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 years. 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 <60 kg and 12 mg for those weighing ≥60 kg. Three different PD-1 inhibitors were utilized based on patient preference (sintilimab 200 mg [Innovent Biologics. Inc, Shanghai, China], camrelizumab 200 mg [Jiangsu Hengrui Pharmaceuticals Co. Ltd, Lianyungang, China], tislelizumab 200 mg [Beigene, Inc, Shanghai, China]). The Gemox regimen involved an intravenous (IV) injection every three weeks for a maximum of eight cycles, consisting of 1000 mg/m² Gem (Eli Lilly and Company, Indianapolis, USA) on days 1 and 8, and 80–100 mg/m² oxaliplatin (Sanofi-Aventis, Paris, France) on the first day. Every three weeks was as a cycle by IV injection, and no more than eight cycles in total. The final decision of patients receiving triple combination or chemotherapy alone was principally not only made by doctors but also by patients based on their financial conditions and safety considerations. Any adverse events (AEs) were recorded during the treatment. The treatment was interrupted in patients who developed grade ≥3 severe AEs or any unacceptable grade 2 drug-related AEs, other treatments were recommended after tumor progression.

The study concluded with a follow-up date of June 30, 2022. Tumor imaging response was evaluated through CT or MRI every 6 weeks. The evaluation of tumor response was based on the criteria specified in Response Evaluation Criteria for Solid Tumors 1.1 (RECIST 1.1).^[6] The target limit for tumor quantity is a maximum of two lesions per organ and a total of five lesions. The maximum allowable number of tumors per organ is two, with a total of five lesions. Complete response (CR) refers to the complete elimination of the tumor, while partial response (PR) indicates a reduction in tumor diameter of at least 30%. Progressive disease (PD) is characterized by an increase of 20% or more in tumor diameter or the emergence of new lesions. Stable disease (SD) was characterized as not satisfying the criteria for CR, PR, or PD. Overall survival (OS) was determined as the start of the Gemox+Len+PD-1 or Gemox therapy until death or the last follow-up, whereas progression-free survival (PFS) was determined as the start of the therapy to tumor progression or the last follow-up.

Using Fisher’s exact test and Pearson’s χ² test, categorical variables were compared and the difference between the two groups was evaluated. The log-rank test was used in conjunction with the Kaplan–Meier method to build the OS and PFS survival curves. The primary outcome was OS. A post hoc calculation revealed that a power of >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 <0.05 was considered statistically significant. The Cox proportional hazards model was utilized to estimate the hazard ratio (HR) for each clinical factor. The P <0.10 in univariable analyses was brought into multivariable analyses.

There were 102 patients included in the analysis according to the inclusion criteria [Supplementary Figure 1, http://links.lww.com/CM9/C567]. A total of 48 patients received Gemox alone (Gemox group), and 54 patients received triple therapy with Gemox, lenvatinib, and PD-1 blockade (Gemox+Len+PD-1 group). The two groups showed no significant differences in their characteristics. Supplementary Table 1, http://links.lww.com/CM9/C567 provided a summary of the baseline clinical information for the two groups.

The analyses showed the median OS in the Gemox+Len+PD-1 group was 15.5 ± 1.7 months (95% confidence interval [CI], 12.2–18.8 months), compared to 10.4 ± 0.4 months (95% CI, 9.8–11.0 months) in the Gemox group. The OS rates at 6-, 12-, and 18-month were 86.8%, 31.1%, and 0% in the Gemox group, respectively. In the Gemox+Len+PD-1 group, these rates were 96.3%, 71.9%, and 42.7%, respectively [Supplementary Table 2, http://links.lww.com/CM9/C567]. The Gemox+Len+PD-1 group demonstrated significantly better OS compared to the Gemox group (P <0.001) [Figure 1A]. Supplementary Table 3, http://links.lww.com/CM9/C567 presented univariable and multivariable assessments of the OS outcomes. Multivariable analysis revealed that Gemox therapy (HR, 2.28; 95% CI, 1.14–4.53; P = 0.019), metastases >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 <0.001) were indicators of poor OS [Supplementary Table 3, http://links.lww.com/CM9/C567].

Figure 1.

Kaplan–Meier curves of OS (A) and PFS (B) in ICC patients with metastases, who were treated with Gemox alone or triple therapy with Gemox, lenvatinib, and PD-1 blockade. ICC: Intrahepatic cholangiocarcinoma; PFS: progression-free survival; PD-1: programmed cell death 1.

For the patients in the Gemox group, the median PFS was 3.5 ± 0.3 months (95% CI, 2.9–4.1 months), and in the Gemox+Len+PD-1 group was 5.5 ± 0.7 months (95% CI, 4.1–6.9 months). The PFS rates at the time of 3-, 6-, and 9-months were 56.3%, 25.0%, and 2.1% in the Gemox group and 95.2%, 44.4%, and 20.4% in the Gemox+Len+PD-1 group, respectively [Supplementary Table 2, http://links.lww.com/CM9/C567]. PFS was considerably longer for patients in the Gemox+Len+PD-1 group than it was in the Gemox group (P <0.001) [Figure 1B]. Univariable and multivariable analyses of PFS were presented in Supplementary Table 4, http://links.lww.com/CM9/C567. Results from multivariable Cox regression analysis showed that Gemox therapy (HR, 1.78; 95% CI, 1.05–2.99; P = 0.033), metastases >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, http://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, http://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, http://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, http://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, http://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.

Supplementary Material

cm9-138-3007-s001.pdf ^{(266.6KB, pdf)}