Mehek Sharma1
Anvay Shah1,2Kimberly A. Rivera-Caraballo1,3
Girindra Raval1,2Balveen Kaur1,3Gerald C. Wallace IV1,2*- 1Medical College of Georgia at Augusta University, Augusta, GA, United States
- 2Georgia Cancer Center at Wellstar Health, Augusta, GA, United States
- 3Department of Pathology, Medical College of Georgia and Georgia Cancer Center at Augusta University, Augusta, GA, United States
Non-small-cell lung cancer (NSCLC) is a leading cause of morbidity and mortality globally, due in large part to the development of NSCLC-associated brain metastases (L-BM). Upon initial presentation, 11-26% of patients with NSCLC will have L-BM, while half of patients with NSCLC will develop L-BM over the course of their disease. The emergence of PD-1/PD-L1 immunotherapy and targeted therapies for EGFR, ALK, and ROS1 mutations has transformed the treatment landscape and improved outcomes for select patient populations. CNS progression remains a major challenge due to therapy resistance, the blood–brain barrier (BBB), and the unique molecular and transcriptomic adaptations exhibited by NSCLC brain metastases which differs markedly from primary lung tumors. In this review, we examine the molecular drivers of CNS metastasis, oncogenic signaling-targeted therapies, and next-generation CNS drug-delivery strategies including intraventricular or intranasal administration, focused ultrasound, nanocarriers, and efflux transporter modulation. Furthermore, we provide a comprehensive update on recent and ongoing preclinical and clinical studies, highlighting novel CNS-penetrant agents with demonstrated intracranial efficacy. Understanding these mechanisms and refining targeted approaches are critical to improving CNS disease control, survival outcomes, and quality of life for NSCLC patients with brain involvement.
Introduction
Lung cancer is the second most common malignancy in the United States. Lung cancers are broadly divided into small cell and non-small cell lung cancer (SCLC and NSCLC, respectively). SCLC is a neuroendocrine carcinoma with a poor prognosis (1, 2), while NSCLC constitutes 85% of all other lung cancer diagnoses (3). NSCLC tumors are further divided by pathologic subtypes: adenocarcinoma, squamous cell carcinoma, or large cell carcinoma (4). Brain metastases from NSCLC (L-BM) occur in up to 50% of all patients, with likely increasing incidence as patients survive with high-stage disease (5). Survival with L-BM has significantly improved over time, with recent reports indicating a median survival of 12–24 months (6, 7). The importance of recognizing and managing L-BM has increased recently, since patients without stage IV disease live longer with increasing year-over-year risk for developing L-BM (1, 7).
Historically, management of L-BM relied on radiation and chemotherapy, but the advent of targeted therapies and immunotherapies has transformed the therapeutic landscape, demonstrating improved central nervous system (CNS) penetration and efficacy. Despite these advances, our understanding of how specific molecular subtypes influence the development, progression, and treatment of brain metastases in NSCLC patients is yet to be elucidated. Synthesizing existing knowledge linking NSCLC molecular subtypes to CNS metastatic risk, resistance mechanisms, and therapeutic response, is crucial to inform surveillance protocols, treatment selection, and clinical trial design. In this review, we will provide an overview of NSCLC development and molecular characteristics, as well as the current treatment strategies to improve outcomes for patients with L-BM.
Etiology and statistics
The American Cancer Society (ACS) projects more than 226,650 new cases of lung cancer and 124,730 deaths in the United States in 2025 (8). The median age at diagnosis is 71 years with 90% of diagnoses and deaths occurring in patients older than 55 years (9, 10). Lung cancer accounts for the highest number of cancer-related deaths, with a lifetime probability of 6.2% in men and 5.8% in women and an incidence of 64.1 cases per 100,000 in men compared to 50.3 per 100,000 in women (8). Incidence varies by race and sex, where Black men have the highest incidence and Hispanic women having the lowest. Cigarette smoking remains the most common risk factor with 80% of NSCLC patients admitting a history of smoking, while environmental radon exposure marks a distant second place (8, 11).
The one, three, and five-year survival rates following diagnosis of L-BM due to any lung cancer are 24%, 6%, and 3%, respectively (12). NSCLC accounts for approximately 25% of all brain metastases (13) and studies have shown 40% prevalence of L-BM (1, 14). L-BM contributes to one in three deaths from NSCLC and is a key reason why lung cancer is the leading cause of death worldwide (6, 8, 15). The association with L-BM is highest for non-squamous adenocarcinoma (16–20).
Risk factors for L-BM include female sex, younger age (particularly those < 30 years old), stage at diagnosis, larger primary tumor size, lymph node involvement, and adenocarcinoma phenotype (16, 18–21). Ceresoli and colleagues examined 112 patients with locally advanced NSCLC and found that L-BM were more common in patients <60 years old and in patients with bulky mediastinal lymph nodes, which they defined as greater than two centimeters in size (17). Bajard and colleagues showed similar findings, along with a particularly high risk among patients < 30 years (22).
At diagnosis, approximately 26% of patients with stage IV NSCLC had L-BM (23). While L-BM can define stage IV NSCLC disease, patients with stage I-III disease are not necessarily spared for a future L-BM diagnosis, with reported incidences of 25.6% for stage I/II and 19.3% for stage III disease (24). The cumulative five-year risk of L-BM increases with stage, ranging from 3.6% in stage I to 25% in stage III disease (25). Moreover, two relatively large cohort studies from the early 2000’s found a statistically significant correlation between the prevalence of L-BM over time if the primary tumor was large and lymph node staging was higher (22, 26). For this reason, patients with stage III or stage IV disease are recommended to receive a screening contrasted MRI of the brain at first diagnosis.
Transcriptomic landscapes of NSCLC brain metastases
Recent genomic and spatial transcriptomic studies have revealed that brain metastases arising from NSCLC frequently exhibit distinct molecular signatures compared to primary lung tumors and extracerebral metastatic sites. Brain metastases have been shown to demonstrate higher chromosomal instability and increased copy number variations (CNVs), particularly involving tumor suppressor loci such as CDKN2A/B, compared to primary tumors (34% vs. 13%, respectively) (27, 28). Spatial transcriptomic profiling of NSCLC primary and brain metastatic regions indicates that brain metastasis niches are characterized by upregulation of extracellular matrix (ECM) and cancer−associated fibroblast signatures, with gene otology (GO) analyses highlighting collagen–ECM–mediated signaling and fibrosis (29). Comparative expression analyses further reveal increased expression of metabolic pathways such as oxidative phosphorylation, glycolysis, fatty−acid metabolism, hypoxia responses, angiogenesis, and PI3K/AKT/mTOR signaling in brain metastases relative to earlier−stage primary tumors, which is consistent with metabolic reprogramming to support survival in the CNS microenvironment (30). Brain metastatic cells also display transcriptional adaptations that reflect close interaction with neural and glial components. Multi−cancer brain metastasis studies suggest that tumor cells in the brain partially adopt neural−like phenotypes to thrive intracranially, an adaptation less evident in non−CNS metastatic sites (29, 31). Together, these data suggest that CNS lesions harbor a unique immune and metabolic landscape not observed in metastatic lesions in other organs (ex. liver, bone, or other extracerebral metastases).
Genetic drivers of NSCLC and L-BM prognosis
While NSCLC brain metastases demonstrate a broad spectrum of unique genomic and transcriptomic alterations, a subset of well-characterized molecular subtypes remain central to understanding the clinical behavior, therapeutic vulnerabilities, and prognosis of CNS disease in lung cancer. Among the principal oncogenic drivers of NSCLC, mutations in KRAS and EGFR as well as rearrangements of ALK and ROS1 are the most prevalent (4). Among all subtypes, patients with EGFR- and ALK-driven L-BM have a more favorable prognosis in the context of CNS-penetrant targeted therapies (32).
KRAS mutated
The KRAS gene is the most commonly mutated oncogene in NSCLC, accounting for nearly 30% of all cases (33, 34). KRAS proteins are activated by growth factors (ex. EGF, PDGF, FGF), chemokines, Ca2+, or receptor tyrosine kinases (RTKs) and can activate downstream effector pathways such as the RAF- MEK- ERK signaling pathway and PI3K- AKT pathway to promote cell growth and proliferation (34, 35). About 90% of KRAS mutations are found in codon 12, with G12C mutations being most prevalent (39-42%), followed by G12V mutations (19%) and G12D (17%) (33, 36). Distributions of KRAS mutations have been well-documented and shown to vary among race, sex, and smoking status. Specifically, KRAS mutations are linked to Caucasian ethnicity (26% in Caucasians vs. 11% in Asians), female sex (31.35% in females vs. 23.7% in males), adenocarcinoma histology (37.2% in adenocarcinomas vs. 4.4% in squamous cell carcinomas), and a history of smoking, where G12C mutations had the highest rate of current smokers at 43% and G12D mutations were common among never or light smokers (33, 36). The KRAS mutation frequently coexists with changes in other significant cancer-related pathways, including TP53, STK11, and KEAP1 in 10.3–28.0%, 6.3–23.0%, and 17.8–50.0% of patients, respectively (37). Importantly, a large cohort study of 899 patients with stage IV NSCLC found that there was no significant difference in the incidence of brain metastases in patients with the G12C mutation than those without (37.2% vs. 33.5%, p=0.26), suggesting that brain metastases are common in KRAS-mutant NSCLC regardless of KRAS subtype, and concurrent mutations in TP53, STK11, and KEAP1 may further exacerbate the treatment resistance observed in these patients (38).
The KRAS protein has been historically deemed as “undruggable”; however, recent advancements in targeted therapies have resulted in the successful development of two drugs in 2022: sotorasib and adagrasib. By binding to the KRAS G12C cysteine residue and locking the abnormal receptor in an inactive conformation, these drugs prevent oncogenic signaling and cell proliferation, leading to potent tumor regression (39).
The CodeBreaK 200 trial, published in 2023, was the first Phase III randomized trial to demonstrate improved outcomes for a KRAS G12C inhibitor. Sotorasib demonstrated superior progression-free survival (PFS) versus docetaxel (mitotic inhibitor), and importantly, intracranial efficacy was observed in a subset of patients (33.3% vs. 15.4%), despite the exclusion of those with active brain metastases at enrollment. Similarly, adagrasib also achieved significant CNS penetration and efficacy. In patients with untreated, asymptomatic brain metastases, adagrasib demonstrated promising CNS penetration, as evidenced by an objective response rate (ORR) of 42% in the KRYSTAL-1 trial published in 2023 (40). The KRYSTAL-12 trial, part of ongoing KRYSTAL-2 program, presented in 2023, has confirmed PFS and ORR benefits over docetaxel in KRAS G12C-mutant NSCLC (see Table 1). The ongoing KRYSTAL-7 trial is further investigating adagrasib in combination with checkpoint inhibitors such as pembrolizumab. The Phase II cohort demonstrated that PD-L1 positive patients achieved a tumor proportion score (TPS) ≥50%, and the combination achieved an ORR of 63% and a disease control rate of 84%, supporting the potential benefit of combining adagrasib with checkpoint inhibitors to improve outcomes (41). See Table 1 for key trial efficacy data.
Table 1. A comparison of key NSCLC clinical trials by mutation, treatment, and efficacy outcomes.
EGFR mutated
Epidermal growth factor receptor (EGFR) a transmembrane tyrosine kinase of the ErbB/HER family, homodimerizes and autophosphorylates to activate pro-tumorigenic Ras, PI3K, and JAK pathways (42, 43). EGFR mutations in NSCLC are more common in East Asians, women, and nonsmokers (44–46), and are associated with a higher risk of CNS metastasis (47). Both the L858R point mutation and exon 19 deletion subtypes of EGFR mutations exhibit a significantly higher risk of L-BM, with a comparable incidence observed between the two (39.5% vs. 34.5%, p=0.770) (48). Multiple studies have shown an association with EGFR mutation status and L-BM based on circulating tumor DNA in serum and cerebrospinal fluid (CSF) (49, 50). EGFR mutations in cerebrospinal fluid were found in 57% of patients with L-BM, and in 81% of these patients who had leptomeningeal disease (LMD), suggesting diagnostic and prognostic purposes in this space (51, 52).
From the United States, a meta-analysis of 68 studies shows an EGFR mutation prevalence of 24% with significant impact on life expectancy (53, 54). A large-scale Chinese data analysis showed higher EGFR mutation rates among stage IA than in stages IIB and IIIA (55). Patients with early-stage NSCLC and EGFR mutations had shorter disease-free survival, an increased risk of disease recurrence, lymphovascular invasion, intrapulmonary metastasis, lymph node involvement, and distant metastasis in early-stage lung cancer (46). Cumulative incidence of L-BM is likely 40% higher among EGFR mutated NSCLC and is associated with worse survival (56).
Three generations of EGFR-TKIs have been approved for NSCLC patients (57). First-generation (gefitinib, erlotinib, and icotinib) and second-generation (afatinib and dacomitinib) irreversible small molecule inhibitors have exhibited robust and durable responses in patients with Ex19del and L858R mutations (57). However, most patients eventually develop acquired resistance to EGFR targeted therapy within 9–14 months, with the T790M mutation most commonly found (58, 59). Most recurrences post-use of first- and second-generation EGFR inhibitors are in the CNS since they do not have CNS efficacy. Fortunately, osimertinib, an irreversible third-generation EGFR inhibitor, effectively overcomes the T790M resistance mutations while also offering higher selectivity, lower toxicity, and improved blood-brain barrier (BBB) penetration (57). The FLAURA trial demonstrated that first-line osimertinib significantly improved median PFS and with lower rates of adverse effects among patients with L-BM compared to earlier generation EGFR-TKIs (60). Moreover, these benefits were sustained regardless of T790M status (61, 62), because of CNS penetration of Osimertinib (63). However, if given as first line treatment and dose is de-escalated to reduce adverse events, osimertinib can promote L-BM or exacerbate the incidence if already an L-BM patient (64).
Combination strategies have further improved CNS control and survival outcomes in EGFR-mutated lung cancer. The FLAURA2 study, published in 2023, showed that the combination of osimertinib and chemotherapy improved PFS and OS compared to osimertinib monotherapy in stage IV EGFR-mutated lung cancer (65). Subsequently, in the MARIPOSA study using amivantamab + lazertinib has shown similarly improved efficacy in patients with CNS metastasis compared to osimertinib alone, including a significantly prolonged PFS, OS, and DOR while maintaining intracranial objective response rates in patients that harbored the exon 19 deletion or exon 21 L858R substitution mutation (66). This led to amivantanab + lazertinib being recognized as a new first-line treatment for EGFR-mutated NSCLC. More recently, patritumab deruxtecan (HER3-DXd), the first HER3-directed antibody drug conjugated with deruxtecan payload designed to minimize systemic toxicity, demonstrated notable CNS activity in patients with EGFR-mutated non-small cell lung cancer with brain metastases. In this phase II trial (HERTHENA-Lung01), an intracranial ORR of 33.3% and a CNS DOR of 8.4 months was observed, opening a new HER-3 mediated therapeutic avenue for EGFR-mutated NSCLC patients (67). A pooled analysis of the TROPION-Lung05 (phase 2) and TROPION-Lung01 (phase 3) trials has shown that after progression on osimertinib, the datopotamab-deruxtecan combination (Dato-DXd) exhibits encouraging and durable antitumor activity (68). Most recently, early data from the SAVANNAH II, trial demonstrated that the combination of osimertinib plus savolitinib resulted in clinically meaningful and durable efficacy for MET-mediated resistance with CNS efficacy in NSCLC (69).
Additionally, multiple trials have shown efficacy of combinatorial treatments utilizing EGFR-TKI’s, chemotherapy, and immunotherapy (43). For example, EGFR-TKI and VEGF-inhibitors have been shown to delay T790M-mediated resistance compared with single-agent EGFR-TKI and resulted in tumor regression in L858R/T790M-positive tumors (43). All of these studies represent recent advances (2023-2025) in the evolving treatment landscape for EGFR-mutated NSCLC, demonstrating a meaningful shift toward molecular targeted therapies to address CNS involvement. Detailed efficacy data from these trials are summarized in Table 1.
ALK rearranged
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase in the insulin receptor family. Homodimerization of ALK activates multiple cell proliferation pathways, including PLC-gamma, JAK-STAT, and mTOR (70). ALK rearrangements occur in approximately 5% of NSCLC cases and result in constitutively active fusion proteins that drive tumor growth (71, 72). In NSCLC, the most prevalent ALK rearrangements include the echinoderm microtubule-associated protein like 4 (EML4) fusion with ALK (EML4-ALK) resulting from a paracentric inversion on chromosome 2p. The EML4-ALK fusion kinase has been implicated in tumorigenicity and driving oncogenesis in up to 6.7% of NSCLC and is commonly seen in Asian patients under the age of 50, with a light-smoking or non-smoking history (73, 74).
Clinically, pathogenic ALK rearrangements are not only significant in guiding treatment options but also in their association with brain metastases (75–77). ALK rearranged disease harbors a 23.8% risk of L-BM at initial diagnosis and nearly 60% incidence of L-BM after three years (78). Multiple other studies have corroborated these findings, reporting ALK-positivity in 30-40% of patients with L-BM at time of diagnosis (51, 79–83). A study of 131 ALK-positive NSCLC patients found that those with ALK variant 1 (EML4-ALK fusion) had larger brain metastases compared to non-variant 1 patients (median size 16.89 mm vs. 11.01 mm, P = 0.031) and significantly shorter time to treatment failure than non-variant 1 with baseline L-BM when treated with first-line crizotinib (median TTF: 9.1 vs. 14.9 months, HR = 2.68, P = 0.037) (84).
The therapeutic landscape of ALK-positive NSCLC has evolved significantly over the past decade. In the PROFILE 1014 trial completed in 2014, crizotinib, the first-generation ALK inhibitor, demonstrated systemic efficacy in ALK-positive NSCLC, prolonging PFS and improving systemic ORR, establishing it as a new standard for systemic treatment of the disease. However, it’s limited CNS penetration (0.26%) resulted only in modest intracranial control (74% vs. 45%). While crizotinib primarily targets the EML4-ALK fusion, resistance mutations such as L1196M, G1269A, and G1202R further reduced its clinical efficacy (85–88). These mutations affect the ATP-binding pocket of the kinase domain, altering inhibitor binding and driving therapeutic resistance, thus prompting the need for more effective CNS therapies in this patient population (89).
Subsequent ALK inhibitors markedly improved treatment options by overcoming both the CNS penetration limitations and resistance mutations of crizotinib. Alectinib achieved an intracranial ORR of approximately 79% in patients with measurable brain metastases in the ALEX trial in 2018, and brigatinib produced a similar intracranial response rate of about 78% in the ALTA-1L trial in 2021, showing strong L-BM control. Alectinib and brigatinib also overcame several crizotinib resistance mutations, yet continued to present challenges with the G1202R mutation, which confers high-level resistance in brain metastases, contributing to CNS progression and treatment failure in ALK-positive patients (87, 90). Importantly, lorlatinib was developed to overcome to G120R resistance, and the CROWN trial completed in 2024 demonstrates that it achieved a significant CNS efficacy advantage, with an intracranial ORR of approximately 78%, in those with brain metastases and without, along with superior PFS compared to earlier ALK inhibitors (91–93). Lorlatinib’s potency against the G120R mutation makes it a highly effective treatment option in overcoming refractory brain metastases in ALK-positive lung cancer (90). Key data from these trials are summarized in Table 1.
However, despite advances in CNS-penetrant ALK inhibitors and their high intracranial response rates, later resistance frequently arises from activation of alternative oncogenic pathways in proto-oncogenes such as RET, EGFR, KRAS, NF1, IDH1, RIT1, ERBB2, BRAF, FGFR3, CREBBP, and NOTCH (94, 95). These off-target mechanisms enable tumor cells to bypass ALK dependency and sustain tumor growth and proliferation despite continued therapy, highlighting the continued need for molecular monitoring and the development of combination therapeutic strategies to achieve durable control in ALK-positive NSCLC (94, 96).
ROS1 mutated
The ROS1 proto-oncogene plays various roles in cellular signaling pathways associated with proliferation, cell growth, and survival. To date, there have been > 20 different ROS1 fusion proteins observed in NSCLC, with some variants more common than others. The five most common fusion with ROS1 are CD74 (49.8%), EZR (23.6%), SDC4 (9.1%), SLC34A2 (5.1%), and TPM3 (2.9%) (97–99).
Patients with ROS1-rearranged NSCLC have a common and significant risk of developing CNS metastases, although no clear increase in risk has been demonstrated specific to these fusion types (100). Several clinical factors are associated with a higher likelihood of harboring ROS1 fusions, including female sex, younger age, and those with early diagnosis of advanced stage NSLC (101). Among 103 patients with ROS1 mutations, 22% had L-BM at diagnosis while 30% developed L-BM later, with a median time to L-BM development of 12 months (98). Incidence of L-BM at initial diagnosis as high as 36% were reported in another study (102).
Crizotinib has achieved excellent systemic responses in treating ROS1-rearranged NSCLC, similar to its efficacy in ALK-positive disease, and was approved for ROS1 mutant NSCLC in 2016 (103). However, its effectiveness within the CNS was again limited due to poor BBB permeability. In 2019, Patil and colleagues showed that the CNS is a common first and sole site of progression in about 47% of ROS1 NSCLC patients on crizotinib (103). This frequent CNS progression occurred after 24 months of therapy, suggesting that L-BM, despite presenting at a low percentage at the initiation of crizotinib, can occur quite late in the course of treatment, and remains a major source of morbidity (103). This limited CNS efficacy has driven the development of next-generation ROS tyrosine kinase inhibitors such as entrectinib. An integrated analysis of the ALKA-372-001, STARTRK-1, and STARTRK-2 trials from 2022 showed that entrectinib achieved an intracranial ORR of about 80%, with a median intracranial DOR of 12.9 months and median intracranial PFS of 8.8 months in patients with baseline CNS metastases (104). In patients with CNS-only progression post-crizotinib, the intracranial efficacy of entrectinib was modest, with 11% of patients achieving a partial response and 22% achieving a stable response and decrease in tumor size (104). Still, entrectinib’s CNS penetration remains superior to crizotinib, supporting entrectinib as a standard option for ROS1 fusion-positive NSCLC with L-BM (104).
Current therapeutic approach: immunotherapy
Primary NSCLC tumors vary dramatically from L-BM lesions, although both reflect profound immunosuppressive environments. Some reports suggest that the immunosuppressive nature of primary NSCLC might contribute to L-BM (105, 106). Compared with L-BM, primary NSCLC tumors contain more lymphocytic and dendritic cell infiltrates, with no significant differences in macrophages compared to L-BM (105, 107, 108), which strongly correlates with poor prognosis (109, 110). PD-1 to PD-L1 interaction between T lymphocytes and tumor cells leads to immune quiescence, impairing the immune system’s ability to recognize and attack tumor cells. The ligand-receptor complex elicits various reactions including suppression of IL-2 synthesis required for T cell survival, differentiation, and self-tolerance (109, 110) as well as activation of Src homology region 2 domain containing phosphatase-2 (SHP2), which dephosphorylates T-cell receptor-associated CD3 and ZAP70 signalosomes thereby inhibiting cytokine secretion and attenuating cytokine-triggered signaling (111).
One important regulator of PD-L1 is the tumor suppressor gene p53, which is mutated in approximately 50% of NSCLC cases (111). Aberrant p53 expression associates with PD-L1 positivity, aggressive clinicopathologic features, and shorter survival in NSCLC (112, 113). PD-L1 expression is notably elevated KRAS-mutant and ALK-positive NSCLC, activating PI3K-AKT-mTOR and MEK-ERK signaling pathways implicated in metastatic spread and CNS tropism (114–118). Among KRAS mutations, the G12C subtype typically shows the highest rates of PD-L1 positivity (54%), compared to 46% for all KRAS mutations and 38% for the overall NSCLC population (119). Expression of the immune checkpoint PD-1 by cytological or histological analysis (120) has served a molecular biomarker of favorable response to immunotherapies, alone or in combination with standard of care or targeted therapies against the genetic drivers (121).
Like PD-L1, CTLA-4 also negatively regulates T-cell activation by binding to the co-stimulatory receptor CD28 on antigen-presenting cells and facilitating immunological tolerance (122). Therapeutic immune checkpoint inhibitor (ICI) antibodies prevent immune checkpoint interactions, thereby reversing immune cell avoidance and enhancing anti-tumor immunity (123). To date, the FDA has approved 6 ICIs consisting of 1) PD-1 inhibitors such as pembrolizumab, nivolumab, and cemiplimab, 2) PD-L1 inhibitors such as atezolizumab and durvalumab, and 3) a CTLA-4 inhibitor known as ipilimumab (102, 122, 124). ICI treatment indeed prolongs survival of L-BM patients, although prognosis becomes unfavorable with increasing L-BM lesion numbers and size (125–127).
While PD-L1 predicts ICI response and prognosis, evidence does not support a correlation between PD-L1 positivity and the risk of developing CNS metastases. ICIs benefit wildtype NSCLC (i.e. without genetic drivers) (121), and efficacy of ICI treatment of L-BM can be monitored through cerebrospinal fluid analysis for circulating PD-1+ T cells. In the context of the tumor cells, Lee and colleagues conducted a retrospective study of 270 patients in 2021 where PD-L1 positivity had similar two-year CNS progression rates compared to PD-L1-negative patients (26.3% vs. 28.4%, p = 0.944), and PD-L1 status did not affect CNS progression or overall survival in those with synchronous brain metastases (128). Another systematic review and meta-analysis of 230 patients performed by Tonse and colleagues in 2021 also reported PD-L1 discordance rates of approximately 20% between primary tumors and L-BM but did not identify PD-L1 as a determinant of CNS spread or prognosis (129).
The data demonstrating the efficiency of ICIs in NSCLC L-BM is limited, though studies have indicated significant survival advantages associated with ICIs. For instance, a pooled analysis of multiple trials (KEYNOTE-001, 010, 024, and 042) revealed that pembrolizumab extended overall survival (OS) compared to chemotherapy (13.4 months vs. 10.3 months, HR = 0.83) (102). Notably, in patients with PD-L1 expression ≥50%, the survival benefit was even greater (19.7 months vs. 9.7 months, HR = 0.67) (130). Similarly, a combined analysis of CheckMate-017 and 057 showed that nivolumab improved OS (7.6 months vs. 6.2 months, HR = 0.81) and the five-year OS rate (8% vs. 0%) compared to docetaxel (130). Cemiplimab, a recently approved anti-PD-1 agent, also showed enhanced progression-free survival (PFS) and OS in the BMs subgroup compared to platinum-based chemotherapy (130). Atezolizumab delayed onset of new BMs when compared to docetaxel, with median time to development of new BMs not reached at 9.3 months (HR = 0.38). The PACIFIC trial demonstrated that maintenance therapy with durvalumab following chemoradiotherapy significantly reduced the incidence of new BMs (6.5% vs. 11.8%) at five-year follow up (130). Collectively, these findings indicate that PD-L1 inhibitors offer significant survival advantages over traditional therapies. However, PD-L1 status does not appear to influence CNS metastatic spread, emphasizing the need for additional biomarkers in L-BM prediction.
Limitations in patient-centered outcomes
While advances in molecularly targeted agents and immune therapies have markedly improved systemic and CNS disease control in NSCLC brain metastases, key gaps remain in assessing patient-centered outcomes. Many trials report on systemic toxicities and drug related adverse-events, yet the overall quality-of-life (QoL) and neurocognitive profile of these treatments remains inadequately characterized - critical aspects that require further research to ensure truly patient-centered care.
For example, the FLAURA2 trial has cited similar safety outcomes among patients with baseline CNS lesions and the overall study population. It reports a doubling in the frequency of grade 3 or higher adverse events (AEs) (64% versus 29%), serious AEs (37% versus 22%), and fatal AEs (6% versus 3%) in the combination arm compared to the osimertibib monotherapy arm (131). HERTHENA-Lung01 (phase II, patritumab deruxtecan) documented hematologic side effects such as thrombocytopenia, neutropenia, anemia, and leukopenia. Yet, despite safety reporting, details on neurotoxicity, neurocognitive decline, or patient-reported QoL metrics are often limited or entirely absent (132). Among the few exceptions, the CROWN and ALTA-1L trials both incorporated patient-reported outcomes data using validated cancer-related quality of life questionnaires such as the EORTC and QLQ-C30. The ALTA-1L trial demonstrated that brigatinib significantly delayed the time to deterioration of global health status (GHS)/quality of life (QoL) compared to crizotinib in patients with advanced ALK-positive NSCLC (26.74 mo vs. 8.31 mo) (133). Similarly, CROWN showed that lorlatinib maintained or improved QoL, functioning, and symptom burden, yet had a higher incidence of adverse neurocognitive effects - cognitive, mood, psychotic, and speech related (134). Additionally, CodeBreaK 200 utilized multiple instruments (EORTC QLQ-C30, EORTC QLQ-LC1330, FACT-G, PRO-CTCAE) to assess patient perception of symptom burden, supporting that sotorasib may be a more tolerable option than docetaxel for KRAS-mutant NSCLC given the lesser severity of pain, muscle and joint aches, as well as reduced interference with daily activities (135).
Despite these efforts, comprehensive assessment of QoL and neurocognitive considerations in L-BM patients remains largely overlooked in clinical research. Several factors contribute this. For one, most clinical trials prioritize hard clinical outcomes and on efficacy via objective, quantifiable endpoints like progression-free survival, overall survival, response rate, and duration of response (136). Subjective experiences such as memory complaints and psychological wellbeing present a high degree of heterogeneity throughout the disease process, progression, and experience (136). The distinct brain pathology across etiologies and varying response to the disease process makes difficult to draw valid statistical and clinical inferences and raises the risk of misinterpreting intervention efficacy, disease progression, or functional status in patients (136).
Moreover, DiRisio and colleagues report discrepancies in the assessment of health-related quality of life among patients with brain metastases due to variability in the tools and approaches used. Many patient-reported outcome measures (PROMs), such as EORTC QLQ-30 and FACT-G- which have been employed in trials such as ALTA-1L and CodeBreaK 200 - were originally developed for general cancer populations, and do not adequately address the unique neurocognitive challenges experienced by L-BM patients (137). These tools often focus on capturing functional symptoms over cognitive impairments, resulting in insufficient quality of PROM data reporting for L-BM patients undergoing diverse treatment modalities (137).
Matsui and colleagues highlight that neurocognitive decline in BM patients is associated with significant reductions in QoL including memory and executive function deficits caused by both the tumor and treatments like whole-brain radiation therapy (WBRT), on-radiation treatments (chemotherapy, immunotherapy, surgery), additional medications (steroids, anti-depressants), and disease progression (138). While these therapies may prolong overall survival, they also increase the risk of complications and treatment-related adverse events, underscoring the importance of including a more comprehensive evaluation of treatment impact and disease progression to improve patient-centered care in patients with brain tumors and metastases.
Future directions
Emerging CNS-directed EGFR-targeted combinations
The future of treatment likely lies in combinatorial therapy for patients with L-BM. For example, a trial of carboplatin and pemetrexed in combination with lazertinib, a newer third-generation EGFR inhibitor, is ongoing (139). Lazertinib is also being investigated in combination with amivantamab, a dual EGFR and cMET inhibitor [NCT05746481]. Other novel third-generation EGFR inhibitors under study include almonertinib, keynatinib, rezivertinib, and alflutinib [NCT04965090].
Next-generation immunotherapy and bispecific checkpoint blockade
In the immunotherapy space, tiragolumab to the combination of carboplatin, pemetrexed, and atezolizumab in patients with NSCLC and untreated L-BMs (140). Tiragolumab, which targets TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain) provides another option for immune checkpoint inhibition beyond PD-1/PD-L1 or CTLA-4 (141). TIGIT inhibits T-cell activation by inhibiting stimulatory immune signaling from CD226 (141, 142). Candonilimab is a bispecific antibody that targets both PD-1 and CTLA-4 which may be less toxic than traditional combinatorial therapies like ipilimumab and nivolumab and is being trialed alone and in combination with chemotherapy and bevacizumab in patients with NSCLC and untreated L-BM (143, 144).
Antibody-drug conjugates and novel cytotoxic platforms
Chemotherapy treatment modalities are also evolving for better drug delivery. Patritumab deruxtecan, an antibody-drug conjugate (ADC), is currently being assessed for efficacy in patients with L-L-BM or leptomeningeal disease [NCT05477615][NCT04965090, NCT05746481] (140–142),. Recently approved for use against breast cancer, sacituzumab govitecan-hziy is also being trialed in NSCLC patients, including L-BM [NCT05812534].
Targeting DNA damage response pathways in L-BM
Furthermore, novel agents such as berzosertib, an inhibitor of ATR (ataxia telangiectasia and Rad3-related protein kinase) shows promise by disrupting DNA damage repair pathways. [NCT05865990]. Because of this mechanism, it is believed that berzosertib may synergize with chemotherapy and/or radiation with at least one study combining the drug with whole brain radiation (84) [NCT05865990].
Innovative CNS drug−delivery strategies
Therapeutic management of NSCLC brain metastases faces unique challenges due to the BBB, which restricts drug penetration and efficacy across all cancer types with CNS involvement. Advances in molecularly targeted therapies have introduced sequential generations of TKIs - such as osimertinib for EGFR, lorlatinib for ALK, and entrectinib for ROS1 – which exhibit enhanced BBB penetration and improved survival outcomes. However, CNS relapse remains common. Furthermore, resistance mechanisms - including mutation-dependent alterations in drug binding or increased ABC transporter activity - may further restrict drug efficacy at the BBB (145–147).
To address these challenges, several innovative strategies are under active investigation and early clinical translation. Approaches such as intranasal administration and intraventricular/intrathecal delivery can deliver peptides, proteins, and antibodies to the CNS within minutes while avoiding first-pass metabolism, enhancing therapeutic concentration at brain metastatic sites (148). Clinical and translational studies of intraventricular chemotherapy and immuno−/virotherapy show that delivering agents directly into the ventricles or CSF bypasses many BBB constraints and allows more targeted exposure of brain and leptomeningeal metastases to therapeutics (149, 150). Other modalities such as focused ultrasound with microbubbles can transiently disrupt the BBB, permitting higher drug entry into parenchyma, although long−term safety and standardization remain under investigation (151, 152). Emerging molecular “Trojan horse” and nanocarrier technologies exploit receptor-mediated transcytosis or transport systems such as transferrin receptor (TfR) and low−density lipoprotein receptor−related protein−1 (LRP1) to enhance CNS uptake of anticancer agents (153). In addition, pharmacological or genetic inhibition of efflux transporters such as P-glycoprotein represents another goal, though clinical efficacy remains to be demonstrated on a broad scale (154). Looking ahead, truly effective CNS disease management will likely depend on integrating these advanced drug delivery platforms with subtype-directed molecular therapies.
Integrating patient-reported outcomes in future trials
As molecular therapies continue to expand the treatment landscape for NSCLC-BM patients, future trials must expand beyond traditional endpoints such as progression-free survival and response rate to integrate patient-centered outcomes as a core component of clinical design. This includes the use of brain-tumor specific PROMs, such as Functional Assessment of Cancer Therapy-Brain (FACT-Br), Brain Neoplasm Module (EORTC QLQ-BN20), and the BC-Brain Patient Reported Outcome Questionnaire to evaluate the physical, social, emotional, and functional wellbeing specifically for brain tumor patients (155, 156). The FDA’s 2024 core-patient reported outcomes document recognizes the strong scientific rationale of incorporating PROMs into the benefit/risk assessment in clinical trials, along with standardized efficacy assessments using overall survival and tumor measures, to fully capture patient perspectives (157).
In addition to PROMs, objective neuropsychological evaluations should also be integrated into clinical trials, particularly those involving CNS-penetrating agents, along with long-term follow-up protocols (137). Together, these strategies will allow researchers to understand the durability of patient-centered benefits or harms as QoL and cognitive changes emerge and evolve over the course of the treatment.
Conclusions
Molecular biomarkers are central to guiding treatment for NSCLC and L-BM. Overall, studies agree that molecular variations in KRAS, EGFR, ALK, PD-L1, and ROS1 correlate with risk of L-BM and targeting these changes improve outcomes for patients with L-BM. Current clinical trials are increasingly, focusing on combining targeted therapy, immunotherapy, and traditional chemotherapy to enhance survival, overcome resistance mechanisms, and improve CNS drug penetration – one of the principal challenges in L-BM management. Future progress will depend on deeper integration of genomic and transcriptomic profiling, including comparative analyses of brain and extracranial metastases, to refine risk stratification. Importantly, as treatment efficacy improves, maintaining and improving quality of life (QoL) must also remain a central goal to ensure that extended survival is accompanied by preserved wellbeing. Such efforts will allow ultimately pave the way for effective, personalized treatment regimens, improving both quality of life and survival for patients with brain metastases from NSCLC.
Author contributions
MS: Data curation, Formal analysis, Writing – original draft. AS: Writing – original draft. KR-C: Writing – review & editing. GR: Validation, Writing – review & editing. BK: Writing – review & editing. GW: Conceptualization, Data curation, Supervision, Validation, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Siegel RL, Miller KD, Wagle NS, and Jemal A. Cancer statistics, 2023. CA Cancer J Clin. (2023) 73:17–48. doi: 10.3322/caac.21763
2. Li YS, Lai W, Yin K, Tu HY, Li L, Lin SH, et al. Cellular dynamics in cerebrospinal fluid unveils the key regulators of intracranial response to immune checkpoint inhibitors in NSCLC brain metastases. J Immunother Cancer. (2025) 13. doi: 10.1136/jitc-2025-012071
3. Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, et al. Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. (2011) 103:714–36. doi: 10.1093/jnci/djr077
4. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. (2015) 10:1243–60. doi: 10.1097/JTO.0000000000000630
5. Ostrom QT, Wright CH, and Barnholtz-Sloan JS. Brain metastases: epidemiology. Handb Clin Neurol. (2018) 149:27–42. https://doi.org/10.1016/B978-0-12-811161-1.00002-5
6. Berger A, Mullen R, Bernstein K, Alzate JD, Silverman JS, Sulman EP, et al. Extended survival in patients with non-small-cell lung cancer-associated brain metastases in the modern era. Neurosurgery. (2023) 93:50–9. doi: 10.1227/neu.0000000000002372
7. Cagney DN, Martin AM, Catalano PJ, Redig AJ, Lin NU, Lee EQ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic Malignancy: a population-based study. Neuro Oncol. (2017) 19:1511–21. doi: 10.1093/neuonc/nox077
9. Rudin CM, Brambilla E, Faivre-Finn C, and Sage J. Small-cell lung cancer. Nat Rev Dis Primers. (2021) 7:3. doi: 10.1038/s41572-020-00235-0
10. Molina JR, Yang P, Cassivi SD, Schild SE, and Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. (2008) 83:584–94. doi: 10.1016/S0025-6196(11)60735-0
11. Wu SY, Xing F, Sharma S, Wu K, Tyagi A, Liu Y, et al. Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. J Exp Med. (2020) 217, e20191131. doi: 10.1084/jem.20191131
12. Yuan C and Zheng H. Brain metastases in newly diagnosed lung cancer: epidemiology and conditional survival. Transl Cancer Res. (2024) 13:5417–28. doi: 10.21037/tcr-24-776
13. Waqar SN, Samson PP, Robinson CG, Bradley J, Devarakonda S, Du L, et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. (2018) 19:e373–9. doi: 10.1016/j.cllc.2018.01.007
14. Klos KJ and O’Neill BP. Brain metastases. Neurologist. (2004) 10:31–46. doi: 10.1097/01.nrl.0000106922.83090.71
16. Hubbs JL, Boyd JA, Hollis D, Chino JP, Saynak M, Kelsey CR, et al. Factors associated with the development of brain metastases: analysis of 975 patients with early stage nonsmall cell lung cancer. Cancer. (2010) 116:5038–46. doi: 10.1002/cncr.25254
17. Ceresoli GL, Reni M, Chiesa G, Carretta A, Schipani S, Passoni P, et al. Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment: risk factors analysis. Cancer. (2002) 95:605–12. doi: 10.1002/cncr.10687
18. Gaspar LE, Chansky K, Albain KS, Vallieres E, Rusch V, Crowley JJ, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol. (2005) 23:2955–61. doi: 10.1200/JCO.2005.08.026
19. Carolan H, Sun AY, Bezjak A, Yi QL, Payne D, Kane G, et al. Does the incidence and outcome of brain metastases in locally advanced non-small cell lung cancer justify prophylactic cranial irradiation or early detection? Lung Cancer. (2005) 49:109–15. doi: 10.1016/j.lungcan.2004.12.004
20. Robnett TJ, Machtay M, Stevenson JP, Algazy KM, and Hahn SM. Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol. (2001) 19:1344–9. doi: 10.1200/JCO.2001.19.5.1344
21. Schouten LJ, Rutten J, Huveneers HA, and Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. (2002) 94:2698–705. doi: 10.1002/cncr.10541
22. Bajard A, Westeel V, Dubiez A, Jacoulet P, Pernet D, Depierre A, et al. Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma. Lung Cancer. (2004) 45:317–23. doi: 10.1016/j.lungcan.2004.01.025
23. Sperduto PW, Yang TJ, Beal K, Pan H, Brown PD, Bangdiwala A, et al. Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA). JAMA Oncol. (2017) 3:827–31. doi: 10.1001/jamaoncol.2016.3834
24. Villano JL, Durbin EB, Normandeau C, Thakkar JP, Moirangthem V, Davis FG, et al. Incidence of brain metastasis at initial presentation of lung cancer. Neuro Oncol. (2015) 17:122–8. doi: 10.1093/neuonc/nou099
25. Dunne EG, Fick CN, Mastrogiacomo B, Tan KS, Toumbacaris N, Vanstraelen S, et al. Clinicopathologic and genomic features associated with brain metastasis after resection of lung adenocarcinoma. JTCVS Open. (2024) 22:458–69. doi: 10.1016/j.xjon.2024.09.030
26. Mujoomdar A, Austin JH, Malhotra R, Powell CA, Pearson GD, Raftopoulos H, et al. Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology. (2007) 242:882–8. doi: 10.1148/radiol.2423051707
27. Skakodub A, Walch H, Tringale KR, Eichholz J, Imber BS, Vasudevan HN, et al. Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis. Nat Commun. (2023) 14:4980. doi: 10.1038/s41467-023-40793-x
28. Li F, Sun L, and Zhang S. Acquirement of DNA copy number variations in non-small cell lung cancer metastasis to the brain. Oncol Rep. (2015) 34:1701–7. doi: 10.3892/or.2015.4188
29. Zhang Q, Abdo R, Iosef C, Kaneko T, Cecchini M, Han VK, et al. The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis. Nat Commun. (2022) 13:5983. doi: 10.1038/s41467-022-33365-y
30. Yi Y, Xu W, Yu H, Luo Y, Zeng F, Luo D, et al. Integrated multi-omics reveals glycolytic gene signatures of lung adenocarcinoma brain metastasis and the impact of Rac2 lactylation on immunosuppressive microenvironment. J Transl Med. (2025) 23:1193. doi: 10.1186/s12967-025-07207-6
31. You H, Baluszek S, and Kaminska B. Immune microenvironment of brain metastases-are microglia and other brain macrophages little helpers? Front Immunol. (2019) 10:1941. https://doi.org/10.3389/fifimmu.2019.01941
32. Lin CW, Huang KY, Lin CH, Hou MH, and Lin SH. Diverse clinical outcomes for the EGFR−mutated and ALK−rearranged advanced non−squamous non−small cell lung cancer. Oncol Lett. (2025) 29:125. doi: 10.3892/ol.2025.14872
33. Cascetta P, Marinello A, Lazzari C, Gregorc V, Planchard D, Bianco R, et al. KRAS in NSCLC: state of the art and future perspectives. Cancers (Basel). (2022) 14, 5430. doi: 10.3390/cancers14215430
34. Reita D, Pabst L, Pencreach E, Guerin E, Dano L, Rimelen V, et al. Direct targeting KRAS mutation in non-small cell lung cancer: focus on resistance. Cancers (Basel). (2022) 14, 1321. doi: 10.3390/cancers14051321
35. Huang L, Guo Z, Wang F, and Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Targ Ther. (2021) 6:386. doi: 10.1038/s41392-021-00780-4
36. Judd J, Abdel Karim N, Khan H, Naqash AR, Baca Y, Xiu J, et al. Characterization of KRAS mutation subtypes in non-small cell lung cancer. Mol Cancer Ther. (2021) 20:2577–84. doi: 10.1158/1535-7163.MCT-21-0201
37. Lim TKH, Skoulidis F, Kerr KM, Ahn MJ, Kapp JR, Soares FA, et al. KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing. Lung Cancer. (2023) 184:107293. doi: 10.1016/j.lungcan.2023.107293
38. Lamberti G, Aizer A, Ricciuti B, Alessi JV, Pecci F, Tseng SC, et al. Incidence of brain metastases and preliminary evidence of intracranial activity with sotorasib in patients with KRAS(G12C)-mutant non-small-cell lung cancer. JCO Precis Oncol. (2023) 7:e2200621. https://doi.org/10.1200/PO.22.00621
39. Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med. (2021) 384:2382–93. doi: 10.1056/NEJMoa2105281
40. Negrao MV, Spira AI, Heist RS, Jänne PA, Pacheco JM, Weiss J, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRAS(G12C)-mutated non-small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. (2023) 41:4472–7. doi: 10.1200/JCO.23.00046
41. Luo FX and Arter ZL. Adagrasib in KRYSTAL-12 has broken the KRAS (G12C) enigma code in non-small cell lung carcinoma. Lung Cancer (Auckl). (2024) 15:161–7. https://doi.org/10.2147/LCTT.S490942
42. Ji Z, Bi N, Wang J, Hui Z, Xiao Z, Feng Q, et al. Risk factors for brain metastases in locally advanced non-small cell lung cancer with definitive chest radiation. Int J Radiat Oncol Biol Phys. (2014) 89:330–7. doi: 10.1016/j.ijrobp.2014.02.025
43. Johnson M, Garassino MC, Mok T, and Mitsudomi T. Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: Focus on novel therapies. Lung Cancer. (2022) 170:41–51. doi: 10.1016/j.lungcan.2022.05.011
44. Bell DW, Brannigan BW, Matsuo K, Finkelstein DM, Sordella R, Settleman J, et al. Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms. Clin Cancer Res. (2008) 14:4079–84. doi: 10.1158/1078-0432.CCR-07-5030
45. Matsuo K, Ito H, Yatabe Y, Hiraki A, Hirose K, Wakai K, et al. Risk factors differ for non-small-cell lung cancers with and without EGFR mutation: assessment of smoking and sex by a case-control study in Japanese. Cancer Sci. (2007) 98:96–101. doi: 10.1111/j.1349-7006.2006.00347.x
46. Park HK, Choi YD, Yun JS, Song SY, Na KJ, Yoon JY, et al. Genetic alterations and risk factors for recurrence in patients with non-small cell lung cancer who underwent complete surgical resection. Cancers (Basel). (2023) 15, 5679. doi: 10.3390/cancers15235679
47. Han G, Bi J, Tan W, Wei X, Wang X, Ying X, et al. A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma: is EGFR mutation associated with a higher incidence of brain metastasis? Oncotarget. (2016) 7:56998–7010. doi: 10.18632/oncotarget.10933
48. Hsiao SH, Chou YT, Lin SE, Hsu RC, Chung CL, Kao YR, et al. Brain metastases in patients with non-small cell lung cancer: the role of mutated-EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination. Oncotarget. (2017) 8:53405–18. doi: 10.18632/oncotarget.18509
49. Tan CS, Gilligan D, and Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. (2015) 16:e447–59. doi: 10.1016/S1470-2045(15)00246-6
50. Sharma SV, Bell DW, Settleman J, and Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. (2007) 7:169–81. doi: 10.1038/nrc2088
51. Yang P, Kulig K, Boland JM, Erickson-Johnson MR, Oliveira AM, Wampfler J, et al. Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol. (2012) 7:90–7. doi: 10.1097/JTO.0b013e31823c5c32
52. Griesinger F, Roeper J, Pottgen C, Willborn KC, and Eberhardt WEE. Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms. Oncotarget. (2018) 9:35181–94. doi: 10.18632/oncotarget.26073
53. Alexander M, Kim SY, and Cheng H. Update 2020: management of non-small cell lung cancer. Lung. (2020) 198:897–907. doi: 10.1007/s00408-020-00407-5
54. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. (2010) 16:5873–82. doi: 10.1158/1078-0432.CCR-10-1588
55. Ito M, Miyata Y, Tsutani Y, Ito H, Nakayama H, Imai K, et al. Positive EGFR mutation status is a risk of recurrence in pN0–1 lung adenocarcinoma when combined with pathological stage and histological subtype: A retrospective multi-center analysis. Lung Cancer. (2020) 141:107–13. doi: 10.1016/j.lungcan.2020.01.018
56. Hsu F, De Caluwe A, Anderson D, Nichol A, Toriumi T, and Ho C. EGFR mutation status on brain metastases from non-small cell lung cancer. Lung Cancer. (2016) 96:101–7. doi: 10.1016/j.lungcan.2016.04.004
57. Fu K, Xie F, Wang F, and Fu L. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J Hematol Oncol. (2022) 15:173. doi: 10.1186/s13045-022-01391-4
58. Westover D, Zugazagoitia J, Cho BC, Lovly CM, and Paz-Ares L. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. (2018) 29:i10–9. doi: 10.1093/annonc/mdx703
59. Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ, Yang PC, et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. (2016) 7:12404–13. doi: 10.18632/oncotarget.7189
60. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. (2018) 378:113–25. doi: 10.1056/NEJMoa1713137
61. Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. (2011) 17:1616–22. doi: 10.1158/1078-0432.CCR-10-2692
62. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. (2013) 19:2240–7. doi: 10.1158/1078-0432.CCR-12-2246
63. Cooper AJ, Sequist LV, and Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol. (2022) 19:499–514. doi: 10.1038/s41571-022-00639-9
64. Tozuka T, Noro R, Miyanaga A, Nakamichi S, Takeuchi S, Matsumoto M, et al. Osimertinib early dose reduction as a risk to brain metastasis control in EGFR-mutant non-small cell lung cancer. Cancer Med. (2023) 12:17731–9. doi: 10.1002/cam4.6393
65. Gautam Roy P, Reingold D, Pathak N, Verma S, Gupta A, Meti N, et al. Recent advances in the management of EGFR-mutated advanced non-small cell lung cancer-A narrative review. Curr Oncol. (2025) 32, 448. doi: 10.3390/curroncol32080448
66. Canadian Agency for Drugs and Technologies in Health. CADTH Reimbursement Reviews and Recommendations, in Lazertinib and Amivantamab (Lazcluze and Rybrevant): Indication: For the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations: Reimbursement Recommendation. 2025, Canadian Agency for Drugs and Technologies in Health: Ottawa (ON).
67. Arter ZL and Nagasaka M. Spotlight on patritumab deruxtecan (HER3-DXd) from HERTHENA lung01. Is a median PFS of 5.5 months enough in light of FLAURA-2 and MARIPOSA? Lung Cancer (Auckl). (2024) 15:115–21. https://doi.org/10.2147/LCTT.S467169
68. Ahn MJ, Lisberg A, Goto Y, Sands J, Hong MH, Paz-Ares L, et al. A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC. J Thorac Oncol. (2025) 20:1669–82. doi: 10.1016/j.jtho.2025.06.002
69. de Marinis F, Kim TM, Bonanno L, Cheng S, Kim SW, Tiseo M, et al. Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification following disease progression on osimertinib: primary results from the phase II SAVANNAH study. Ann Oncol. (2025) 36:920–33. doi: 10.1016/j.annonc.2025.04.003
70. Della Corte CM, Viscardi G, Di Liello R, Fasano M, Martinelli E, Troiani T, et al. Role and targeting of anaplastic lymphoma kinase in cancer. Mol Cancer. (2018) 17:30. doi: 10.1186/s12943-018-0776-2
71. Javanmardi N, Fransson S, Djos A, Sjöberg RM, Nilsson S, Truvé K, et al. Low frequency ALK hotspots mutations in neuroblastoma tumours detected by ultra-deep sequencing: implications for ALK inhibitor treatment. Sci Rep. (2019) 9:2199. doi: 10.1038/s41598-018-37240-z
72. Berlak M, Tucker E, Dorel M, Winkler A, McGearey A, Rodriguez-Fos E, et al. Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells. Mol Cancer. (2022) 21:126. doi: 10.1186/s12943-022-01583-z
73. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. (2007) 448:561–6. doi: 10.1038/nature05945
74. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. (2014) 371:1963–71. doi: 10.1056/NEJMoa1406766
75. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. (2014) 371:2167–77. doi: 10.1056/NEJMoa1408440
76. Fang DD, Zhang B, Gu Q, Lira M, Xu Q, Sun H, et al. HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. J Thorac Oncol. (2014) 9:285–94. doi: 10.1097/JTO.0000000000000087
77. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. (2016) 17:234–42. doi: 10.1016/S1470-2045(15)00488-X
78. Bearz A, De Carlo E, Del Conte A, Spina M, Da Ros V, Bertoli E, et al. The change in paradigm for NSCLC patients with EML4-ALK translocation. Int J Mol Sci. (2022) 23, 7322. doi: 10.3390/ijms23137322
79. Wang BX, Ou W, Mao XY, Liu Z, Wu HQ, and Wang SY. Impacts of EGFR mutation and EGFR-TKIs on incidence of brain metastases in advanced non-squamous NSCLC. Clin Neurol Neurosurg. (2017) 160:96–100. doi: 10.1016/j.clineuro.2017.06.022
80. Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. (2015) 88:108–11. doi: 10.1016/j.lungcan.2015.01.020
81. Tan L, Wu Y, Ma X, Yan Y, Shao S, Liu J, et al. A comprehensive meta-analysis of association between EGFR mutation status and brain metastases in NSCLC. Pathol Oncol Res. (2019) 25:791–9. doi: 10.1007/s12253-019-00598-0
82. Karimpour M, Ravanbakhsh R, Maydanchi M, Rajabi A, Azizi F, and Saber A. Cancer driver gene and non-coding RNA alterations as biomarkers of brain metastasis in lung cancer: A review of the literature. BioMed Pharmacother. (2021) 143:112190. doi: 10.1016/j.biopha.2021.112190
83. Fallet V, Cadranel J, Doubre H, Toper C, Monnet I, Chinet T, et al. Prospective screening for ALK: clinical features and outcome according to ALK status. Eur J Cancer. (2014) 50:1239–46. doi: 10.1016/j.ejca.2014.02.001
84. Qiao M, Zhao C, Liu Q, Wang Y, Shi J, Ng TL, et al. Impact of ALK variants on brain metastasis and treatment response in advanced NSCLC patients with oncogenic ALK fusion. Transl Lung Cancer Res. (2020) 9:1452–63. doi: 10.21037/tlcr-19-346
85. Sakamoto H, Yanagitani N, Manabe R, Tsugitomi R, Ogusu S, Tozuka T, et al. Characteristics of central nervous system progression in non-small cell lung cancer treated with crizotinib or alectinib. Cancer Rep (Hoboken). (2021) 4:e1414. doi: 10.1002/cnr2.1414
86. Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. (2016) 34:2858–65. doi: 10.1200/JCO.2015.63.5888
87. Cheon SY and Kwon S. Molecular anatomy of the EML4-ALK fusion protein for the development of novel anticancer drugs. Int J Mol Sci. (2023) 24, 5821. doi: 10.3390/ijms24065821
88. Nagasundaram N, Wilson Alphonse CR, Samuel Gnana PV, and Rajaretinam RK. Molecular dynamics validation of crizotinib resistance to ALK mutations (L1196M and G1269A) and identification of specific inhibitors. J Cell Biochem. (2017) 118:3462–71. doi: 10.1002/jcb.26004
89. Pan Y, Deng C, Qiu Z, Cao C, and Wu F. The resistance mechanisms and treatment strategies for ALK-rearranged non-small cell lung cancer. Front Oncol. (2021) 11:713530. doi: 10.3389/fonc.2021.713530
90. Nelson TA and Wang N. Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease. Transl Lung Cancer Res. (2023) 12:379–92. doi: 10.21037/tlcr-22-638
91. Solomon BJ, Bauer TM, Ou SH, Liu G, Hayashi H, Bearz A, et al. Post hoc analysis of lorlatinib intracranial efficacy and safety in patients with ALK-positive advanced non-small-cell lung cancer from the phase III CROWN study. J Clin Oncol. (2022) 40:3593–602. doi: 10.1200/JCO.21.02278
92. Camidge DR, Sugawara S, Kondo M, Kim HR, Ahn MJ, Yang JCH, et al. Efficacy and safety of brigatinib in patients with ALK TKI-naive advanced ALK+ NSCLC: Integrated analysis of the ALTA-1L and J-ALTA trials. Lung Cancer. (2025) 201:108424. doi: 10.1016/j.lungcan.2025.108424
93. Zou Z, Xing P, Hao X, Wang Y, Song X, Shan L, et al. Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study. BMC Med. (2022) 20:12. doi: 10.1186/s12916-021-02207-x
94. McCoach CE, Le AT, Gowan K, Jones K, Schubert L, Doak A, et al. Resistance mechanisms to targeted therapies in ROS1(+) and ALK(+) non-small cell lung cancer. Clin Cancer Res. (2018) 24:3334–47. doi: 10.1158/1078-0432.CCR-17-2452
95. Liu C, Liu C, Liao J, Yin JC, Wu X, Zhao X, et al. Genetic correlation of crizotinib efficacy and resistance in ALK- rearranged non-small-cell lung cancer. Lung Cancer. (2022) 171:18–25. doi: 10.1016/j.lungcan.2022.07.011
96. Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. (2016) 7:78985–93. doi: 10.18632/oncotarget.12587
97. Gainor JF, Tseng D, Yoda S, Dagogo-Jack I, Friboulet L, Lin JJ, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol. (2017) 2017. doi: 10.1200/PO.17.00063
98. Park S, Ahn BC, Lim SW, Sun JM, Kim HR, Hong MH, et al. Characteristics and outcome of ROS1-positive non-small cell lung cancer patients in routine clinical practice. J Thorac Oncol. (2018) 13:1373–82. doi: 10.1016/j.jtho.2018.05.026
99. Li Z, Shen L, Ding D, Huang J, Zhang J, Chen Z, et al. Efficacy of crizotinib among different types of ROS1 fusion partners in patients with ROS1-rearranged non-small cell lung cancer. J Thorac Oncol. (2018) 13:987–95. doi: 10.1016/j.jtho.2018.04.016
100. Gendarme S, Bylicki O, Chouaid C, and Guisier F. ROS-1 fusions in non-small-cell lung cancer: evidence to date. Curr Oncol. (2022) 29:641–58. doi: 10.3390/curroncol29020057
101. Huang RSP, Haberberger J, Sokol E, Schrock AB, Danziger N, Madison R, et al. Clinicopathologic, genomic and protein expression characterization of 356 ROS1 fusion driven solid tumors cases. Int J Cancer. (2021) 148:1778–88. doi: 10.1002/ijc.33447
102. Bai Y, Yang W, Kasmann L, Sorich MJ, Tao H, and Hu Y. Immunotherapy for advanced non-small cell lung cancer with negative programmed death-ligand 1 expression: a literature review. Transl Lung Cancer Res. (2024) 13:398–422. doi: 10.21037/tlcr-23-144
103. Patil T, Smith DE, Bunn PA, Aisner DL, Le AT, Hancock M, et al. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib. J Thorac Oncol. (2018) 13:1717–26. doi: 10.1016/j.jtho.2018.07.001
104. Drilon A, Smith DE, Bunn PA, Aisner DL, Le AT, Hancock M, et al. Long-term efficacy and safety of entrectinib in ROS1 fusion-positive NSCLC. JTO Clin Res Rep. (2022) 3:100332. doi: 10.1016/j.jtocrr.2022.100332
105. Liu JS, Cai YX, He YZ, Xu J, Tian SF, and Li ZQ. Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC. BMC Cancer. (2024) 24:123. doi: 10.1186/s12885-024-11875-w
106. Li YD, Lamano JB, Lamano JB, Quaggin-Smith J, Veliceasa D, Kaur G, et al. Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. Cancer Immunol Immunother. (2019) 68:1501–13. doi: 10.1007/s00262-019-02384-y
107. Shi W, Li X, Porter JL, Ostrodi DH, Yang B, Li J, et al. Level of plasmacytoid dendritic cells is increased in non-small cell lung carcinoma. Tumor Biol. (2014) 35:2247–52. doi: 10.1007/s13277-013-1297-7
108. Ikarashi D, Okimoto T, Shukuya T, Onagi H, Hayashi T, Sinicropi-Yao SL, et al. Comparison of tumor microenvironments between primary tumors and brain metastases in patients with NSCLC. JTO Clin Res Rep. (2021) 2:100230. doi: 10.1016/j.jtocrr.2021.100230
109. Sorensen SF, Zhou W, Dolled-Filhart M, Georgsen JB, Wang Z, Emancipator K, et al. PD-L1 expression and survival among patients with advanced non-small cell lung cancer treated with chemotherapy. Transl Oncol. (2016) 9:64–9. doi: 10.1016/j.tranon.2016.01.003
110. Eichhorn F, Kriegsmann M, Klotz LV, Kriegsmann K, Muley T, Zgorzelski C, et al. Prognostic impact of PD-L1 expression in pN1 NSCLC: A retrospective single-center analysis. Cancers (Basel). (2021) 13, 641–58. doi: 10.3390/cancers13092046
111. Mogi A and Kuwano H. TP53 mutations in nonsmall cell lung cancer. J BioMed Biotechnol. (2011) 2011:583929. doi: 10.1155/2011/583929
112. Cha YJ, Kim HR, Lee CY, Cho BC, and Shim HS. Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status. Lung Cancer. (2016) 97:73–80. doi: 10.1016/j.lungcan.2016.05.001
113. Qu A, Han J, and Zhu J. Prognostic value of PD-1, PD-L1 and P53 in patients with non-small cell lung cancer after postoperative adjuvant chemoradiotherapy. Am J Transl Res. (2022) 14:4709–18.
114. Lamberti G, Sisi M, Andrini E, Palladini A, Giunchi F, Lollini PL, et al. The mechanisms of PD-L1 regulation in non-small-cell lung cancer (NSCLC): which are the involved players? Cancers (Basel). (2020) 12, B. doi: 10.3390/cancers12113129
115. Chang GC, Yang TY, Chen KC, Hsu KH, Huang YH, Su KY, et al. ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Sci Rep. (2020) 10:21063. doi: 10.1038/s41598-020-78152-1
116. Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res. (2015) 21:4014–21. doi: 10.1158/1078-0432.CCR-15-0016
117. D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. (2015) 112:95–102. doi: 10.1038/bjc.2014.555
118. Hong S, Chen N, Fang W, Zhan J, Liu Q, Kang S, et al. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology. (2016) 5:e1094598. doi: 10.1080/2162402X.2015.1094598
119. Frost MG, Jensen KJ, Gotfredsen DR, Sorensen AMS, Ankarfeldt MZ, Louie KS, et al. KRAS G12C mutated advanced non-small cell lung cancer (NSCLC): Characteristics, treatment patterns and overall survival from a Danish nationwide observational register study. Lung Cancer. (2023) 178:172–82. doi: 10.1016/j.lungcan.2023.02.021
120. Ekin Z, Nart D, Savaş P, and Veral A. Comparison of PD-L1, EGFR, ALK, and ROS1 status between surgical samples and cytological samples in non-small cell lung carcinoma. Balk Med J. (2021) 38:287–95. doi: 10.5152/balkanmedj.2021.20086
121. Sheng J, Li H, Yu X, Yu S, Chen K, Pan G, et al. Efficacy of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer and brain metastases: A real-world retrospective study in China. Thorac Cancer. (2021) 12:3019–31. doi: 10.1111/1759-7714.14171
122. Seidel JA, Otsuka A, and Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. (2018) 8:86. doi: 10.3389/fonc.2018.00086
123. Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, et al. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer. (2024) 23:108. doi: 10.1186/s12943-024-02023-w
124. Zanello A, Bortolotti M, Maiello S, Bolognesi A, and Polito L. Anti-PD-L1 immunoconjugates for cancer therapy: Are available antibodies good carriers for toxic payload delivering? Front Pharmacol. (2022) 13:972046. doi: 10.3389/fphar.2022.972046
125. Qiao M, Zhou F, Hou L, Li X, Zhao C, Jiang T, et al. Efficacy of immune-checkpoint inhibitors in advanced non-small cell lung cancer patients with different metastases. Ann Transl Med. (2021) 9:34. doi: 10.21037/atm-20-1471
126. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. (2018) 378:2288–301. doi: 10.1056/NEJMoa1716948
127. Săftescu S, Negru Ş, Volovăţ S, Popovici D, Chercota V, Stanca S, et al. Predictors of the response to nivolumab immunotherapy in the second or subsequent lines for metastatic non-small cell lung cancers. Exp Ther Med. (2021) 21:605. https://doi.org/10.3892/etm.2021.10037
128. Lee K, Choi YJ, Kim JS, Kim DS, Lee SY, Shin BK, et al. Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications. Thorac Cancer. (2021) 12:2143–50. doi: 10.1111/1759-7714.14006
129. Tonse R, Rubens M, Appel H, Tom MC, Hall MD, Odia Y, et al. Systematic review and meta-analysis of PD-L1 expression discordance between primary tumor and lung cancer brain metastasis. Neurooncol Adv. (2021) 3:vdab166. doi: 10.1093/noajnl/vdab166
130. Yang G, Xing L, and Sun X. Navigate towards the immunotherapy era: value of immune checkpoint inhibitors in non-small cell lung cancer patients with brain metastases. Front Immunol. (2022) 13:852811. doi: 10.3389/fimmu.2022.852811
131. Sun F, Neal JW, and Myall NJ. FLAURA2: evidence for escalated first-line therapy in EGFR-mutated non-small cell lung cancer with central nervous system metastases. Transl Cancer Res. (2025) 14:3295–301. doi: 10.21037/tcr-2024-2589
132. Yu HA, Goto Y, Hayashi H, Felip E, Yang JC-H, Reck M, et al. HERTHENA-lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. (2023) 41:5363–75. doi: 10.1200/JCO.23.01476
133. Garcia Campelo MR, Lin HM, Zhu Y, Pérol M, Jahanzeb M, Popat S, et al. Health-related quality of life in the randomized phase III trial of brigatinib vs crizotinib in advanced ALK inhibitor-naive ALK + non-small cell lung cancer (ALTA-1L). Lung Cancer. (2021) 155:68–77. https://doi.org/10.1016/j.lungcan.2021.03.005
134. Mazieres J, Iadeluca L, Shaw AT, Solomon BJ, Bauer TM, de Marinis F, et al. Patient-reported outcomes from the randomized phase 3 CROWN study of first-line lorlatinib versus crizotinib in advanced ALK-positive non-small cell lung cancer. Lung Cancer. (2022) 174:146–56. doi: 10.1016/j.lungcan.2022.11.004
135. Waterhouse DM, Rothschild S, Dooms C, Mennecier B, Bozorgmehr F, Majem M, et al. Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation. Lung Cancer. (2024) 196:107921. doi: 10.1016/j.lungcan.2024.107921
136. Kolanowski A, Gilmore-Bykovskyi A, Hill N, Massimo L, and Mogle J. Measurement challenges in research with individuals with cognitive impairment. Res Gerontol Nurs. (2019) 12:7–15. doi: 10.3928/19404921-20181212-06
137. DiRisio AC, Harary M, van Westrhenen A, Nassr E, Ermakova A, Smith TR, et al. Quality of reporting and assessment of patient-reported health-related quality of life in patients with brain metastases: a systematic review. Neurooncol Pract. (2018) 5:214–22. doi: 10.1093/nop/npy024
138. Matsui JK, Perlow HK, Baiyee C, Ritter AR, Mishra MV, Bovi JA, et al. Quality of life and cognitive function evaluations and interventions for patients with brain metastases in the radiation oncology clinic. Cancers (Basel). (2022) 14, 4301. doi: 10.3390/cancers14174301
139. Roskoski R Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol Res. (2019) 139:395–411. doi: 10.1016/j.phrs.2018.11.014
140. Nagasaka M, Zhu VW, Lim SM, Greco M, Wu F, and Ou SI. Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC. J Thorac Oncol. (2021) 16:740–63. doi: 10.1016/j.jtho.2020.11.028
141. Cho BC, Abreu DR, Hussein M, Cobo M, Patel AJ, Secen N, et al. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol. (2022) 23:781–92. doi: 10.1016/S1470-2045(22)00226-1
142. Tang W, Chen J, Ji T, and Cong X. TIGIT, a novel immune checkpoint therapy for melanoma. Cell Death Dis. (2023) 14:466. doi: 10.1038/s41419-023-05961-3
143. Manieri NA, Chiang EY, and Grogan JL. TIGIT: A key inhibitor of the cancer immunity cycle. Trends Immunol. (2017) 38:20–8. doi: 10.1016/j.it.2016.10.002
144. Pang X, Huang Z, Zhong T, Zhang P, Wang ZM, Xia M, et al. Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity. MAbs. (2023) 15:2180794. doi: 10.1080/19420862.2023.2180794
145. Upton DH, Ung C, George SM, Tsoli M, Kavallaris M, and Ziegler DS. Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy. Theranostics. (2022) 12:4734–52. doi: 10.7150/thno.69682
146. Wu D, Chen Q, Chen X, Han F, Chen Z, and Wang Y. The blood-brain barrier: structure, regulation, and drug delivery. Signal Transduct Targ Ther. (2023) 8:217. doi: 10.1038/s41392-023-01481-w
147. Stewart DJ. Has the blood-brain barrier finally been busted? Oncologist. (2024) 29:645–7. https://doi.org/10.1093/oncolo/oyae131
148. Le Rhun E, O'Brien BJ, Pentsova E, Preusser M, Weller M, and Boire A. Point/Counterpoint: Intrathecal therapy for patients with leptomeningeal metastases from solid tumors. Neuro Oncol. (2025) 27:2225–31. doi: 10.1093/neuonc/noaf126
149. Gutova M, Flores L, Adhikarla V, Tsaturyan L, Tirughana R, Aramburo S, et al. Quantitative evaluation of intraventricular delivery of therapeutic neural stem cells to orthotopic glioma. Front Oncol. (2019) 9:68. doi: 10.3389/fonc.2019.00068
150. Zhao S, Sun P, Zhang X, Cao J, Nyalali AM, Hou Y, et al. Intraventricular medication with or without ventricular shunt for leptomeningeal metastases with different intracranial pressure: A single-center, large-scale retrospective study. World Neurosurg. (2025) 195:123544. doi: 10.1016/j.wneu.2024.12.003
151. Burgess A and Hynynen K. Drug delivery across the blood-brain barrier using focused ultrasound. Expert Opin Drug Delivery. (2014) 11:711–21. doi: 10.1517/17425247.2014.897693
152. Teleanu RI, Preda MD, Niculescu AG, Vladâcenco O, Radu CI, Grumezescu AM, et al. Current strategies to enhance delivery of drugs across the blood-brain barrier. Pharmaceutics. (2022) 14, 987. doi: 10.3390/pharmaceutics14050987
153. Pedder JH, Sonabend AM, Cearns MD, Michael BD, Zakaria R, Heimberger AB, et al. Crossing the blood-brain barrier: emerging therapeutic strategies for neurological disease. Lancet Neurol. (2025) 24:246–60. doi: 10.1016/S1474-4422(24)00476-9
154. Hu J and Kesari S. Strategies for overcoming the blood-brain barrier for the treatment of brain metastases. CNS Oncol. (2013) 2:87–98. doi: 10.2217/cns.12.37
155. Yan L, Nichol A, and Olson R. Validation of the BC-brain patient-reported outcome questionnaire for patients with central nervous system tumours treated with radiotherapy. Curr Oncol. (2022) 29:2798–807. doi: 10.3390/curroncol29040228
156. Dirven L, Vos ME, Walbert T, Armstrong TS, Arons D, van den Bent MJ, et al. Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative. Neurooncol Pract. (2021) 8:417–25. doi: 10.1093/nop/npab013
157. Office of CommunicationsDivision of drug information, editor. Food and Drug Administration: 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 (2024). Communications, O.o., Core Patient-Reported Outcomes in Cancer Clinical Trials Guidance for Industry, C.f.D.E.a.R.
Keywords: BBB penetration, brain metastases, molecular biomarkers, non-small cell lung cancer, patient-centered outcomes, targeted therapies
Citation: Sharma M, Shah A, Rivera-Caraballo KA, Raval G, Kaur B and Wallace IV GC (2026) Brain metastases from non-small cell lung cancer: molecular subtypes and emerging CNS-directed precision therapies. Front. Oncol. 16:1717432. doi: 10.3389/fonc.2026.1717432
Received: 10 October 2025; Accepted: 02 January 2026; Revised: 17 December 2025;
Published: 22 January 2026.
Edited by:
Guilhem Bousquet, Université Sorbonne Paris Nord, FranceReviewed by:
Hongru Li, Fujian Medical University, ChinaEurydice Angeli, Université Sorbonne Paris Nord, France
Copyright © 2026 Sharma, Shah, Rivera-Caraballo, Raval, Kaur and Wallace. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Gerald C. Wallace IV, Z2V3YWxsYWNlQGF1Z3VzdGEuZWR1