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Effectiveness and safety of radiotherapy plus programmed death-1 inhibitors and lenvatinib in patients with advanced biliary tract carcinoma: a real-world study

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Abstract

Background

Radiotherapy (RT) may function synergistically with immunotherapy and targeted agents (TA). This study aimed to assess the effectiveness and safety of RT combined with programmed death-1 (PD-1) inhibitors and lenvatinib in patients with relapsed or refractory advanced biliary tract carcinoma (BTC).

Methods

This retrospective study included patients with relapsed or refractory advanced BTC who received RT combined with PD-1 inhibitors and lenvatinib at the Peking Union Medical College Hospital (PUMCH). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated.

Results

Thirty-one patients who received RT combined with PD-1 inhibitors and lenvatinib as a second- or later-line therapy were analyzed. RT sites were mainly distributed in the liver lesions (64.5%) and lymph nodes (58.1%). The ORR and DCR were 32.3% (10/31; 95% CI: 14.8–49.7) and 87.1% (27/31; 95% CI: 74.6–99.6), respectively. The median PFS (mPFS) and median OS (mOS) were 7.9 (95% CI: 7.1–8.7) and 11.7 (95% CI: 8.3–15.0) months, respectively. Subgroup analyses of this cohort included 12 and 19 patients who received concurrent and salvage (> 6 weeks after commencing PD-1 inhibitor therapy) RT, respectively. The salvage RT group had higher mOS (11.7 vs. 10.5; p = 0.75) and mPFS (7.9 vs. 6.9; p = 0.85) than the concurrent RT group; however, statistical significance was not reached. All patients experienced any-grade adverse events (AEs), and excessive PD-1 inhibitors or RT toxicity were not observed.

Conclusions

RT, PD-1 inhibitors, and lenvatinib may be safely combined and have antitumor effectiveness in patients with advanced BTC.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

AEs:

Adverse events

BTCs:

Biliary tract cancers

CR:

Complete response

CTCAE:

Common Terminology Criteria Coastocellular Group

DCR:

Disease control rate

ECC:

Extrahepatic cholangiocarcinoma

GBC:

Gallbladder cancer

HR:

Hazard rate

ICC:

Intrahepatic cholangiocarcinoma

Lenvatinib:

Tyrosine kinase inhibitors

ORR:

Objective response rate

OS:

Overall survival

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death ligand 1

PFS:

Progression-free survival

PR:

Partial response

RECIST:

Response evaluation criteria in solid tumors

RT:

Radiotherapy

SD:

Stable disease

TA:

Targeted agents

References

  1. Brindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, Teh BT, Wongkham S, Gores GJ (2021) Cholangiocarcinoma. Nat Rev Dis Prim 7:65. https://doi.org/10.1038/s41572-021-00300-2

    Article  PubMed  Google Scholar 

  2. Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D (2016) Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol Official J European Soc Med Oncol 27:v28–v37. https://doi.org/10.1093/annonc/mdw324

    Article  CAS  Google Scholar 

  3. Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX (2021) Biliary tract cancer. Lancet (London, England) 397:428–444. https://doi.org/10.1016/s0140-6736(21)00153-7

    Article  CAS  PubMed  Google Scholar 

  4. Boilève A, Hilmi M, Delaye M, Tijeras-Raballand A, Neuzillet C (2021) Biomarkers in hepatobiliary cancers: What is useful in clinical practice? Cancers. https://doi.org/10.3390/cancers13112708

    Article  PubMed  PubMed Central  Google Scholar 

  5. Shroff RT, Kennedy EB, Bachini M et al (2019) Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J clin oncol offi j Am Soc Clin Oncol 37:1015–1027. https://doi.org/10.1200/jco.18.02178

    Article  Google Scholar 

  6. Valle J, Wasan H, Palmer DH et al (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281. https://doi.org/10.1056/NEJMoa0908721

    Article  CAS  PubMed  Google Scholar 

  7. Lamarca A, Palmer DH, Wasan HS et al (2021) Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 22:690–701. https://doi.org/10.1016/s1470-2045(21)00027-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Yang X, Wang D et al (2022) lenvatinib beyond first-line therapy in patients with advanced biliary tract carcinoma. Front Oncol 12:785535. https://doi.org/10.3389/fonc.2022.785535

    Article  PubMed  PubMed Central  Google Scholar 

  9. Piha-Paul SA, Oh DY, Ueno M et al (2020) Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer 147:2190–2198. https://doi.org/10.1002/ijc.33013

    Article  CAS  PubMed  Google Scholar 

  10. Villanueva L, Lwin Z, Chung HCC, Gomez-Roca CA, Graham DMJ (2021) Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase 2 LEAP-005 study. J Clin Oncol 39:4080

    Article  Google Scholar 

  11. Taggar AS, Mann P, Folkert MR, Aliakbari S, Myrehaug SD, Dawson LA (2021) A systematic review of intraluminal high dose rate brachytherapy in the management of malignant biliary tract obstruction and cholangiocarcinoma. Radiother Oncol J European Soc Ther Radiol Oncol 165:60–74. https://doi.org/10.1016/j.radonc.2021.10.011

    Article  Google Scholar 

  12. Liu Y, Dong Y, Kong L, Shi F, Zhu H, Yu J (2018) Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol 11:104. https://doi.org/10.1186/s13045-018-0647-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liniker E, Menzies AM, Kong BY et al (2016) Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Oncoimmunology. 5:e1214788. https://doi.org/10.1080/2162402x.2016.1214788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lin J, Yang X, Long J et al (2020) Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma. Hepatobiliary Surg Nutr 9:414–424. https://doi.org/10.21037/hbsn-20-338

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jian Z, Fan J, Shi GM et al (2021) Lenvatinib plus toripalimab as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-arm, phase 2 trial. J Clin Oncol 39:4099

    Article  Google Scholar 

  16. Mody K, Starr J, Saul M, Poorman K, Shields AF (2019) Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers. J Gastrointest Oncol 10:1099–1109

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lan Y, Moustafa M, Knoll M et al (2021) Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell 39:1388–403.e10. https://doi.org/10.1016/j.ccell.2021.08.008

    Article  CAS  PubMed  Google Scholar 

  18. Mondini M, Levy A, Meziani L, Milliat F, Deutsch E (2020) Radiotherapy-immunotherapy combinations: perspectives and challenges. Mol Oncol 14:1529–1537. https://doi.org/10.1002/1878-0261.12658

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zuo B, Yang X, Yang X et al (2022) A real-world study of the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer. Cancer immunol immunother CII. https://doi.org/10.1007/s00262-021-03121-0

    Article  PubMed  Google Scholar 

  20. Chicas-Sett R, Morales-Orue I, Rodriguez-Abreu D, Lara-Jimenez P (2018) Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: a systematic review. Clin transl radiat oncol 9:5–11. https://doi.org/10.1016/j.ctro.2017.12.004

    Article  PubMed  Google Scholar 

  21. Salama AK, Postow MA, Salama JK (2016) Irradiation and immunotherapy: from concept to the clinic. Cancer 122:1659–1671. https://doi.org/10.1002/cncr.29889

    Article  PubMed  Google Scholar 

  22. Patel RB, Hernandez R, Carlson P et al (2021) Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade. Sci transl med. https://doi.org/10.1126/scitranslmed.abb3631

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dovedi SJ, Adlard AL, Lipowska-Bhalla G et al (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Can Res 74:5458–5468. https://doi.org/10.1158/0008-5472.Can-14-1258

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2021–1-I2M-003 and 2021-I2M-1–061), CSCO-hengrui Cancer Research Fund (Y-HR2019-0239, Y-HR2020MS-0415, Y-HR2020QN-0414), CSCO-MSD Cancer Research Fund (Y-MSDZD2021-0213) and National Ten-thousand Talent Program.

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Author notes

  1. Yunchao Wang, Xiaobo Yang and Yanyu Wang authors contributed equally to this work.

Authors and Affiliations

  1. Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), No. 1, Shuaifuyuan, Dongcheng District, Beijing, China

    Yunchao Wang, Xiaobo Yang, Yanyu Wang, Jingnan Xue, Nan Zhang, Xu Yang, Ning Cong, Junwei Zhang, Chengpei Zhu, Longhao Zhang & Haitao Zhao

  2. Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), No. 1, Shuaifuyuan, Dongcheng District, Beijing, China

    Xiaorong Hou

Authors
  1. Yunchao Wang
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Contributions

YCW and XBY collected the data and wrote the manuscript. XRH and HTZ designed and examined the study. NZ, JYL, and XY helped to collect the literature and participated in discussions. ZYX, JNX, and YYW performed the statistical analyses. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaorong Hou or Haitao Zhao.

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Conflict of Interest

The authors have no conflicts of interest to declare.

Ethical approval

All patients were fully informed about the objectives of this study and provided formal written consent a priori. The protocols of this study were compliant with the principles of the Declaration of Helsinki and were also approved by the institutional review board and ethics committee at Peking Union Medical College Hospital (PUMCH-JS-1391).

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Wang, Y., Yang, X., Wang, Y. et al. Effectiveness and safety of radiotherapy plus programmed death-1 inhibitors and lenvatinib in patients with advanced biliary tract carcinoma: a real-world study. Cancer Immunol Immunother 72, 2197–2204 (2023). https://doi.org/10.1007/s00262-023-03399-2

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