Intrahepatic cholangiocarcinoma (ICC), derived from intrahepatic bile duct, ranks as the second most common malignant tumor in liver (1, 2). The incidence of ICC has been steadily increasing worldwide, from 0.1 cases per 100,000 to 0.6 per 100,000 over the past 30 years (3, 4). The most common risk factors for ICC in Jilin Province, China are chronic hepatitis B and C infections, as well as exposure to environment toxins such as aflatoxin (5). ICC patients are often diagnosed at an advanced stage due to non-specific symptom and high malignant aggressiveness, which makes anti-cancer treatments challenging (6). Notably, only 22% of ICC patients are eligible for curative surgery, owing to delayed diagnosis. The high recurrence and metastasis rates also negatively affect post-surgery survival rates (7, 8). The development of effective systemic therapies is needed for advanced ICC patients. Gemcitabine plus cisplatin (GC) is currently the standard first-line chemotherapy for advanced ICC patients worldwide. However, its efficacy is not satisfactory as expected, given that the progression-free survival (PFS) and overall survival (OS) of GC treatment are only 8.0 and 11.7 months, respectively (9). A meta-analysis involving seven published clinical trials also showed that gemcitabine-based regimens were associated with increased adverse events (8). The poor performance status of advanced ICC patients due to frequent biliary obstruction and infection may cause chemotherapy intolerance. Therefore, identifying more effective and safer anti-cancer treatments for advanced ICC patients is imperative.

In recent years, immunotherapy such as programmed cell death 1 (PD-1) and programmed cell death ligand (PD-L1) inhibitors has shown clinical success in treating a range of solid tumors, particularly advanced cancer patients (10). Many previous studies have investigated the efficacy of immunotherapy alone or in combination with other agents in ICC patients. A multicenter phase III randomized controlled clinical study reported that compared with chemotherapy in combination with placebo, biliary tract cancer patients receiving durvalumab combined with GC showed significantly improved median OS (11.5 vs. 12.8 months, p = 0.021) and PFS (5.7 vs. 7.2 months, p = 0.001) (11). These findings suggest a promising landscape of chemotherapy combined with immunotherapy as first-line treatment in biliary tract system tumors. Nonetheless, as mentioned previously, the poor performance status of advanced ICC patients may influence their response to chemotherapy. A standard first-line anti-cancer treatment for advanced ICC patients who refuse or are intolerant to chemotherapy is urgently required.

Lenvatinib is a multi-targeted inhibitor that suppresses vascular endothelial growth factor receptor (VEGFR) 1–3, fibroblast growth factor receptor (FGFR) 1–4, platelet-derived growth factor receptor (PDGFR)α, and proto-oncogenes RET and KIT (12). Preclinical data show that lenvatinib decreases the number of tumor-associated macrophages, thereby affecting antitumor immune responses and leading to increased efficacy of PD-L1 inhibition (13). In a recent study, Dr. Zhao tested the efficacy and safety of pembrolizumab plus lenvatinib as a second-line treatment for advanced biliary tract cancer (14). The trial showed an objective response rate (ORR) of 25% and a disease control rate (DCR) of 78.1%. Notably, no grade 5 adverse events were reported and only 59.3% of patients suffered from grade 3 treatment-related adverse events. This trial manifests the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with lenvatinib. However, data on immunotherapy in combination with lenvatinib as the first-line treatments for advanced ICC patients in the real world are limited.

The present study aimed to compare the efficacy and safety of PD-1/PD-L1 in combination with GC regimen and lenvatinib as the first-line anti-cancer treatment in advanced ICC cancer patients, which may provide guidance in clinical practice.

Owing to delayed diagnosis, ICC patients are always diagnosed at an advanced stage, inappropriate for curative surgery and with poor prognosis. Adjuvant systemic treatment will be recommended after surgery resection or in the palliative care. GC is currently accepted as the standard first-line chemotherapy for advanced ICC patients; however, its limited efficacy and potential toxicity fail to significantly improve prognosis. The occurrence of immunotherapy has revolutionized treatment landscape of various solid tumors, including ICC. However, many previous studies showed that the efficacy of immunotherapy as a monotherapy was modest in advanced ICC patients (15, 16). The present study aimed to explore the efficacy and safety of combination treatments based on PD-1/PD-L1 in advanced ICC patients. We retrospectively analyzed patients receiving PD-1/PD-L1 inhibitors combined with GC or lenvatinib. Objective tumor response and survival analysis were used to compare the efficacy between two combination treatments. Adverse events were also recorded to evaluate the safety. The results of our study showed that both ICIs combined with GC and lenvatinib may be promising first-line treatments for advanced ICC patients, with no significant prognostic difference between two groups.

Chemotherapy has been confirmed to upregulate the expression of immune checkpoint, which can result in significant modifications in immune cell infiltrate (17). Combining chemotherapy with ICIs may achieve longer survival for cancer patients. Many previous clinical studies have confirmed a better tumor response and survival of receiving PD-1/PD-1 inhibitors plus chemotherapy than standard chemotherapy in patients with non-small cell lung cancer (18), breast cancer (19), esophagus cancer (20), and biliary tract cancer (11). The results of our study revealed that PD-1/PD-L1 inhibitors plus GC treatment had an ORR and DCR of 23.1% and 46.2%, respectively, in advanced ICC patients, with 6-month and 9-month OS rates of 87.4% and 71.5%, respectively. Similarly, in a phase II trial, camrelizumab plus gemcitabine plus oxaliplatin (GEMOX) has shown a promising antitumor activity and acceptable safety profile as first-line treatment in advanced biliary tract cancer patients. Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and the median OS was 11.8 months, respectively (21). Moreover, some studies also indicated that PD-1 inhibitors can resensitize biliary tract cancer to chemotherapy. In a phase II study, patients treated primarily with gemcitabine- or cisplatin-based chemotherapy were subsequently treated with nivolumab plus gemcitabine and cisplatin. Some patients showed a CR, and one showed a PR, suggesting that nivolumab is able to resensitize chemotherapy with gemcitabine and cisplatin (22).

Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors (12). Notably, preclinical research showed that the antitumor activity of lenvatinib will improve when combined with ICIs by reducing tumor-associated macrophages (TAMs) and increasing the percentage of activated CD8+ T cells secreting interferon (IFN)-γ+ and granzyme B (GzmB) (23). Wang et al. reported that the ORR was 12% (95% CI: 1.7–22.7), with a median PFS of 3.8 months (95% CI: 1.3–6.3) and an OS of 11.4 months in advanced biliary tract carcinoma patients receiving lenvatinib as first-line therapy (24). Compared with lenvatinib alone, our study showed a higher ORR (16.0%) and longer median PFS (9.5 months) of lenvatinib plus PD-1/PD-L1 inhibitors. Consistent with our results, the median PFS of lenvatinib plus PD-1/PD-L1 inhibitors from a recent study was 8.63 months in ICC patients, longer than lenvatinib alone though slightly shorter than the results of our study (25). In the same trend, Xie et al. recorded a median PFS of 5.83 months, with an ORR and DCR of 17.5% and 75.0% respectively (26). In a phase II study, the ORR and DCR reached 42.1% and 76.3%, respectively, in unresectable biliary tract cancer patients receiving lenvatinib plus PD-1 inhibitors as first-line treatment (27). Zhu et al. recently reported that PD-1/PD-L1 inhibitors plus chemotherapy combined with lenvatinib represented an effective and tolerable treatment option in patients with advanced biliary tract cancer (28). One possible reason why their results were significantly better than ours is because of the difference in patients’ baseline profile. Moreover, there may be a difference in the efficacy of targeted therapy combined with immunotherapy and chemotherapy between patients with gallbladder cancer, ICC, and extrahepatic cholangiocarcinoma (29). Although there are mild differences from various studies, it is apparent that the combination of lenvatinib with PD-1/PD-L1 could be an effective treatment for advanced ICC patients.

In the current study, we found that patients receiving PD-1/PD-L1 inhibitors plus lenvatinib had a poorer physical status, had a higher ECOG grade, and had frequent presence of ascites. This may be due to the selection bias that patients would be treated with lenvatinib only when they are intolerant to chemotherapy in the clinical practice. However, no significant difference was observed in tumor objective response and survival between patients receiving PD-1/PD-L1 inhibitors plus GC and lenvatinib. In the multivariate Cox analysis adjusting for confounding factors, only ECOG grade was the independent risk factor for PFS and OS. As for safety, the incidence of side effects was higher in the chemotherapy group, but it was not statistically significant. Moreover, no grade 4 adverse event and related death was recorded in both groups. Therefore, we speculated that PD-1/PD-L1 plus lenvatinib would be recommended as a promising first-line treatment for advanced ICC patients who refuse or are intolerant to chemotherapy. In the clinical practice, we can formulate individualized anti-cancer treatments depending on the patient’s physical performance.

This study has some limitations. First, this is a retrospective single-center study, with a small number of participants and short follow-up. The median OS was not reached in both groups. There may be type II error in our study considering that the conclusions were generated based on non-statistically significant results. A large-scale randomized controlled prospective study is needed to confirm the results of the present study. Second, we included all patients receiving PD-1/PD-L1 inhibitors plus chemotherapy or lenvatinib in this retrospective study, not differentiating specific drugs. The choice of the PD-1/PD-L1 inhibitor is highly individualized in the real world considering drug accessibility, price, medical insurance coverage, and other factors. Moreover, there is no evidence showing which PD-1/PD-L1 inhibitor is better than others in advanced ICC patients. Most patients also lacked data on PD-L1 expression testing, which may have an influence on their response to immunotherapy. Third, all patients enrolled in our study were from one medical institution in China. The efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy and lenvatinib as the first-line treatment beyond the current region and race need to be proven in the future.

In conclusion, PD-1/PD-L1 inhibitors in combination with chemotherapy and lenvatinib are both beneficial to tumor control and survival extension as first-line treatment in advanced ICC patients, with no severe adverse events. As for patients with poor physical performance or intolerance to chemotherapy, ICIs plus lenvatinib could be recommended.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by The ethics committees of the First Hospital of Jilin University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

All authors have read and approved the final manuscript. N-YW conceived and designed the study. J-XH, BL YL, XL, and L-JD assisted with the development of the methods. J-XH, BL, and YL performed the data analysis. J-XH and BL drafted the initial manuscript. L-JD and N-YW gave many valuable comments on the draft and polished it. All authors assisted with the interpretation of the findings, commented on drafts of the manuscript, and approved the final version.