated the efficacy of ICIs in BTC patients with or without KRAS mutations. Design: Retrospective observational study. Methods: We conducted molecular profiling in BTC patients who received ICIs as salvage therapy. The expression of programmed death ligand 1 (PD-L1) on tumor cells was assessed using immunohistochemistry. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to KRAS mutation and PD-L1 expression. Results: A total of 62 patients were included in this analysis. The median age was 68.0 years; 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% received fluoropyrimidine plus oxaliplatin (FOLFOX) before ICI. The median number of lines of prior chemotherapy was 2.5. The KRAS mutation was found in 13 patients (19.1%), and 28 patients (45.2%) showed 1% or more of tumor cells out of visible tumor cells positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS with ICI were 5.6 [interquartile range (IQR): 3.3–8.0] and 3.8 (IQR: 3.0–4.5) months, respectively. There were no statistically significant differences in PFS with ICIs according to KRAS mutation (mutant type versus wild type) and PD-L1 expression (positive versus negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS compared with patients with KRAS mutation and PD-L1 negativity (10.1 versus 2.6 months, p = 0.047). This finding was not shown in patients with wild-type KRAS. Conclusion: Our analysis suggested that PD-L1 expression might be a useful biomarker for ICIs in BTC patients with KRAS mutation but not in those with wild-type KRAS.

KRAS Allelic Variants in Biliary Tract Cancers

“…The results showed that GBC had a relative higher mean and median TMB and proportion of PD-L1 high expression, which are favorable factors for ICI therapy response in KRAS -mutated GBC . In a 2023 study by Jeong et al, patients with KRAS allelic variants and PD-L1 positivity had a longer progression-free survival than patients with KRAS allelic variants and PD-L1 negativity. Preclinically, KRAS inhibitors have been associated with promotion of a proinflammatory tumor microenvironment, increased major histocompatibility complex class I protein expression, and synergies with immunotherapy to enhance antitumor activity .…”

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

“…Though RAS mutations have been reported in 37% of patients with eCCA, actionable RAS mutations such as KRAS G12C are much rarer, occurring in 1–2% of BTC [ 25 •, 114 ]. The phase II KRYSTAL-1 trial [ 94 ] evaluated adagrasib, an oral KRAS G12C irreversible inhibitor, in 12 patients (21% of study population) with BTC.…”

Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer

“…Interestingly, this finding is not discovered in patients without KRAS mutation. 222 Fatty acid-binding protein 1 (FABP1) is reported to induce the uptake of fatty acids to mediate lipid metabolism of cancer cells during metastasis. 223 The expression of FABP1 is significantly higher in direct liver invasion tumor than in primary tumor of GBC and is associated with lymph node metastasis and OS.…”