Discussion
neutropenia, activityOwing, intrahepatic cholangiocarcinoma, toxicity, thrombocytopenia, hematological toxicities, HRD, gallbladder carcinoma, tumors, extrahepatic cholangiocarcinoma
EXTRAHEPATIC CHOLANGIOCARCINOMA, NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, GALLBLADDER CARCINOMA, INTRAHEPATIC CHOLANGIOCARCINOMA, TUMOR GROWTH, TUMORS
GemCis has been the standard first-line treatment for unresectable or metastatic BTCs for decades. Although the ABC-02 and BT22 study demonstrated the clinical efficacy of GemCisIn our study, 15.9 months of median OS and 36.7% of ORR emerged as a benefit tendency compared with chemotherapy and were comparable to TOPAZ-1In our study, a treatment containing sintilimab combined with GemCis was well tolerated and within acceptable toxicity levels. The most frequently reported treatment-related grade 3 or above adverse events were hematological toxicities, which were widely perceived to be associated with cisplatin and gemcitabine. However, we observed a much higher incidence of grade 3 or above thrombocytopenia and a lower incidence of neutropenia in this study compared with that reported for GemCis chemotherapyAlthough efforts have been made to reveal the genetic and immunological characteristics of BTC for determining its prognostic value, progress is slow and the findings may be difficult for widespread application. TMB, as a widely used immunotherapy predictive biomarker, was not associated with the clinical benefit of sintilimab combined with GemCis in our trial. This observation is consistent with that in KEYNOTE 407 and KEYNOTE 189 studies for NSCLCHomologous recombination deficiency (HRD) prevents DNA-damaging agents such as platinum-based chemotherapy from repairing gene damage, disrupts the ability of cells to undergo homologous recombination, and further causes gene instabilityTumor-infiltrating lymphocytes (TILs) have been proposed as a crucial prognostic indicator, and the TILs density has great predictive power for survival in solid cancersActivated MCs are thought to release a wide range of bioactive molecules that affect invasion, tumor-associated angiogenesis, and immune cell activity, leading to tumor growth and metastasisThe TiME mainly comprised cellular and non-cellular components that play an important role in anti-tumor activityOwing to the limited number of clinical studies, our study had some limitations. As it is a single-center study and intrahepatic cholangiocarcinoma is the main type of BTCs in this ward at the center, the patients enrolled were relatively restricted in diversity of BTC subgroups. Thus, the significance of extrahepatic cholangiocarcinoma and gallbladder carcinoma is limited. A larger randomized and multi-center trial is warranted to verify the study results. Besides, while we formulated the standard of the specimens, since the heterogeneity and purity difference of biopsy tumors, and the exploration on bulk-tumor level have inherent limitations in providing precise information, these are the unavoidable methodological limitations in our study. Not only that, biomarker analyses in our study were retrospective and hypothesis-generating in limited sample size, and therefore the results should be interpreted with caution. In summary, our study suggested that sintilimab plus GemCis delivered promising antitumor efficacy and an acceptable safety profile in advanced BTCs. Moreover, the genetic and TiME characteristics were deeply investigated to establish effective biomarkers for predicting the clinical response. Our findings provide a potential treatment option and a certain basis for further study of this regimen in BTCs.