Introduction
Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary malignant liver cancer after hepatocellular carcinoma.1,2 Owing to its highly aggressive nature and significant heterogeneity, ICC often lacks specific clinical indications in the early stages, and diagnosis is typically made at an advanced stage. Radical surgical resection is the best option for achieving long-term survival. However, only 30–40% of patients with ICC are candidates for curative surgery.3 Moreover, the postoperative recurrence rates of ICC are very high, ranging from 40% to 80%,3 with fewer than one-third of patients undergoing curative-intent surgery surviving beyond five years after resection.4
Currently, the first-line treatment for ICC is chemotherapy, with or without programmed cell death protein 1 and programmed cell death ligand 1 inhibitors. However, an effective second-line treatment is still lacking for patients who cannot tolerate chemotherapy or who experience disease progression after first-line therapy.5 Molecular-targeted therapy based on genetic testing has emerged as a potential therapeutic option for ICC. Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) deletion is common in ICC, and the targeted drug palbociclib (a CDK4/6 inhibitor) is used to treat solid tumors harboring the CDKN2A/2B deletion.6 However, a phase 2 clinical trial demonstrated that palbociclib monotherapy lacked clinical efficacy in advanced biliary tract cancer with CDKN2A/2B deletions.7 Moreover, the clinical benefit of lenvatinib as a second-line treatment for advanced ICC is limited.8 The combined application of multiple targeted drugs produces a synergistic anti-tumor effect, maximizing anti-tumor efficacy.9 Here, we report a case of ICC with CDKN2A/2B deletion treated with palbociclib plus lenvatinib, which resulted in long-term survival after chemotherapy progression.
Case presentation
A 64-year-old Chinese woman had a history of drinking and smoking but no history of hepatitis B, other infectious diseases, cirrhosis, or a family history of genetic disorders. She was scheduled for a physical examination, during which a space-occupying lesion in the liver was detected on imaging. Malignancy was suspected, and intrahepatic cholangiocarcinoma was diagnosed by fine-needle aspiration. Subsequently, she underwent radical resection at Peking Union Medical College Hospital. Pathological analysis revealed adenocarcinoma, and genetic testing identified a CDKN2A/2B deletion. The CDKN2A/2B status of the patient was determined using a large-panel next-generation sequencing assay. Next-generation sequencing results did not indicate mutations in vascular endothelial growth factor receptor and/or fibroblast growth factor receptor (FGFR) but predominantly revealed deletions in the CDKN2A/2B genes (Supplementary Tables 1 and 2). One month after surgery, the patient received capecitabine as adjuvant therapy. She repeatedly experienced severe nausea, vomiting, and diarrhea with oral capecitabine treatment, which was only slightly relieved by symptomatic treatment. Enhanced computed tomography (CT) performed after two cycles of treatment showed a 1.9-cm metastasis in the right lung and a 1.1-cm metastasis in the right adrenal gland. Additionally, due to headache, cranial magnetic resonance imaging (MRI) was performed, revealing a 1.2-cm intracranial metastasis. Tumor recurrence was diagnosed based on enhanced CT and MRI findings. Glucoprotein antigen 199 levels, liver and kidney functions, and routine blood values were within the normal range. Oxaliplatin in combination with infusional 5-fluorouracil/leucovorin regimen was administered as the standard second-line treatment according to the National Comprehensive Cancer Network guidelines;2 however, the patient refused chemotherapy due to concerns about toxicity. Genetic testing revealed palbociclib sensitivity. The patient requested targeted anticancer drugs. Nevertheless, a phase II trial demonstrated that palbociclib monotherapy lacked clinical activity.7 Recognizing the limitations of palbociclib monotherapy, a combination therapy with lenvatinib was proposed to enhance efficacy through synergistic mechanisms. After a comprehensive discussion of the potential benefits and risks of palbociclib plus lenvatinib, the patient opted for the combination therapy: palbociclib6 (100 mg orally per day for two weeks, followed by one week off) and lenvatinib (8 mg orally daily).8 Stereotactic radiotherapy was used to treat the intracranial metastasis.
Tumor assessments were conducted every six to nine weeks using enhanced CT or MRI, with clinical responses evaluated based on RECIST v1.1 criteria.10 At nine months, MRI showed resolution of the intracranial metastasis, and CT revealed significant shrinkage of the pulmonary metastases, with a 22% reduction in gross tumor volume. The disease remained stable until progression at 32 months when CT showed a new 1.7-cm right lung metastasis and growth of the right adrenal gland metastasis to 2.0 cm (Fig. 1). The patient succumbed to progressive disease at 33 months. The overall survival (OS) was 33.4 months, with progression-free survival (PFS) of 32.2 months. No serious adverse events occurred, besides mild stomach discomfort during treatment.
Discussion
This case represents the first report of significant survival improvement in advanced ICC with CDKN2A/2B deletion using palbociclib plus lenvatinib as a new second-line treatment. The combination of palbociclib and lenvatinib demonstrated substantial clinical benefits and a favorable safety profile, highlighting its potential as a promising second-line treatment option for this patient population.
Second-line options for ICC are limited, with the oxaliplatin in combination with infusional 5-fluorouracil/leucovorin regimen recommended for patients with good performance status and chemotherapy tolerance.11 However, many patients are either unable or unwilling to undergo chemotherapy or are ineligible for immunotherapy, necessitating alternative treatment approaches.
A phase II clinical trial showed some clinical activity for palbociclib monotherapy as a first-line treatment for biliary tract cancer with CDKN2A/2B deletions; however, the mOS was only 11.1 weeks,7 suggesting that palbociclib monotherapy may not be a suitable second-line treatment. Recently, multi-target drugs have been explored for second-line therapy in ICC. Another phase II clinical trial showed an mOS of 7.35 months for lenvatinib monotherapy as a second-line treatment.8 Combining palbociclib with other anticancer drugs may offer a superior effect by enhancing therapeutic efficacy and overcoming drug resistance.12 Hence, we adopted a combination regimen (palbociclib plus lenvatinib) in this case. Our patient showed long PFS and OS without serious adverse events. This result may be attributed to the potential synergistic mechanisms between the two drugs.
CDKN2A/2B deletions activate pathways such as p16INK4α-CDK4/6-pRb and p14ARF-MDM2-p53, promoting cell proliferation and tumor progression.13 Palbociclib, a CDK4/6 inhibitor, induces apoptosis and cell cycle arrest but has shown limited efficacy as monotherapy.7,13 Lenvatinib, a multi-target tyrosine kinase inhibitor, targets vascular endothelial growth factor receptors 1–3 and FGFR1-4.8 Additionally, it suppresses tumor angiogenesis and proliferation by targeting the vascular endothelial growth factor/vascular endothelial growth factor receptor and fibroblast growth factor/FGFR signaling pathways. This dual inhibition confers greater anti-tumor activity to lenvatinib than other drugs, such as sorafenib. Furthermore, lenvatinib modulates the immune microenvironment, reducing programmed cell death ligand 1 expression and inhibiting Treg differentiation. Taken together, lenvatinib demonstrates anti-tumor activity in ICC through the inhibition of the FGFR signaling pathway and immune-modulatory effects.8,14
The combination of palbociclib and lenvatinib may offer a synergistic effect through multiple mechanisms. Firstly, FGFR1 amplification or upregulation can cause resistance to CDK4/6 inhibitors. When lenvatinib blocks FGFR1,15 it may improve the sensitivity of palbociclib in ICC. Secondly, lenvatinib can induce cell cycle arrest in CDKN2A/2B-deleted ICC cells, effectively inhibiting tumor cell proliferation and significantly reducing the migration and invasion abilities of tumor cells.16 Thirdly, lenvatinib’s inhibition of autophagy and modulation of immune responses further enhance its anti-tumor activity.16 Finally, CDK6 is an important protein kinase that contributes to lenvatinib resistance. CDK4/6 inhibitors can inhibit CDK6, reducing tumor resistance to lenvatinib (Fig. 2).12
Preclinical studies suggest that combined treatment remodels the immune microenvironment, increasing memory effector T cells and reducing immunosuppressive CD8+ T cells, thereby improving immune-mediated tumor suppression.12
Conclusions
Palbociclib plus lenvatinib demonstrated significant and synergistic efficacy as a second-line treatment for advanced ICC with CDKN2A/2B deletions, achieving prolonged PFS and OS without severe adverse events. This chemo-free regimen warrants further investigation in clinical trials for this subset of ICC patients.
Supporting information
Supplementary Table 1
Gene list of ultra-deep targeted NGS panel (YuansuTM, OrigiMed).
(XLSX)
Supplementary Table 2
The mutational profile of patient with intrahepatic cholangiocarcinoma.
(XLSX)
Declarations
Ethical statement
This study was approved by the Ethics Committee of Peking Union Medical College Hospital (NCT02715089). Informed consent to participate in this study was obtained from the patient’s direct relatives.
Data sharing statement
The data and materials used and/or analyzed during the current study are included in this case. The data are available from the corresponding author upon reasonable request.
Funding
This research was funded by the National High-Level Hospital Clinical Research Funding [2022-PUMCH-B-128], CAMS Innovation Fund for Medical Sciences ([2022-I2M-C&T-A-003], [2021-I2M-1-061]), CSCO-Hengrui Cancer Research Fund ([Y-HR2019-0239]), CSCO-MSD Cancer Research Fund [Y-MSDZD2021-0213], and the National Ten-thousand Talent Program. LZ is supported by the National Natural Science Foundation of China (No. 81960125) and the Department of Science and Technology of Guizhou Province (No. Qiankehe Foundation [2020] 1Y302).
Conflict of interest
The authors have no conflict of interests related to this publication.
Authors’ contributions
Conception and design (HZ, LZ), data analysis and interpretation, and manuscript writing (KL). All authors contributed to data collection. All authors approved the final version and publication of the manuscript.