The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Jun 13

PMID 35693805

Authors

Xianjing Chu

Lishui Niu

Gang Xiao

Haiqin Peng

Fuxing Deng

Zhiyuan Liu

Honghua Wu

Lei Yang

Zhuguilong Tan

Zhanzhan Li

Rongrong Zhou

Affiliations

Soon will be listed here.

Abstract

Background: Although immunotherapy has been widely used, there is currently no research comparing immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This meta-analysis addresses a gap in the comparison of immunotherapy efficacy, including immune checkpoint inhibitors (ICIs), chemotherapy (CT), radiotherapy (RT), and ICI combined CT or RT.

Methods: A search of Pubmed, Cochrane, EMBASE, and ClinicalTrial.gov was conducted to identify studies which enrolled NSCLC patients with BM treated with ICIs. The outcomes consisted of intracerebral overall response rate (iORR), intracerebral disease control rate (iDCR), extracranial overall response rate (EORR), distant brain failure (DBF), local control (LC), progression-free survival (PFS), and overall survival (OS).

Results: A total of 3160 participants from 46 trials were included in the final analysis. Patients treated with immunotherapy were associated with a longer PFS (0.48, 95%CI: 0.41-0.56), and a longer OS (0.64, 95%CI: 0.60-0.69) compared with immunotherapy-naive patients. In prospective studies, dual ICI combined CT and ICI combined CT achieved a better OS. The hazard ratio (HR) of dual ICI combined CT versus dual ICI was 0.61, and the HR of ICI combined CT versus ICI monotherapy was 0.58. Moreover, no statistical difference in PFS, OS, EORR, iORR, iDCR, and EDCR was found between patients with ICI monotherapy and ICI combined cranial radiotherapy. Concurrent ICI combined RT was shown to decrease the rate of DBF (OR = 0.15, 95% CI: 0.03-0.73) compared with RT after ICI. Patients treated with WBRT might have an inferior efficacy than those with SRS because the iORR of SRS was 0.75 (0.70, 0.80) and WBRT was 0. Furthermore, no obvious difference in PFS and OS was observed among the three different types of ICI, which targets PD-1, PD-L1, and CTLA-4, respectively.

Conclusions: Patients treated with ICI got superior efficacy to those without ICI. Furthermore, dual ICI combined CT and ICI combined CT seemed to be optimal for NSCLC patients with BM. In terms of response and survival, concurrent administration of SRS and ICI led to better outcomes for patients with BMs than non-concurrent or non-SRS.

Importance Of The Study: In the new era of immunotherapy, our meta-analysis validated the importance of immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). By comparing the long-term and short-term impacts of various regimens, all immunotherapy treatments had superior efficacy to immunotherapy-naive. At the same time, through pairwise comparison in immunotherapy, our findings can help clinicians to make treatment decisions for NSCLC patients with BMs.

Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=269621, identifier CRD42021269621.

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References

Mansfield A, Aubry M, Moser J, Harrington S, Dronca R, Park S . Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol. 2016; 27(10):1953-8. PMC: 5035793. DOI: 10.1093/annonc/mdw289. View

Schapira E, Hubbeling H, Yeap B, Mehan Jr W, Shaw A, Oh K . Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases. Int J Radiat Oncol Biol Phys. 2018; 101(3):624-629. DOI: 10.1016/j.ijrobp.2018.02.175. View

Dong Y, Wong J, Sugimura R, Lam K, Li B, Kwok G . Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC. Cancers (Basel). 2021; 13(8). PMC: 8072916. DOI: 10.3390/cancers13081949. View

Yousefi M, Bahrami T, Salmaninejad A, Nosrati R, Ghaffari P, Ghaffari S . Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options. Cell Oncol (Dordr). 2017; 40(5):419-441. DOI: 10.1007/s13402-017-0345-5. View

Soria J, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee K . Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 378(2):113-125. DOI: 10.1056/NEJMoa1713137. View

Enright T, Witt J, Burr A, Yadav P, Leal T, Baschnagel A . Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non-small-cell Lung Cancer Brain Metastases. Clin Lung Cancer. 2020; 22(2):110-119. DOI: 10.1016/j.cllc.2020.10.014. View

Zhang G, Cheng R, Wang H, Zhang Y, Yan X, Li P . Comparable outcomes of nivolumab in patients with advanced NSCLC presenting with or without brain metastases: a retrospective cohort study. Cancer Immunol Immunother. 2020; 69(3):399-405. PMC: 11027805. DOI: 10.1007/s00262-019-02462-1. View

Hendriks L, Henon C, Auclin E, Mezquita L, Ferrara R, Audigier-Valette C . Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors. J Thorac Oncol. 2019; 14(7):1244-1254. DOI: 10.1016/j.jtho.2019.02.009. View

Singh C, Qian J, Yu J, Chiang V . Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases. J Neurosurg. 2019; 132(2):512-517. DOI: 10.3171/2018.10.JNS181371. View

10.

Yang Y, Deng L, Yang Y, Zhang T, Wu Y, Wang L . Efficacy and Safety of Combined Brain Radiotherapy and Immunotherapy in Non-Small-Cell Lung Cancer With Brain Metastases: A Systematic Review and Meta-Analysis. Clin Lung Cancer. 2021; 23(2):95-107. DOI: 10.1016/j.cllc.2021.06.009. View

11.

Xiao G, Liu Z, Gao X, Wang H, Peng H, Li J . Immune checkpoint inhibitors for brain metastases in non-small-cell lung cancer: from rationale to clinical application. Immunotherapy. 2021; 13(12):1031-1051. DOI: 10.2217/imt-2020-0262. View

12.

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

13.

Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S . Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020; 15(10):1636-1646. DOI: 10.1016/j.jtho.2020.07.014. View

14.

Patchell R, Tibbs P, Walsh J, Dempsey R, Maruyama Y, Kryscio R . A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990; 322(8):494-500. DOI: 10.1056/NEJM199002223220802. View

15.

Herter-Sprie G, Koyama S, Korideck H, Hai J, Deng J, Li Y . Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight. 2016; 1(9):e87415. PMC: 5033933. DOI: 10.1172/jci.insight.87415. View

16.

Sheng L, Gao J, Xu Q, Zhang X, Huang M, Dai X . Selection of optimal first-line immuno-related therapy based on specific pathological characteristics for patients with advanced driver-gene wild-type non-small cell lung cancer: a systematic review and network meta-analysis. Ther Adv Med Oncol. 2021; 13:17588359211018537. PMC: 8165528. DOI: 10.1177/17588359211018537. View

17.

Dudnik E, Yust-Katz S, Nechushtan H, Goldstein D, Zer A, Flex D . Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer. 2016; 98:114-117. DOI: 10.1016/j.lungcan.2016.05.031. View

18.

Kong X, Lu P, Liu C, Guo Y, Yang Y, Peng Y . A combination of PD‑1/PD‑L1 inhibitors: The prospect of overcoming the weakness of tumor immunotherapy (Review). Mol Med Rep. 2021; 23(5). PMC: 7985997. DOI: 10.3892/mmr.2021.12001. View

19.

Crino L, Bronte G, Bidoli P, Cravero P, Minenza E, Cortesi E . Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. 2019; 129:35-40. DOI: 10.1016/j.lungcan.2018.12.025. View

20.

Kang Y, Jin Y, Li Q, Yuan X . Advances in Lung Cancer Driver Genes Associated With Brain Metastasis. Front Oncol. 2021; 10:606300. PMC: 7848146. DOI: 10.3389/fonc.2020.606300. View