The global landscape of clinical trials and drug discovery for brain metastasis

To 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