Combination of gemox, lenvatinib, and PD-1 blockade vs. gemox monotherapy as first-line treatment for intrahepatic cholangiocarcinoma with metastases

To the Editor: Intrahepatic cholangiocarcinoma (ICC) ranks second among liver malignancies, and system chemotherapy is the current choice for controlling the tumor for patients with advanced ICC.1 Gemcitabine (Gem)-based chemotherapy has been a dominating treatment for advanced ICC.2 Generally, the outcome of systemic chemotherapy is poor and dissatisfied, and patients easily obtain therapy resistance.2 Recently, programmed cell death 1 (PD-1) blockade has shown great potential in tumor-specific immune therapy.3 Lenvatinib which targets multi-vascular endothelial growth factor receptors (VEGFR), and lenvatinib alliance of PD‑1 blockade have shown great promise in advanced ICC.4 This retrospective multicenter research compares the prognosis of triple therapy with Gemox, lenvatinib, and PD-1 blockade with Gemox monotherapy for treating ICC with extrahepatic metastases. A total of 102 patients with advanced ICC were included in three hospitals (the Second Affiliated Hospital of Guangzhou Medical University, the First Hospital of Hunan University of Chinese Medicine, and the First Affiliated Hospital of Jinzhou Medical University) from June 2019 to June 2022. This study was approved by the Ethics Committee of The First Hospital of Hunan University of Chinese Medicine (No. HN-LL-LW-2024-006). Here were the criteria for inclusion: (1) histologically confirmed primary ICC; (2) all patients undergoing triple therapy with Gemox, lenvatinib, and PD-1 blockade (Gemox+Len+ PD-1 group) or Gemox monotherapy (Gemox group) as primary therapy; (3) at least one extrahepatic metastasis; (4) Eastern Cooperative Oncology Group (ECOG) performance levels range from 0–2; (5) Normal liver performance (Child–Pugh class A or B liver function); (6) kidney function within normal range; (7) ages of 18 to 75. Exclusion criteria were as follows: (1) PD‑1 blockade or lenvatinib intolerance; (2) duration of lenvatinib or PD-1 blockade less than 1 month; (3) duration of Gemox less than two cycles; (4) lost follow-up or death within 3 months; (5) insufficient kidney or liver performance; and (6) treatment was concomitant with other tyrosine kinase inhibitor, with/without PD‑1 blockade. Utilizing abdominal ultrasonography, positron emission tomography/computer tomography (PET/CT), magnetic resonance imaging (MRI), or enhanced CT imaging, were used to evaluate tumor status. Blood testing and liver function baseline levels were obtained. For each patient, the following formula was used to get the albumin-bilirubin (ALBI) grade: ALBI score = (log10 Bilirubin × 0.66) + (–Albumin × 0.085).5 All patients were scheduled to undergo CT or MRI scans enhanced with contrast material within two weeks. Lenvatinib (Eisai Co. Inc, Tokyo, Japan) was given orally once a day at doses of 8 mg for those weighing 80% was required for the primary outcome. The statistical analyses were conducted using the Statistical Package for the Social Science (SPSS) software (version 22.0, SPSS Inc., Chicago, IL, USA) and R software for Windows (Version 4.1.3 http://www.r-project.org). Two-sided tests were used, and P 5 (HR, 2.34; 95% CI, 1.01–5.42; P = 0.047), macrovascular tumor thrombus (HR, 2.94; 95% CI, 1.44–5.99; P = 0.003), and ECOG status 2 (HR, 13.70; 95% CI, 4.5–41.60; P 5 (HR, 2.47; 95% CI, 1.33–4.60; P = 0.004), and ECOG status 2 (HR, 2.29; 95% CI, 1.01–5.23; P = 0.048) were factors indicating poor PFS. Assessing the efficacy of tumor treatment with RECIST 1.1; the results are shown in Supplementary Table 5, https://links.lww.com/CM9/C567. In the 1.5-month evaluation, the objective response rates (ORR) in the Gemox group and Gemox+ Len+PD-1 group were 8.3% and 29.6%, respectively, and the disease control rates (DCR) were 64.6% and 88.9%. A significant difference was seen in the CR, PR, SD, and PD ratios in the two groups at 1.5-month (P = 0.002) Supplementary Table 5, https://links.lww.com/CM9/C567. The ORR and DCR for the Gemox and Gemox+Len+PD-1 groups at the 3-month evaluation were 12.5% and 33.3%, 39.6% and 74.1%, respectively. The CR, PR, SD, and PD in the two groups were disparity (P = 0.001) Supplementary Table 5, https://links.lww.com/CM9/C567. Data on OS with power (0.9996) and PFS with power (0.9857) conferred sufficient reliability to our results Supplementary Table 6, https://links.lww.com/CM9/C567. This study did not report any deaths that were directly linked to the treatment; however, most patients reported treatment-related AEs Supplementary Table 7, https://links.lww.com/CM9/C567. In the Gemox+Len+PD-1 group, lenvatinib displayed a median duration of 6.8 months while the median duration of PD‑1 blockade was 11.5 months. Patients with grade 1–2 AEs experienced relief after receiving dosage reduction or symptomatic therapy. If a patient experienced grade 3–4 AEs, before symptom resolution, Lenvatinib or PD-1 blockade therapy would be temporarily paused. Once possible, low doses of lenvatinib were resumed along with PD-1 blockade infusion. There were four patients discontinued PD-1 blockade and eight patients adjusted lenvatinib reduction due to the severe AEs. In summary, our study preliminarily demonstrated that triple therapy of Gemox, lenvatinib, and PD-1 blockade was more effective in treating advanced cholangiocarcinoma metastasis than Gemox alone. The results demonstrated extended OS and PFS, as well as enhanced disease control. The application of this combination therapy had manageable side effects and good effectiveness, offering a novel treatment approach for advanced ICC with metastases. Funding This study was supported by a grant from National Natural Science Foundation of China (No. 82102082). Conflicts of interest None.