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Real-world cohort study of PD-1 blockade plus lenvatinib for advanced intrahepatic cholangiocarcinoma: effectiveness, safety, and biomarker analysis

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Abstract

Background

In clinical practice, some patients with advanced intrahepatic cholangiocarcinoma (ICC) cannot tolerate or refuse chemotherapy due to the toxicity, necessitating alternative treatments. PD-1 blockade combined with lenvatinib showed promising results in phase II studies with small sample size, but there is a lack of data on the routine use with this regimen. This study aimed to evaluate the effectiveness and safety of the regimen in patients with advanced ICC, and to identify predictors for treatment response and prognosis.

Methods

We conducted a retrospective cohort study of patients treated with PD-1 inhibitors plus lenvatinib for advanced ICC between July 2017 and August 2022. The study endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Biomarker analysis for CA19-9 and PD-L1 expression was performed. Exploratory analysis for genetic alternation was conducted.

Results

The study included 103 patients. It demonstrated a median PFS of 5.9 months and a median OS of 11.4 months. ORR was 18.4% and DCR was 80.6%. The incidence of grade 3 or 4 adverse events was 50.5%. Positive PD-L1 expression (TPS ≥ 1%) was associated with higher ORR (P = 0.013) and prolonged PFS (P = 0.023). Elevated CA19-9 (> 37 U/ml) was associated with decreased ORR (P = 0.019), poorer PFS (P = 0.005) and OS (P = 0.034). Patients with IDH1 mutations exhibited a favorable response to the treatment (P = 0.011), and patients with TP53 mutations tended to have worse OS (P = 0.031).

Conclusions

PD-1 blockade plus lenvatinib is effective and safe in routine practice. PD-L1 expression and CA19-9 level appear to predict the treatment efficacy. IDH1 mutations might indicate a better treatment response.

Clinical trial registration: NCT03892577.

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Data availability

The data that support the findings of our study are available from the corresponding author upon request.

Abbreviations

AE:

Adverse event

BTC:

Biliary tract cancer

CA19-9:

Carbohydrate antigen 19-9

CI:

Confidence interval

CR:

Complete response

CSCO:

Chinese Society of Clinical Oncology

CTCAE:

Common Terminology Criteria for Adverse Events

DCR:

Disease control rate

ECOG PS:

Eastern Cooperative Oncology Group performance status

ICC:

Intrahepatic cholangiocarcinoma

IHC:

Immunohistochemistry

MMR:

Mismatch repair

MSI-H/L:

Microsatellite instability-high/low

NCCN:

National Comprehensive Cancer Network

NGS:

Next-generation sequencing

ORR:

Objective response rate

OS:

Overall survival

PD-1:

Programmed death 1

PFS:

Progression-free survival

PR:

Partial response

PUMCH:

Peking Union Medical College Hospital

RECIST:

Response evaluation criteria in solid tumors

SD:

Stable disease

TPS:

Tumor proportion score

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Acknowledgements

We thank Dr. Jianzhen Lin (the First Affiliated Hospital of Nanjing Medical University) for his sincere assistance.

Funding

This work was supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-128), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-035, 2021-I2M-1-061, 2022-I2M-C&T-A-003), CSCO-Hengrui Cancer Research Fund (Y-HR2019-0239, Y-HR2020QN-0414), CSCO-MSD Cancer Research Fund (Y-MSDZD2021-0213), and the National Ten-thousand Talent Program.

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Author notes

  1. Jiashuo Chao, Shanshan Wang and Hao Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China

    Jiashuo Chao, Shanshan Wang, Hao Wang, Nan Zhang, Yunchao Wang, Xu Yang, Chengpei Zhu, Cong Ning, Xinmu Zhang, Jingnan Xue, Longhao Zhang, Mingjian Piao, Mingming Wang, Xiaobo Yang & Haitao Zhao

  2. Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Nanjing, China

    Jiashuo Chao, Hao Wang, Mingming Wang & Ling Lu

  3. Affiliated Hospital of Xuzhou Medical University, Xuzhou, China

    Ling Lu

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  1. Jiashuo Chao
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Contributions

HZ and LL contributed to the conception and design of the study. All authors participated in patient follow-up and contributed to data collection. JC, SW, and HW collated the data and performed analysis. JC, SW, and HW drafted the manuscript. All authors contributed to reviewing or revising the manuscript and approved the final version.

Corresponding authors

Correspondence to Ling Lu or Haitao Zhao.

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Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. JS-1391), and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients.

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Chao, J., Wang, S., Wang, H. et al. Real-world cohort study of PD-1 blockade plus lenvatinib for advanced intrahepatic cholangiocarcinoma: effectiveness, safety, and biomarker analysis. Cancer Immunol Immunother 72, 3717–3726 (2023). https://doi.org/10.1007/s00262-023-03523-2

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