
==== Front
J Transl Med
J Transl Med
Journal of Translational Medicine
1479-5876
BioMed Central London

39107814
5310
10.1186/s12967-024-05310-8
Letter to the Editor
The global landscape of clinical trials and drug discovery for brain metastasis
Ding Jiatong
Jiang Yale
Zhou Jiawei
Tang Qiyu
Xing Shujun
Wang Shuhang snowflake201@gmail.com

http://orcid.org/0000-0002-3945-2536
Li Ning lining@cicams.ac.cn

https://ror.org/02drdmm93 grid.506261.6 0000 0001 0706 7839 Clinical Trials Center, National Clinical Research Center for Cancer/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
6 8 2024
6 8 2024
2024
22 74410 5 2024
14 5 2024
© The Author(s) 2024, corrected publication 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
National Key Research and Development Program of ChinaNational Key Research and Development Program of China2023YFC2508500 Li Ning issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcTo the editor,

Brain metastasis (BrM) remains a serious complication of systemic cancer due to its consistent association with poor clinical outcomes [1]. Given the increasing incidence but unsatisfactory clinical outcomes of BrM, many new therapies have been tested in clinical trials to explore reliable strategies [2]. Here, we present a comprehensive analysis of the interventional clinical trials including patients with BrM during the last 10 years. The classification and targets of drug interventions for BrM treatment in these trials were also analyzed to provide supporting data for future research on treatment of BrM.

Using ClinicalTrials.gov database, a total of 434 eligible interventional BrM clinical trials were identified from Jan 1, 2013, to Dec 1, 2023, based on the inclusion criteria (Methods in the Supplement). The annual number of trials maintained at a relatively stable level in recent years, which reached its highest peak in 2021 but showed a downward trend in the past two years (Fig. 1A). Phase II trials accounted for the highest proportion (202, 46.5%), while the proportions of phase III and IV trials are only 8.3% (36) and 0.7% [3]. Most trials (194, 44.7%) included multiple primary tumor sites. Among trials focusing on a single primary tumor site, non-small cell lung cancer (NSCLC) (99, 22.8%), breast cancer (77, 17.7%), and melanoma (46, 10.6%) were the most frequent cancer types (Fig. 1B). NSCLC also occupied the highest proportion (15, 41.7%) in phase III trials. There were only three phase IV trials that covered BrM from NSCLC, breast cancer and unspecific primary tumor sites (Fig. 1C).

For drug treatment mode, 286 clinical trials involving pharmaceutical interventions were included. Among them, target therapy (192, 67.1%), immunotherapy (90, 31.5%), and chemotherapy (76, 26.6%) have attracted more attention. Moreover, target therapy and immunotherapy showed a trend of occupying higher proportions (Fig. 1D). The peptide-drug conjugates (PDC) and nanoparticles (NP) have also gained certain attention. In breast cancer BrM, endocrine therapy appears to become an available combination partner of target therapy. Target therapy also constituted the most widely used treatment modality in BrM from NSCLC, breast cancer, and unspecified solid cancer, but immunotherapy accounted for the highest proportion in melanoma (Fig. 1E). Apart from the classic targets, such as PD-1 (programmed death-1) and EGFR (epidermal growth factor receptor), novel targets were also tested in recent trials (Table 1). For cell therapies, dendritic cells, NK cells, tumor-infiltrating lymphocytes, autologous progenitor expansion T cells, CAR-T cells, personalized cellular vaccine, peripheral blood mononuclear cells, and TCR-gene engineered lymphocytes are emerging.

Notably, most of the clinical trials have tested combination regimens including drug treatment and radiotherapy. More confirmatory evidence is needed to determine the optimal sequence of treatment options. Drug delivery systems have also attracted much attention in recent years. For example, ANG1005, the most well-known brain permeable PDC, has entered a phase III clinical trial (NCT03613181) for BrM and leptomeningeal disease [2]. PDC has its advantages in tumor penetration, production cost and immunogenicity, making it a research hot spot and a promising track for investment [4]. The theragnostic potential of NPs has also been highlighted in the management of BrM, while researches on the clinical applicability of NPs for BrM are still in early stages (for example, NCT04899908 and NCT05255666).

In conclusion, the clinical trials for BrM have developed rapidly worldwide, but still at early exploratory stages. Due to the biological heterogeneity, the potential differences in BrM between cancer types should receive more attention. With research on novel therapeutic strategies against BrM gathering momentum, several new drugs targeting different molecules and drug delivery approaches have entered clinical trials, which is expected to increase the treatment opportunities for BrM patients.

Fig. 1 The landscape of clinical trials and drug discovery for brain metastasis. (A) Annual numbers of the clinical trials registered worldwide in ClinicalTrials.gov. (B) Interventional clinical trials for brain metastasis across primary tumor types. (C) Phase III and phase IV clinical trials across primary tumor types. (D) Annual numbers of the clinical trials across different drug therapy strategies. (E) Drug treatment across primary tumor types

Table 1 Recent clinical trials involving drugs targeting novel therapeutic targets

NCT Number	Primary tumor site	Phases	First Posted	Drug interventions	Target	
NCT05620914	Unspecified Solid Tumor	EARLY_PHASE1	2022	Patritumab deruxtecan	HER3	
NCT05704933	Melanoma	EARLY_PHASE1	2023	Nivolumab, Ipilimumab, Relatlimab	PD-1 + CTLA-4 + LAG3	
NCT03796273	Breast Cancer	EARLY_PHASE1	2019	Ketoconazole	tGLI1	
NCT02429570	Unspecified Solid Tumor	NA	2015	Meclofenamate	FTO	
NCT03423628	Unspecified Solid Tumor	PHASE1	2018	AZD1390	ATM	
NCT02589522	Unspecified Solid Tumor	PHASE1	2015	Berzosertib	ATR	
NCT06137651	Breast Cancer	PHASE1	2023	Trotabresib, Vinorelbine	BET	
NCT02215512	Unspecified Solid Tumor	PHASE1	2014	RRx-001	CD47 + SIRP-α	
NCT04396717	Unspecified Solid Tumor	PHASE1	2020	Pritumumab	EDV	
NCT05669352	Melanoma	PHASE1	2022	CA-4948, Pembrolizumab	IRAK-4 + PD-1	
NCT04430842	Unspecified Solid Tumor	PHASE1	2020	QBS10072S	LAT1	
NCT04250545	NSCLC	PHASE1	2020	Sapanisertib, Telaglenastat Hydrochloride	mTOR + GLS1	
NCT04789668	Unspecified Solid Tumor	PHASE1	2021	Bintrafusp Alfa, Pimasertib	PD-L1/TGF-β + MEK	
NCT04631029	SCLC	PHASE1	2020	Atezolizumab, Carboplatin, Entinostat, Etoposide	PD-L1 + HDAC	
NCT05789589	Unspecified Solid Tumor	PHASE1	2023	Azeliragon, Corticosteroid	RAGE	
NCT06128148	Unspecified Solid Tumor	PHASE1	2023	JYP0322	ROS1	
NCT04334863	Unspecified Solid Tumor	PHASE1	2020	WP1066	STAT3	
NCT04460937	Esophageal and GEJ Cancer	PHASE1	2020	Adavosertib	Wee1	
NCT05866432	Breast Cancer	PHASE2	2023	Datopotamab deruxtecan	TROP2	
NCT02014545	NSCLC	PHASE2	2013	Lucanthone	APE-1	
NCT03964090	Secondary Central Nervous System Lymphoma	PHASE2	2019	TEDD-R, TEDDI-R, Ibrutinib, Cytarabine, Isavuconazole, Methotrexate	BTK + CYP3A4 + CD20	
NCT04899921	Melanoma	PHASE2	2021	Ipilimumab, Nivolumab, Troriluzole	EAAT2 + PD-1 + CTLA-4	
NCT05999357	NSCLC	PHASE2	2023	JDQ443	KRAS G12C	
NCT04460729	NSCLC	PHASE2	2020	Capmatinib	MET	
NCT02595905	Breast Cancer	PHASE2	2015	Cisplatin, Veliparib	PARP	
NCT02452294	Melanoma	PHASE2	2015	Buparlisib	PI3K	
NCT05909618	Melanoma	PHASE2	2023	Crizanlizumab-Tmca, Nivolumab	P-selectin + PD-1	
NCT05746481	NSCLC	PHASE2	2023	Tiragolumab, Atezolizumab, Pemetrexed, Carboplatin	TIGIT + PD-L1	
NCT04647916	Breast Cancer	PHASE2	2020	Sacituzumab Govitecan	Trop-2	
NCT04674683	Melanoma	PHASE3	2020	HBI-8000, nivolumab	HDAC + PD-1	
GEJ, gastroesophageal junction; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We thank all the participants for their contribution to this study.

Author contributions

Li Ning: Writing – review & editing, Supervision, Methodology, Conceptualization. Wang Shuhang: Writing – review & editing, Conceptualization. Ding Jiatong: Writing – review & editing, Writing – original draft. Jiang Yale: Writing – original draft. Zhou Jiawei: Writing – original draft, Visualization, Data curation. Tang Qiyu: Writing – original draft. Xing Shujun: Writing – original draft.

Funding

This work was supported by the grant Beijing Municipal Health Commission (Beijing Demonstration Research Ward BCRW20200303); National Natural Science Foundation of China (82272951, 82272953); Chinese Academy of Medical Sciences (2022-I2M-C&T-B-070); The National Key Research and Development Program of China(Grant No. 2023YFC2508500).

Data availability

All data used and/or analyzed in this manuscript is publicly available on the ClinicalTrials.gov database (https://clinicaltrial.gov/).

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jiatong Ding and Yale Jiang contributed equally to this work.

Change history

9/12/2024

Supplementary file was mentioned in the body text of the article, but not added.
==== Refs
References

1. Suh JH, Kotecha R, Chao ST, Ahluwalia MS, Sahgal A, Chang EL. Current approaches to the management of brain metastases. Nat Rev Clin Oncol. 2020;17(5):279 − 99.
2. Wang J, Pan H, Lin Z, Xiong C, Wei C, Li H, et al. Neuroprotective effect of Fractalkine on radiation-induced brain injury through promoting the M2 polarization of Microglia. Mol Neurobiol. 2021;58(3):1074-87.
3. Yang Y, Wang S, Ma P, Jiang Y, Cheng K, Yu Y, et al. Drug conjugate-based anticancer therapy - Current status and perspectives. Cancer Lett. 2023;552:215969.
4. Fu C, Yu L, Miao Y, Liu X, Yu Z, Wei M. Peptide-drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope? Acta Pharm Sin B. 2023;13(2):498–516.
