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Treatment of Brain Metastases in Non-Small Cell Lung Cancer
Haiying Xue 1, a, †, Yuzhu Chen 2, †
1 School of Medicine, Sun Yat-sen University, Shenzhen Guangdong, 518107, China
2 Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis
and Thoracic Tumor Research Institute, Beijing 101149, China
a xuehy6@mail2.sysu.edu.cn
†Haiying Xue and Yuzhu Chen have made the same contribution to this article.
Abstract. Non-small cell lung cancer is the most common subtype of lung cancer, and brain
metastases are a frequent and devastating complication with poor prognosis. The blood-brain barrier
and blood-tumor barrier limit intracranial drug delivery, resulting in suboptimal therapeutic effects.
Recent advances in molecular targeted therapy and immunotherapy have markedly improved
survival, particularly in patients harboring EGFR or ALK alterations, where next-generation tyrosine
kinase inhibitors demonstrate strong intracranial activity. Radiotherapy remains essential for local
control, while chemotherapy contributes mainly to systemic disease management. Increasingly,
multidisciplinary and combination strategies are shaping the treatment paradigm. Nevertheless,
challenges such as drug resistance, BBB limitations, and neurocognitive preservation persist. This
review summarizes current therapeutic strategies for NSCLC with brain metastases, highlights their
strengths and limitations, and discusses future directions for optimizing patient outcomes.
Keywords: Non-Small Cell Lung Cancer; Brain Metastases; Treatment; Targeted Therapy.
1. Introduction
Lung cancer is the most common malignant tumor worldwide, among which non-small cell lung
cancer (NSCLC) accounts for approximately 85% [1]. The brain is one of the most common
metastatic sites, affecting 10–25% of patients at diagnosis and more than half during the course of
disease [2]. Brain metastases (BM) often cause intracranial hypertension and focal neurological
deficits, severely compromising quality of life and survival. Without treatment, median overall
survival is only about one month [3].
The blood–brain barrier (BBB), composed of endothelial cells, tight junctions, pericytes,
astrocytes, and the basement membrane, maintains central nervous system homeostasis. In the setting
of brain metastases, structural and functional changes give rise to the blood–tumor barrier (BTB).
Although more permeable than the BBB, the BTB exhibits marked heterogeneity, leading to uneven
drug distribution and limited efficacy of systemic therapies [4].
Current treatment options include surgery, whole-brain radiotherapy (WBRT), stereotactic
radiosurgery (SRS), chemotherapy, targeted therapy, and immunotherapy, most of which are applied
in combination. Advances in molecular profiling and targeted agents have shifted the treatment
paradigm from purely palliative local interventions toward individualized, multidisciplinary
strategies integrating systemic and local therapies. Systematically summarizing the progress and
shortcomings in this field is of great significance for optimizing clinical decision-making and
improving patient prognosis.
2. Therapeutic Mechanisms
The blood–brain barrier plays a pivotal role in maintaining intracerebral homeostasis. Its barrier
function is reflected in two main aspects: first, tight junctions between endothelial cells form a
physical barrier that prevents macromolecules and most drugs from entering the brain; second, a
system of uptake and efflux transporters regulates transmembrane exchange, allowing essential
nutrients in while expelling potentially harmful substances. Following the development of brain
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metastases, the BBB undergoes structural and functional changes, evolving into the blood–tumor
barrier. Although the BTB exhibits higher permeability than the intact BBB, persistent efflux
transporter activity results in limited intracranial drug accumulation, thereby restricting the efficacy
of chemotherapy and certain targeted agents [5] (Figure 1).
Molecular targeted therapies inhibit oncogenic signaling pathways driven by alterations such as
EGFR and ALK, thereby blocking tumor cell survival and proliferation at their source. For instance,
EGFR mutations activate downstream PI3K/AKT/mTOR and RAS/RAF/MEK/ERK cascades, which
are closely associated with tumor growth and cell cycle progression. Epidermal growth factor receptor
tyrosine kinase inhibitors (EGFR-TKIs) suppress tumor growth by inhibiting EGFR activation and
subsequent signaling (Figure 2). New-generation TKIs not only enhance systemic efficacy but also
penetrate the BBB effectively, demonstrating superior activity against brain metastases.
In contrast, most conventional chemotherapeutics have poor BBB penetration due to high
molecular weight and low lipophilicity, limiting their intracranial effect. Consequently, they are
primarily applied for systemic control. Consequently, they are primarily applied for systemic control.
Intrathecal administration can bypass the BBB entirely, enabling direct drug delivery into
cerebrospinal fluid and offering therapeutic benefits for leptomeningeal metastases.
Radiotherapy remains a cornerstone of local treatment by inducing DNA damage with high-energy
radiation, leading to rapid tumor shrinkage and symptom relief. Whole-brain radiotherapy (WBRT)
is suited for diffuse or multiple metastases, whereas stereotactic radiosurgery (SRS) delivers precise
high-dose radiation to limited lesions, striking a balance between tumor control and preservation of
neurological function [6].
Immune checkpoint inhibitors (ICIs) reactivates anti-tumor immunity by blocking PD-1/PD-L1 or
CTLA-4 signaling. Disruption of the BBB in metastatic lesions facilitates immune cell infiltration,
thereby enabling ICIs to produce durable responses both intracranially and systemically [7].
3. Treatment
3.1 Monotherapy
3.1.1. Molecular Targeted Therapy
Molecular targeted therapy has brought major breakthroughs for patients with NSCLC brain
metastases, significantly improving intracranial disease control and overall survival (OS) in
populations with driver gene mutations.
3.1.1.1. EGFR-TKIs
EGFR is one of the most critical targets in NSCLC brain metastases. Approximately 50% of Asian
patients and 10%-15% of Caucasian patients carry EGFR mutations [8]. EGFR-targeted agents have
undergone several generations of development. First-generation TKIs (gefitinib, erlotinib and icotinib)
are reversible TKIs, second-generation TKIs (afatinib and dacomitinib) are irreversible inhibitors
with additional HER2 activity, third-generation osimertinib not only target sensitive mutations and
the T790M resistance mutation but also demonstrate superior BBB penetration.
Studies have shown that all generations of EGFR-TKIs exhibit intracranial efficacy in patients
with brain metastases. With first-generation TKIs, patients with baseline brain metastases achieve a
median intracranial progression-free survival (miPFS) of approximately 9 months and a median OS
of 26–29 months [9-11]. In real-world studies, the second-generation agent afatinib yielded an
mPFS of 13–14 months and an OS of nearly 30 months, though it was associated with relatively high
incidences of diarrhea and rash [12].Among all EGFR-TKIs, osimertinib demonstrates significantly
superior intracranial disease control compared with earlier generations. Its miPFS is three times
longer than that of gefitinib, with manageable toxicity, and it has become a first-line standard regimen
recommended by international guidelines [13, 14].
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3.1.1.2. ALK-TKIs
ALK fusions are detected in 4% of NSCLC patients [15]. First-generation crizotinib has limited
central nervous system (CNS) penetration and low intracranial efficacy, second-generationTKIs such
as alectinib and brigatinib offer improved CNS activity and markedly enhance intracranial disease
control, third-generation lorlatinib covers a broad spectrum of resistance mutations and possesses the
strongest BBB penetration and CNS activity among ALK inhibitors.
In patients with brain metastases treated with crizotinib, the mPFS is only 6–11 months, with
limited intracranial activity and a high risk of resistance [16, 17]. In contrast, when alectinib is used
in patients with baseline BM, the mPFS extendes to 27.7 months, significantly reducing the risk of
intracranial progression [18, 19]. Brigatinib achieves a 3-year intracranial progression-free survival
(iPFS) rate of 31% and a 3-year OS rate exceeding 74%, and both alectinib and brigatinib have been
recommended as first-line treatment options [20]. Lorlatinib provides durable intracranial control,
with a 5-year iPFS rate of 83%, making it particularly suitable for patients with brain metastases or
drug resistance [17, 21].
3.1.1.3. Inhibitors for Other Mutations
Some targeted drugs for rare driver mutations also demonstrate CNS activity. For patients with
ROS1 fusions (1%-2%), entrectinib and repotrectinib achieve an intracranial objective response rate
(iORR) exceeding 50% [22, 23]. For BRAF V600E mutation (1%-2%), combined BRAF/MEK
inhibitors such as dabrafenib plus trametinib has shown efficacy [24, 25]. Although NTRK fusions
are rare, entrectinib and larotrectinib both exhibit favorable CNS activity [26]. In METex14 skipping
mutations (3%-4%), capmatinib demonstrates a high iORR [27, 28]. For RET fusions (1%-2%),
selpercatinib achieves an iORR of more than 80% [29]. Moreover, novel antibody-drug conjugates
(ADCs), such as the HER2-targeted drug trastuzumab deruxtecan, have shown promising activity
against intracranial lesions [30]. In contrast, KRAS G12C-targeted agents have limited efficacy, and
immunotherapy or chemotherapy remains the mainstay of treatment for such patients.
Overall, new-generation EGFR-TKIs and ALK-TKIs provide excellent intracranial control and
durable survival benefits. Landmark phase III trials, such as AENEAS and CROWN studies, have
established the pivital role of osimertinib and lorlatinib in the management of driver gene-positive
NSCLC brain metastases. For rare driver gene mutations, studies such as TRIDENT-1 have also
shown encouraging efficacy. Therefore, molecular targeted therapy has become the cornerstone of
treatment for NSCLC patients with brain metastases harboring driver gene alterations.
3.1.2. Chemotherapy
The overall efficacy of systemic chemotherapy in NSCLC brain metastases remains limited. Most
chemotherapeutic agents penetrate the BBB poorly, and efflux transporters further reduce their
intracranial concentrations, resulting in insufficient activity against CNS lesions. Moreover, patients
with brain metastases are often excluded from large-scale clinical trials, leading to relatively scarce
high-quality evidence in this population. Commonly used agents include platinum-based compounds,
taxanes, and pemetrexed, which are mainly primarily administered for the control of extracranial
disease.
Several studies have indicated that chemotherapy achieves only modest outcomes in patients with
brain metastases. For instance, in trials such as KEYNOTE-021, 189, and 407, patients with BM had
an mPFS of 4.1 months and an OS of 7.6 months [31]. Among patients with KRAS G12C mutation
and CNS involvement, docetaxel resulted in an mPFS of 2.9 months [32]. Similarly, the combination
of pemetrexed plus carboplatin resulted in an mPFS of approximately 4.1 months in those with BM
[33]. Although systemic chemotherapy has limited impact on intracranial disease control, it remains
a viable option when targeted therapies or immunotherapies are unavailable.
Intrathecal injection aims to bypass the BBB by directly delivering drugs into the cerebrospinal
fluid, thereby achieving high local drug exposure for patients with leptomeningeal metastases.
Intrathecal pemetrexed, for example, has shown clinical benefit in certain patients with EGFR-mutant
leptomeningeal metastases, leading to symptom relief and prolonged survival [34]. However,
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common adverse effects include myelosuppression and nausea, while additional risks such as
infection, bleeding, and neurological injury require careful monitoring. Although intrathecal
administration offers particular advantages for leptomeningeal disease, its efficacy against
parenchymal brain metastases is limited, and clinical application necessitates a cautious balance
between therapeutic benefit and potential risks.
3.1.3. Radiotherapy
Radiotherapy is a key local treatment option for NSCLC brain metastases, primarily including
whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS).
WBRT enables simultaneous coverage of multiple lesions, with reported intracranial response
rates of 70%–90%. It can prolong PFS to some extent and alleviate neurological symptoms, however,
long-term use is associated with risks of cognitive decline and high recurrence rates [35, 36].
Consequently, WBRT is mainly reserved for patients with multiple or diffuse brain metastases,
particularly those requiring rapid symptom relief.
SRS delivers highly precise, focused radiation to tumor sites while sparing surrounding normal
brain tissue. It can be applied as a standalone treatment, in combination with WBRT, or as an adjuvant
therapy following surgery, and is generally more suitable for patients with a limited number of lesions.
Retrospective analyses show a mOS of approximately 8 months for patients receiving single-session
SRS, while those undergoing multiple SRS sessions may achieve survival exceeding 3 years,
underscoring its potential role in long-term intracranial control [37].
In summary, radiotherapy remains an indispensable component of NSCLC brain metastasis
management. Evidence from studies such as HYBRID suggests that SRS provides superior
intracranial disease control and better preservation of neurocognitive function, whereas WBRT
remains more appropriate for patients with diffuse or extensive metastatic disease.
3.1.4. Immunotherapy
Immune checkpoint inhibitors (ICIs) restore antitumor immunity by blocking the PD-1/PD-L1 or
CTLA-4 pathways, thereby reactivating exhausted T cells. Patients with NSCLC brain metastases
may be more responsive to ICIs due to BBB disruption and increased immune cell infiltration.
Multiple studies have confirmed that ICIs exert durable intracranial activity and provide meaningful
survival benefits. In particular, PD-1/PD-L1 inhibitors have shown clear efficacy, and their
combination with chemotherapy or radiotherapy can further enhance both intracranial and systemic
responses.
Among PD-1 inhibitors, nivolumab was the first to be applied in patiens with brain metastases.
Retrospective cohort studies have reported an mPFS of approximately 3 months and an mOS of nearly
15 months, while clinical studies demonstrated an mOS exceeding 9 months with favarable safety
profiles [38, 39]. Pembrolizumab, in phase II studies, achieved an intracranial PFS of about 2 months,
however, real-world data suggest that when administered as first-line therapy, PFS can be extended
to 10 months , indicating greater benefits with earlier use [40, 41].
The PD-L1 inhibitor atezolizumab, when conbined with chemotherapy and bevacizumab, achieved
an OS of 11 months in patients with baseline brain metastases. As monotherapy, atezolizumab also
conferred survival benefits in this subgroup, with good overall tolerability [42, 43].
CTLA-4 inhibitors have limited efficacy as monotherapy but demonstrate synergistic effect when
combined with PD-1 inhibitors. For instance, the combination of nivolumab and ipilimumab resulted
in an mOS of 17 months in patients with brain metastases, outperforming single-agent regimens [44].
In conclusion, representative studies such as the KEYNOTE series and CheckMate 227 highlight
that immunotherapy can induce durable intracranial and extracranial responses in selected patients
with NSCLC brain metastases, offering the potential for long-term survival.
3.2 Combined Therapy
Combined therapy plays an important role in the management of NSCLC brain metastases.
Monotherapy has clear limitations: although targeted agents are effective, resistance inevitably
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depelops; chemotherapy and immunotherapy are hindered by BBB penetration; and radiotherapy is
associated with considerable adverse effects. By integrating different treatment modalities,
combination strategies can improve intracranial control rates, prolong survival, and enhance overall
prognosis.
Combining TKIs directed against the same molecular target results in overlapping mechanisms,
which increase toxicity without conferring meaningful benefits. Therefore, current research
emphasizes combinations targeting distinct pathways. For example, MET amplification is a key
mechanism of resistance to EGFR-TKIs. The combination of tepotinib and osimertinib has been
shown to improve the iORR in patients with baseline brain metastases [45]. Retrospective studies of
EGFR-TKI combined with VEGFR-TKI have reported an mPFS of 18.8 months, while the FL-
ALTER trial also demonstrated a significant PFS benefit [46, 47]. Although this approach shows
promise for intracranial control, its safety profile and long-term efficacy remain to be further validated.
The combination of EGFR-TKIs and chemotherapy has also demonstrated clinical benenfit, In
patients with brain metastases, gefitinib plus chemotherapy prolonged mPFS to 16.3 months and the
mOS to 35.0 months [10]. Similarly, osimertinib combined with chemotherapy yielded an mPFS of
24.9 months, which was significantly superior to osimertinib monotherapy [14]. However, the
incidence of grade ≥3 adverse events increased to 64% in the combination group, presominantly
hematologic and cardiac toxicities. Such regimens may be more appropriate for patients with a high
tumor burden or those who have not received prior local therapy.
Combining TKIs with radiotherapy can further enhance local control. A meta-analysis revealed
that third-generation TKIs plus radiotherapy significantly improved intracranial disease control and
OS [48]. The URBO-NSCLC study suggested that combining TKI with SRS increased local control
rate in patients with large lesions [49]. Nevertheless, study outcomes remain inconsistent, and
treatment-related toxicity is increased, underscoring the importance of carful patient selection.
In patients with EGFR mutations, the efficacy of PD-1/PD-L1 inhibitors is limited. The
combination of TKIs with ICIs has not demonstrate consistent clinical benefit, with low ORR and
high rates of severe adverse events. As such, this approach is not recommended for routine use in
patients with NSCLC-BM [50].
Anti-vascular endothelial growth factor (VEGF) drugs may normalized tumor vasculated and
improve drug delivery. The combination of erlotinib and bevacizumab was shown to extend both
mPFS and mOS. Similarly, osimertinib plus bevacizumab as first-line treatment achieved a CNS
mPFS of 26.7 months, while combinations of ALK inhibitor with bevacizumab also demonstrated
improve disease control [11, 51, 52]. However, attention must be paid to the risks of bleeding and
vascular-related toxicities.
4. Discussion
Lung cancer remains one of the most common malignancies worldwide. With the rising incidence
of brain metastases, treatment strategies have continued to evolve. Third-generation EGFR-TKIs such
as osimertinib and ALK-TKIs such as lorlatinib have significantly improved intracranial disease
control rates and overall survival due to their strong BBB penetration and high intracranial activity,
but acquired drug resistance remains a major challenge. Fourth-generation EGFR-TKIs, such as
BLU-945, have shown preliminary anti-tumor activity in early clinical trials and may be combined
with osimertinib, yet their safety and intracranial efficacy still require further validation [53].
Radiotherapy remians indispensable for local control, sympton relief, and prevention of new
lesions. SRS, with its high precision and ability to spare normal brain tissue, has become the standard
for patients with oligometastases, while WBRT is reversed for diffuse or multiple brain metastases,
albeit at the cost of a high risk of cognitive decline. Memory-preserving WBRT can mitigate
neurotoxicity, and hypofractionated SRS may be applied to larger lesions or those located in critical
brain regions.
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For patients without actionable driver gene mutations but with high PD-L1 expression, ICI, either
alone or combined with chemotherapy or CTLA-4 inhibitors, can provide durable systemic and
intracranial responses. However, patients with EGFR or ALK alterations derive limited benefit from
ICIs, and evidence for combining ICIs with TKIs is scarce and associated with significant toxicity,
making this approach not currently recommended.
Systemic chemotherapy is limited by poor intracranial response rates due to the BBB. Pemetrexed
and platinum-based regimens can be combined with TKIs or ICIs, but systemic toxicity requires close
monitoring. Intrathecal therapy is particularly important for leptomeningeal metastases, yet its
efficacy against parenchymal metastases is modest, and it carries risks of procedural complications
and neurotoxicity.
Monotherapy is often insufficient for durable disease control, highlighting the importance of
combinaton strategies. Combining targeted therapy with chemotherapy can prolong PFS and OS;
pairing targeted therapy and anti-angiogenic agents may further improve outcomes, though at the cost
of increased toxicity. The benefit of combining targeted therapy with radiotherapy depends on lesion
size and treatment timing, requiring individualized planning. By contrast, combining targeted therapy
with immunotherapy remains poorly supported by current evidence and is accociated with high
toxicity, and thus s not recommended in routine practice. Key challenges of combination therapy
include accurate patient selection, optimizion of drug choice, and sequencing, as well as management
of cumulative toxicity and financial burden. SRS offers both efficacy and cost-effectiveness in
patients with oligometastases, whereas hippocampal-avoidant WBRT (HA-WBRT) can preserve
cognitive function but increases economic burden. Bevacizumab may relieve radiation necrosis, yet
its cost alsolimits widespread use [54-56]. Therefore, in clinical decision-making, efficacy, safety,
and cost-effectiveness must be carefully balanced to formulate individualized treatment strategies
tailored to survival expectations and resource accessibility.
Future research should focus on overcoming drug resistance and BBB-related barriers, advancing
next-generation targeted therapies, exploring rational combination regiments to bypass resistance,
and developing innovative drug delivery systems to enhance intracranial efficacy. Dynamic
monitoring of circulating tumor DNA (ctDNA) in plasma or cerebrospinal fluid may also enable more
precise and individualized treatment. Although significant progress has been made in the management
of NSCLC-BM, challenges remain, including resistance mechanisms, optimization of combination
approaches, preservation of neurocognitive function, and treatment of patients with complex
resistance patterns. Moving forward, individualized strategies that integrate novel drug development,
advanced diagnostic and therapeutic technologies, and multidisciplinary collaboration will be critical
to improving both survival and quality of life in this population.
5. Conclusion
This study systematically reviews the comprehensive treatment strategies for non-small cell lung
cancer with brain metastases. With the growing understanding of molecular driver genes and the
advancement of therapeutic approaches, the management of NSCLC-BM has evolved from palliative
local therapy to a multidisciplinary model integrating local and systemic treatments. Molecular
targeted agents, particularly third-generation EGFR-TKIs and ALK-TKIs, have become preferred
first-line options owing to their superior blood–brain barrier penetration and robust intracranial
efficacy. Radiotherapy remains indispensable for local control and symptom relief, while immune
checkpoint inhibitors provide durable benefit in patients with high PD-L1 expression and no driver
mutations. Chemotherapy and intrathecal therapy also retain value, particularly for systemic disease
control and leptomeningeal metastases.
Nevertheless, significant challenges persist, including blood–brain barrier limitations, acquired
resistance, optimization of combination strategies, scarcity of dedicated evidence-based data, and
risks of long-term neurotoxicity. Future research should prioritize strategies to overcome BBB-related
barriers and resistance mechanisms, refine individualized combination regimens, generate high-
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quality data specific to brain metastasis populations, and balance efficacy with safety. These efforts
will be critical to further improving prognosis and quality of life for patients with NSCLC-BM.
Declarations
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Author Contributions
Yuzhu Chen: Data curation; Resources; Writing, review & editing.
Ziyu: Writing – review & editing.
Competing Interests
The authors declare that there is no conflict of interest.
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Availability of Data and Materials
Table 1. Clinical Trials of Targeted Therapy for Brain Metastases in Non-Small Cell Lung Cancer
References
Registration
number
Study
name
Intervetion
group
Control
group
Study
design
N
Intracranial/
CNS efficacy
Systemic
efficacy
[9] NCT03849768 AENEAS Aumolertinib Gefitinib
phase
Ⅲ
51
(CG:55)
mCNS
PFS:29.0m(CG:8.3m)
CNS
ORR:62.7%(CG:49.1%)
CNS
DCR:94.1%(CG:96.4%)
mCNS
DoR:27.7m(CG:6.9m)
6-month
PFS:86.0%(CG:71.8%)
12-month
PFS:72.5%(CG:30.4%)
18-month
PFS:59.9%(CG:8.9%)
24-month
PFS:56.8%(CG:8.9%)
[10] NCT01951469 GAP BRAIN
Gefitinib plus
chemotherapy
Gefitinib
phase
Ⅲ
80
(CG:81)
miPFS:15.6m(CG:9.1m)
iORR:85.0%(CG:63.0%)
iDCR:95.0%(CG:93.8%)
mPFS:16.3m(CG:9.3m)
mOS:35.0m(CG:28.9m)
ORR:76.3%(CG:58.0%)
DCR:97.5%(CG:95.1%)
[47] NCT04028778 FL-ALTER
Gefitinib plus
anlotinib
Gefitinib
phase
Ⅲ
49
(CG:50)
- mPFS:13.8m(CG:8.3m)
[11] NCT02759614
ARTEMIS-
CTONG1509
Erlotinib plus
bevacizumab
Erlotinib
phase
Ⅲ
44
(CG:47)
-
mPFS:17.9m(CG:11.1m)
mOS:31.6m(CG:26.8m)
[13, 14] NCT04035486 FLAURA2
Osimertinib
plus
chemotherapy
Osimertinib
phase
Ⅲ
118
(CG:104)
116
(CG:110)
mCNS
PFS:30.2m(CG:27.6m)
CNS ORR:73%(CG:69%)
CNS DCR:91%(CG:93%)
mCNS
DoR:NR(CG:26.2m)
mPFS:24.9m(CG:13.8m)
[16] NCT04632758 INSPIRE Iruplinalkib Crizotinib
phase
Ⅲ
37
(CG:44)
iORR:90.9%(CG:60.0%)
miDoR:20.1m(CG:9.3m)
mPFS:22m(CG:11m)
24-month
PFS:49.0%(CG:4.4%)
24-month
OS:85.6%(CG:84.0%)
[17, 21] NCT03052608 CROWN Lorlatinib Crizotinib
phase
Ⅲ
38
(CG:40)
5-year iPFS:83%(CG:NE)
iORR:92%(CG:33%)
mPFS:NR(CG:6.0m)
12-month
PFS:78%(CG:22%)
5-year PFS:53%(CG:NE)
[18, 19] NCT02075840 ALEX Alectinib Crizotinib
phase
Ⅲ
64
(CG:58)
CNS
ORR:81.0%(CG:50.0%)
mPFS:27.7m(CG:7.4m)
[20] NCT02737501 ALTA-1L Brigatinib Crizotinib
phase
Ⅲ
47
(CG:49)
3-year
miPFS:31%(CG:9%)
4-year
miPFS:22%(CG:NE)
miDoR:27.9m(CG:9.2m)
3-year OS:74%(CG:55%)
4-year OS:71%(CG:44%)
[22]
NCT02097810
NCT02568267
EudraCT, 2012-
000148-88
STARTRK-1
STARTRK-2
ALKA-372-
001
Entrectinib -
phase
Ⅰ
phase
Ⅱ
phase
Ⅰ
23
miPFS:7.7m
iORR:55%
miDoR:12.9m
mPFS:13.6m
230
Continue from Table 1
[23] NCT03093116 TRIDENT-1
Repotrectinib
(ROS1 TKI-
naïve)
Repotrectinib
(ROS1-TKI
pretreated and
chemotherapy-
naïve)
phase
Ⅱ
17
(CG:26)
iORR:89%(CG:38%) -
[57]
NCT02576431
NCT02122913
- Larotrectinib -
phase
Ⅱ
phase
Ⅰ
10 CNS ORR:63% -
[58] NCT02864992 VISION Tepotinib -
phase
Ⅱ
23 - mPFS:9.5m
[29] NCT04194944 - Selpercatinib
Pemetrexed
plus
platinum
therapy
phase
Ⅲ
17
(CG:12)
iORR:82%(CG:58%) -
[30] NCT03505710
DESTINY-
Lung01
Trastuzumab
deruxtecan
-
phase
Ⅱ
33 -
mPFS:7.1m
mOS:13.8m
CNS, central nervous system; PFS, progression free survival; ORR, objective response rate; DCR, disease control rate; DoR, duration of response; OS, overall survival
Table 2. Clinical Trials of Chemotherapy for Brain Metastases in Non-Small Cell Lung Cancer
References Registration number Study name Intervetion group Control group
Study
design
N Systemic efficacy
[31]
NCT02039674
NCT02578680
NCT02775435
KEYNOTE-
021
KEYNOTE-
189
KEYNOTE-
407
Pembrolizumab
Plus
Platinum-Based
Chemotherapy
Platinum-Based
Chemotherapy
phase
Ⅲ
105
(CG:66)
mPFS:6.9m(CG:4.1m)
mOS:18.8m(CG:7.6m)
[33] NCT05184712
HARMONi-
A
Ivonescimab plus
pemetrexed and
carboplatin
Pemetrexed and
carboplatin
phase
Ⅲ
35
(CG:37)
mPFS:5.75m(CG:4.14m)
[34] ChiCTR1800016615 -
Intrathecal
Pemetrexed
-
phase
Ⅱ
132 mOS:12.0m
PFS, progression free survival; OS, overall survival
Table 3. Clinical Trials of Radiotherapy for Brain Metastases in Non-Small Cell Lung Cancer
References
Registration
number
Study
name
Intervention
group
Control
group
Study
design
N
Intracranial
efficacy
Systemic
efficacy
[36] NCT02882984 HYBRID WBRT SRS
phase
Ⅲ
41
(CG:44)
month
iPFS:91.7%(CG:91.1%)
miPFS:21.4m(CG:22.3m)
2-year
OS:75.6%(CG:90.9%)
3-year
OS:36.6%(CG:52.3%)
[59] NCT01887795 -
WBRT plus
erlotinib
WBRT
phase
Ⅲ
109
(CG:115)
miPFS:11.2m(CG:9.1m) mPFS:5.3m(CG:4.0m)
[60] NCT03614065 -
Rh-
endostatin
plus WBRT
WBRT
phase
Ⅲ
19
(CG:24)
miPFS:11.6m(CG:4.8m)
mPFS:8.1m(CG:4.9m)
mOS:14.2m(CG:6.4m)
WBRT, whole brain radiation therapy; SRS, Stereotactic Radiosurgery; PFS, progression free survival; OS, overall survival
Table 4. Clinical Trials of Immunotherapy for Brain Metastases in Non-Small Cell Lung Cancer
References
Registration
number
Study
name
Intervetion
group
Control
group
Study
design
N
Intracranial/
CNS efficacy
Systemic
efficacy
[40] NCT02085070 - Pembrolizumab -
phase
Ⅱ
42
Medium CNS
PFS:2.3m
mPFS:1.9m
1-year OS:40%
2-year OS:34%
mOS:9.9m
[44] NCT02477826
CheckMate
227
Nivolumab plus
ipilimumab
Platinum-
doublet
chemotherapy
phase
Ⅲ
68
(CG:66)
5-year
iPFS:16%(CG:6%)
5-year
PFS:12%(CG:0%)
mOS:17.4m(CG:13.9m)
5-year
OS:23%(CG:13%)
CNS, central nervous system; PFS, progression free survival; OS, overall survival
231
Figure 1. | Schematic representation of the structure and function of the blood–brain barrier
(BBB). The BBB is primarily composed of brain microvascular endothelial cells, pericytes,
astrocytes, and the basement membrane. Tight junctions between endothelial cells establish a
physical barrier, while uptake and efflux transporters regulate transmembrane substance exchange.
This highly selective system restricts the entry of harmful compounds while permitting essential
nutrients to maintain cerebral homeostasis. During tumorigenesis and the development of brain
metastases, structural and functional alterations in the BBB lead to the formation of the blood–
tumor barrier (BTB), which exhibits distinct permeability and transport properties compared with
the normal BBB.
Figure 2. | Epidermal growth factor receptor (EGFR) signaling pathway and the mechanism
of action of tyrosine kinase inhibitors (EGFR-TKIs). Ligand binding induces EGFR
dimerization and autophosphorylation, which subsequently activate multiple downstream pathways,
including PI3K/AKT/mTOR and RAS/RAF/MEK/ERK. These cascades regulate cell survival,
proliferation, and cell-cycle progression. EGFR-TKIs exert antitumor effects by blocking EGFR
activation and downstream signal transduction, thereby suppressing tumor growth and progression.