Central nervous system efficacy of third generation vs. first generation EGFR-TKIs in the first line treatment for EGFR-mutated non-small cell lung cancer with central nervous system metastases: a systematic review and meta-analysis of phase 3 randomized controlled trials

Abstract

Background

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastases poses significant treatment challenges, as first-generation EGFR-tyrosine kinase inhibitors (TKIs) (FGET) show limited CNS efficacy. Although third-generation EGFR-TKIs (TGET) exhibit superior CNS penetration, the optimal choice for first-line treatment remains debated. This meta-analysis aims to resolve this controversy by directly comparing the CNS efficacy of TGET vs. FGET in patients with EGFR-mutant NSCLC and CNS metastases.

Methods

A thorough literature search was performed for phase 3 randomized controlled trials (RCTs) comparing TGET and FGET in patients with EGFR-mutated NSCLC and CNS metastases. The primary outcome was CNS-progression-free survival (PFS), and secondary outcomes included overall survival (OS), PFS, CNS response rates, and adverse events (AEs). The study was registered in PROSPERO (ID: CRD42024629581).

Results

A total of 5 phase 3 RCTs (AENEAS, FLAURA, FURLONG, IBIO-103, and LASER301) met the inclusion criteria. TGET demonstrated superior efficacy in CNS-PFS [hazard ratio (HR): 0.44 (0.33, 0.58), P<0.001], PFS [HR: 0.44 (0.35, 0.54), P<0.001], CNS-objective response rate (ORR) [risk ratio (RR): 1.32 (1.15, 1.52), P<0.001], CNS-complete response (CR) [RR: 3.40 (1.39, 8.28), P=0.007], and CNS-duration of response (DOR) [HR: 0.39 (0.21, 0.73), P=0.003]. The CNS-PFS rate at 4–24 months and PFS at 10–24 months were significantly higher in the TGET group. OS data were available from only 2 of the 5 included phase 3 RCTs. In this analysis, OS numerically favored the TGET group but did not reach statistical significance [HR: 0.79 (0.55, 1.13), P=0.20]. At the cutoff time, more CNS progressions were found in the FGET [RR: 0.59 (0.44, 0.80), P=0.001]. Additionally, less grade 3–5 treatment-related AEs (TRAEs) were found in the TGET group [RR: 0.67 (0.46, 0.98), P=0.04].

Conclusions

TGET appeared to be better than FGET for patients with EGFR-mutated NSCLC and CNS metastases, showing improved survival, CNS efficacy, and safety.

Highlight box.

Key findings

• Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) (TGETs) significantly improved central nervous system (CNS) progression-free survival and reduced CNS progression risk compared with first-generation EGFR-TKIs (FGETs) in EGFR-mutated advanced non-small cell lung cancer (NSCLC). TGETs also improved progression-free survival, whereas overall survival (OS) benefits remain uncertain due to limited data availability.

What is known and what is new?

• TGETs have enhanced CNS activity and are increasingly used for EGFR-mutated NSCLC.

• This meta-analysis of randomized controlled trials provides updated evidence supporting the CNS and disease-control advantages of TGETs over FGETs, while highlighting limitations in OS and economic evidence.

What is the implication, and what should change now?

• TGETs should be considered the preferred EGFR-TKI option, particularly for patients with CNS involvement or high risk of CNS progression. Future studies with mature OS data and pharmacoeconomic evaluations are needed to define their long-term clinical and economic value.

Introduction

Among non-small cell lung cancer (NSCLC) patients, epidermal growth factor receptor (EGFR) mutations are commonly found (1). For EGFR-mutant NSCLC, first-line treatment usually involves first-generation EGFR-tyrosine kinase inhibitors (TKIs) (FGET), which are highly effective in treating the primary tumor and preventing extracranial metastases (2,3). However, despite their success in treating systemic disease, these agents have limited efficacy in addressing central nervous system (CNS) because of their inadequate penetration through the blood-brain barrier (BBB) (4). CNS metastases are significant causes of morbidity and mortality in EGFR-mutant NSCLC patients, with studies suggesting that up to 40% of patients develop brain metastases (5). CNS metastases are associated with poor prognosis, significantly decreasing quality of life and survival outcomes. Furthermore, the management of CNS metastases in EGFR-mutant NSCLC remains challenging, as these patients often develop resistance to first-line therapies, especially in the presence of resistance mutations such as T790M (6). Whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are often utilized for CNS metastases treatment, but they do not provide a cure and may contribute to neurocognitive decline, particularly in elderly patients (7). The development of more effective systemic therapies that can control both extracranial and intracranial disease has become an urgent clinical need.

The advent of third-generation EGFR-TKIs (TGET), such as Osimertinib, has provided a new therapeutic avenue for patients with CNS metastases (8). These agents offer superior BBB penetration compared to FGET, as well as greater potency against EGFR mutations, including the T790M resistance mutation, which is a key cause of treatment failure with FGET (9). Among TGET, osimertinib has been extensively studied and shown to possess significant intracranial activity. Numerous randomized controlled trials (RCTs) have demonstrated that osimertinib greatly enhances intracranial progression-free survival (PFS) and overall survival (OS) in patients with EGFR-mutant NSCLC and brain metastases, with higher intracranial objective response rates (ORR) compared to FGET (10). Meanwhile, other TGET, such as Aumolertinib and Lazertinib, have also shown promising results (11-14). However, despite these promising results, there remains a paucity of studies that directly compare the CNS efficacy of TGET vs. FGET in treatment-naive EGFR-mutant NSCLC with CNS metastases.

This meta-analysis aims to fill this gap by systematically reviewing and comparing the CNS efficacy of TGET and FGET in treating patients with EGFR-mutant NSCLC and CNS metastases. By synthesizing data from phase 3 RCTs, we assessed the impact of both classes of drugs on CNS PFS, CNS response rates, PFS, OS, and adverse events (AEs). We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1571/rc).

Methods

Search strategy

Keywords such as “Third generation EGFR TKIs”, “Lung cancer”, and “Randomized” were employed in the search strategy. Comprehensive searches spanned six databases, including PubMed, ScienceDirect, The Cochrane Library, Scopus, EMBASE, and Web of Science, targeting relevant RCTs up to August 11, 2025 (Table S1).

Selection criteria

English-published studies were chosen based on PICOS criteria:

1. Participants (P): patients with EGFR-mutated advanced NSCLC and CNS metastases;

2. Intervention (I) and control (C): first line treatment with TGET vs. FGET;

3. Outcomes (O): primary endpoint: CNS-PFS; secondary endpoints: OS, PFS, CNS response rates, and AEs;

4. Study design (S): phase 3 RCTs.

Exclusion criteria included articles without primary data, along with case reports, reviews, and meta-analyses. For trials reported in multiple studies with various outcomes, all were included; however, only the latest data were analyzed for outcomes that were identical.

Data extraction

Data collection was independently performed by two investigators, covering study details (e.g., country, registration ID), participant characteristics (e.g., age, sex), cancer features (e.g., EGFR mutation, CNS lesions), antitumor outcomes (e.g., CNS-responses, CNS-PFS), and AEs [e.g., total AEs, treatment-related AEs (TRAEs)]. Discrepancies were addressed through discussion and re-evaluation.

Outcome assessments

The CNS-PFS rate (CNS-PFSR) and PFS rate (PFSR) were compared between the two groups at 2–24 months. The CNS Responses were analyzed in both central full analysis set (cFAS) population and central efficacy evaluable population (cEFR) population.

Quality assessment

Study quality was evaluated using the Jadad scale, a 5-point system (scores 3–5 signifying high quality), as a supplementary assessment of trial reporting quality (15). The Cochrane Risk Assessment Tool was used to evaluate the risk of bias of included studies (16). The certainty of evidence for each outcome was further assessed using the GRADE framework, in which the risk-of-bias domain was based on the Cochrane assessment, and evidence certainty was classified into four tiers: high, moderate, low, and very low (17).

Statistical analysis

Review Manager 5.3 and STATA 12.0 were used for data analysis. Survival variables were assessed with hazard ratios (HR), and risk ratios (RR) were used for dichotomous outcomes. If heterogeneity was low (I²<50% or P>0.1), a fixed-effects approach was applied; for higher heterogeneity, a random-effects model was utilized. Statistical significance was considered when P<0.05. A funnel plot was employed to visually inspect publication bias. Leave-one-out sensitivity analyses were performed by sequentially excluding each study to evaluate the robustness of the pooled estimates. The study was registered in PROSPERO (ID: CRD42024629581).

Results

Search results

A total of 11 studies based on 5 RCTs (AENEAS, FLAURA, FURLONG, IBIO-103, and LASER301) were included (Figure 1) (10-14,18-23). Table 1 summarized the baseline characteristics of the studies. Two of the RCTs were global multicenter trials (10,14), while the other three were conducted in China across multiple centers (11-13). All 5 RCTs were considered to have high methodological quality according to the Jadad scale and showed low risk of bias according to the Cochrane Risk Assessment Tool (Figure S1, Table S2). According to the GRADE system, all results were rated as medium-high in quality (Table S3).

Figure 1.

Flow chart. CNS, central nervous system; FGET, first generation epidermal growth factor receptor tyrosine kinase inhibitor; OS, overall survival; PFS, progression-free survival.

Table 1. Characteristics of the included studies.

Study (first author, year)	Country	Groups	Patients	Sex (M/F)	Age (mean, year)	ECOG PS		CNS lesions		EGFR mutation		TGET type	FGET type	Follow up (months)
						0	1	Measurable	Non-measurable	19Del	L858R
AENEAS (NCT03849768, 2018.11–2019.09)
Lu 2022 (18), Lu 2024 (11)	China multicenter	TGET	51	19/32	58	7	44	26	5	30	21	Aumolertinib	Gefitinib	26.2
		FGET	55	20/35	61	13	42	30	25	35	20			26.3
FLAURA (NCT02296125, 2014.12–2016.03)
Reungwetwattana 2018 (10), Soria 2018 (19), Ramalingam 2020 (20)	Global multicenter	TGET	61	23/38	63	16	45	22	39	40	21	Osimertinib	Gefitinib/erlotinib	15
		FGET	67	26/41	63	27	39	19	48	45	22			9.7
FURLONG (NCT03787992, 2019.05–2019.12)
Shi 2022 (12), Shi 2022 (21)	China multicenter	TGET	65	25/40	58	14	51	23	42	35	30	Furmonertinib	Gefitinib	21
		FGET	62	23/39	60	9	53	37	25	32	30			21
IBIO-103 (NCT04206072, 2019.12–2020.12)
Lu 2023 (13)†	China multicenter	TGET	59	–	–	–	–	17	42	–	–	Befotertinib	Icotinib	20.7
		FGET	57	–	–	–	–	22	33	–	–			19.4
LASER301 (NCT04248829, 2020.02–2021.09)
Soo 2023 (14), Cho 2023 (22), Reungwetwattana 2023 (23)	Global multicenter	TGET	45	14/31	66	8	37	18	27	25	20	Lazertinib	Gefitinib	17.8
		FGET	41	17/24	59	12	29	15	26	23	18			12.2

^†, IBIO-103 study only has subgroup analysis of survival data for CNS-PFS. CNS, central nervous system; CNS-PFS, central nervous system progression-free survival; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; FGET, first generation EGFR tyrosine kinase inhibitor; M/F, male/female; TGET, third generation EGFR tyrosine kinase inhibitor.

CNS-PFS

CNS-PFS was higher in the TGET group [HR: 0.44 (0.33, 0.58), P<0.001, Figure 2]. At 4–24 months, the TGET group showed a higher CNS-PFSR (Figure 3). Regarding prolonged survival, TGET demonstrated an increasing advantage in CNS-PFSR over FGET (RR: 1.15–1.48–1.89–2.34, Figure 4).

Figure 2.

Forest plots of OS, PFS, and CNS-PFS associated with TGET vs. FGET. CI, confidence interval; CNS-PFS, central nervous system progression-free survival; df, degrees of freedom; EGFR, epidermal growth factor receptor; FGET, first-generation EGFR-TKI; IV, inverse variance; OS, overall survival; PFS, progression-free survival; SE, standard error; TGET, third-generation EGFR-TKI; TKI, tyrosine kinase inhibitor.

Figure 3.

Comparisons of CNS-PFSR (A), and PFSR (B) at 2–24 months associated with TGET vs. FGET. CNS-PFSR, central nervous system progression-free survival rate; EGFR, epidermal growth factor receptor; FGET, first-generation EGFR-TKI; PFSR, progression-free survival rate; TGET, third-generation EGFR-TKI; TKI, tyrosine kinase inhibitor.

Figure 4.

Forest plots of CNS-PFSR (6–24 months) associated with TGET vs. FGET. CI, confidence interval; CNS-PFSR, central nervous system progression-free survival rate; df, degrees of freedom; EGFR, epidermal growth factor receptor; FGET, first-generation EGFR-TKI; m, month; M-H, Mantel-Haenszel; TGET, third-generation EGFR-TKI; TKI, tyrosine kinase inhibitor.

At cutoff time, more CNS progressions were found in the FGET group [RR: 0.59 (0.44, 0.80), P=0.001], especially the new CNS lesions (Figure S2).

OS and PFS

PFS was also higher in the TGET group [HR: 0.44 (0.35, 0.54), P<0.001, Figure 2]. At 10–24 months, the TGET group exhibited a higher PFSR (Figure 3B). Regarding prolonged survival, TGET showed an increasing benefit in PFSR over FGET (RR: 1.09–1.64–2.88–10.39, Figure 5). OS data were reported in only 2 of the 5 included phase 3 RCTs (FLAURA and AENEAS). In this limited subset of trials, OS numerically favored the TGET group; however, the difference was not statistically significant [HR: 0.79 (0.55, 1.13), P=0.20, Figure 2].

Figure 5.

Forest plots of PFSR (6–24 months) associated with TGET vs. FGET. CI, confidence interval; df, degrees of freedom; EGFR, epidermal growth factor receptor; FGET, first-generation EGFR-TKI; m, month; M-H, Mantel-Haenszel; PFSR, progression-free survival rate; TGET, third-generation EGFR-TKI; TKI, tyrosine kinase inhibitor.

CNS responses

In the cEFR population, the CNS-ORR [RR: 1.32 (1.15, 1.52), P<0.001], and CNS-complete response (CR) [RR: 3.40 (1.39, 8.28), P=0.007] were higher in the TGET group. Meanwhile, the CNS-SD [0.25 (0.11, 0.57), P=0.001] was higher in the FGET group. The CNS-DCR [RR: 1.04 (0.97, 1.12), P=0.25], CNS-PR [RR: 1.16 (0.97, 1.38), P=0.09], and CNS-PD [RR: 0.60 (0.19, 1.89), P=0.39] were similar between the two groups (Table 2, Figure S3). Compared with the cEFR population, the favorable tendency of the CNS responses was similar in the cFAS population (Table 2, Figure S4).

Table 2. CNS responses.

CNS responses	Included studies	TGET		FGET		RR [95% CI]	P
		Event/total	%	Event/total	%
In the cFAS population
CNS-ORR	2	72/112	64.29	56/122	45.90	1.40 [1.10, 1.77]	0.005
CNS-DCR	2	103/112	91.96	109/122	89.34	1.03 [0.95, 1.12]	0.49
CNS-CR	2	37/112	33.04	19/122	15.57	2.13 [1.32, 3.44]	0.002
CNS-PR	2	35/112	31.25	37/122	30.33	1.03 [0.71, 1.50]	0.89
CNS-SD	2	31/112	27.68	53/122	43.44	0.64 [0.44, 0.91]	0.01
CNS-PD	2	3/112	2.68	6/122	4.92	0.64 [0.02, 21.07]	0.80
In the cEFR population
CNS-ORR	5	94/104	90.38	82/121	67.77	1.32 [1.15, 1.52]	<0.001
CNS-DCR	5	99/104	95.19	110/121	90.91	1.04 [0.97, 1.12]	0.25
CNS-CR	5	17/104	16.35	4/121	3.31	3.40 [1.39, 8.28]	0.007
CNS-PR	5	77/104	74.04	78/121	64.46	1.16 [0.97, 1.38]	0.09
CNS-SD	5	5/104	4.81	28/121	23.14	0.25 [0.11, 0.57]	0.001
CNS-PD	5	3/104	2.88	7/121	5.79	0.60 [0.19, 1.89]	0.39

cEFR, central efficacy evaluable population; cFAS, central full analysis set; CI, confidence interval; CNS, central nervous system; CNS-CR, central nervous system complete response; CNS-DCR, central nervous system disease control rate; CNS-ORR, central nervous system objective response rate; CNS-PD, central nervous system progressive disease; CNS-PR, central nervous system partial response; CNS-SD, central nervous system stable disease; CR, complete response; DCR, disease control rate; FGET, first generation epidermal growth factor receptor tyrosine kinase inhibitor; PR, partial response; RR, risk ratio; SD, stable disease; TGET, third generation EGFR tyrosine kinase inhibitor.

The CNS-duration of response (DOR) [HR: 0.39 (0.21, 0.73), P=0.003] was longer in the TGET group (Figure S5). The CNS-estimated percentage remaining in response (EPR) was higher in the TGET group at 6 months. In terms of extended survival, TGET displayed a growing advantage in CNS-EPR compared to FGET (RR: 1.30–1.71–2.25–7.70) (Figure S6).

Toxicity

In summary, rate of grade 3–5 TRAEs [RR: 0.67 (0.46, 0.98), P=0.04] was higher in the FGET group. Similar total AEs, grade 3–5 AEs, serious AEs, AEs leading to discontinuation, AEs leading to dose reduction, AEs leading to dose interruption, AEs leading to death, TRAEs, serious TRAEs, TRAEs leading to discontinuation, TRAEs leading to dose reduction, and TRAEs leading to death were found between the two groups (Table 3).

Table 3. Summary of adverse events.

Adverse events	TGET		FGET		RR [95% CI]	P
	Event/total	%	Event/total	%
Total adverse events	221/222	99.55	223/225	99.11	1.01 [0.98, 1.03]	0.64
Grade 3–5 adverse events	76/222	34.23	89/225	39.56	0.86 [0.68, 1.10]	0.23
Serious adverse events	50/222	22.52	47/225	20.89	1.06 [0.75, 1.52]	0.73
Adverse events leading to discontinuation	18/222	8.11	14/225	6.22	1.30 [0.67, 2.51]	0.44
Adverse events leading to dose reduction	11/161	6.83	7/158	4.43	1.48 [0.59, 3.70]	0.40
Adverse events leading to dose interruption	27/110	24.55	26/103	25.24	0.96 [0.62, 1.50]	0.86
Adverse events leading to death	10/222	4.50	5/225	2.22	1.87 [0.67, 5.19]	0.23
TRAEs	205/222	92.34	206/225	91.56	1.01 [0.96, 1.07]	0.66
Grade 3–5 TRAEs	35/222	15.77	53/225	23.56	0.67 [0.46, 0.98]	0.04
Serious TRAEs	10/222	4.50	17/225	7.56	0.59 [0.28, 1.27]	0.18
TRAEs leading to discontinuation	7/161	4.35	4/158	2.53	1.58 [0.51, 4.93]	0.43
TRAEs leading to dose reduction	3/116	2.59	1/117	0.85	2.36 [0.35, 16.10]	0.38
TRAEs leading to death	2/222	0.90	1/225	0.44	1.66 [0.22, 12.62]	0.62

CI, confidence interval; FGET, first generation EGFR tyrosine kinase inhibitor; RR, risk ratio; TGET, third generation EGFR tyrosine kinase inhibitor; TRAEs, treatment-related adverse events.

Sensitivity analysis

Leave-one-out sensitivity analyses were performed for the outcomes, including CNS-PFS, PFS, and CNS-PFSR (12, 24 months), by sequentially excluding each individual study to evaluate the robustness and stability of the pooled estimates (Figure S7).

Publication bias

Funnel plots for survival, CNS-PFSR, CNS response in cFAS, and AEs summary appeared visually symmetrical; however, given the limited number of included RCTs, the reliability of funnel plot-based assessment of publication bias remains uncertain (Figure 6).

Figure 6.

Funnel plots of survival (A), CNS-PFSR (B), responses CNS response in cFAS (C), and AEs summary (D). AE, adverse event; cFAS, central full analysis set; CNS-PFS, central nervous system progression-free survival; CNS-PFSR, central nervous system progression-free survival rate; CR, complete response; DCR, disease control rate; m, month; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RR, risk ratio; SD, stable disease; SE, standard error; TRAE, treatment-related adverse event.

Discussion

The management of EGFR-mutant NSCLC with CNS metastases has long been a clinical conundrum. CNS metastases significantly worsen patient outcomes and quality of life, posing unique therapeutic challenges due to the poor penetration of many systemic therapies across the BBB (24). Although FGET were initially considered revolutionary for EGFR-mutant NSCLC, their limited intracranial efficacy has left a treatment gap that newer agents aim to fill. TGET offer enhanced BBB penetration and greater potency against EGFR resistance mutations such as T790M (25). However, debates persist regarding whether the superior CNS efficacy of TGET justifies their routine use in the first-line setting, especially given the potential trade-offs in cost and accessibility. Our meta-analysis synthesizes data from five high-quality phase 3 RCTs to directly compare the CNS efficacy of TGET and FGET (10-14,18-23). The results underscore the superiority of TGET in key CNS-specific and systemic endpoints. TGET were associated with significantly prolonged CNS-PFS and PFS, higher CNS response rates (including CNS-CR), and reduced CNS progression events. These benefits were achieved alongside a lower incidence of grade 3–5 TRAEs, positioning TGET as a favorable first-line option for patients with EGFR-mutant NSCLC and CNS metastases.

CNS-PFS is a pivotal metric in the evaluation of EGFR-TKIs for patients with CNS metastases, as it reflects the agent’s ability to delay intracranial disease progression-a major determinant of survival and quality of life in this population (5). Our findings demonstrate that TGET significantly improve CNS-PFS compared to FGET. This robust difference persisted across all studies included in the analysis, with consistent benefits observed at 6–24 months, indicating sustained intracranial disease control. These findings align with prior trials, including the FLAURA and AENEAS studies, which reported superior CNS-PFS for Osimertinib and Aumolertinib, respectively, compared to FGET (10,11). The superior CNS-PFS with TGET can be attributed to their improved pharmacokinetic profiles, which enhance BBB penetration and maintain effective intracranial drug concentrations (26). TGET exhibit a high affinity for mutant EGFR while sparing wild-type EGFR, reducing systemic toxicity and enhancing CNS-targeted activity. This pharmacological advantage allows TGET to control CNS disease more effectively, even in patients with baseline brain metastases or asymptomatic lesions (27). For instance, the FLAURA trial demonstrated a median CNS-PFS of 15.2 months for osimertinib, compared to 9.6 months for FGET (10). Furthermore, the sustained CNS-PFS observed with TGET may reduce the need for CNS-directed interventions such as WBRT, thereby preserving cognitive function and quality of life (28). An interesting observation in our analysis is the gradual divergence in CNS-PFS rates between TGET and FGET over time, suggesting that the benefits of TGET become more pronounced with prolonged treatment. This trend may reflect the superior ability of TGET to suppress intracranial resistance mutations, particularly T790M, which is a common driver of CNS progression in patients treated with FGET (25). Importantly, the delay in CNS progression with TGET has downstream implications for OS, as CNS progression often heralds systemic disease deterioration and limits treatment options (29). Although the available OS analysis did not demonstrate a statistically significant difference between treatment groups, it should be noted that OS data were available from only 2 of the 5 included RCTs. Therefore, the numerical advantage observed with TGET (HR: 0.79) should be interpreted cautiously and requires confirmation through additional mature survival data. Nevertheless, the favorable trend may suggest a potential long-term survival benefit associated with improved CNS disease control.

In addition to delaying CNS progression, achieving a robust intracranial response is a critical therapeutic goal for patients with CNS metastases, as it directly impacts symptoms, functional status, and survival outcomes (30). Our meta-analysis revealed significantly higher CNS-ORR and CNS-CR rates with TGET compared to FGET, underscoring their superior intracranial efficacy. These findings are consistent with earlier studies highlighting the enhanced intracranial activity of TGET in this patient population (10-14). The high CNS-CR rates observed with TGET are particularly noteworthy, as complete intracranial remission is rarely achieved with FGET. This advantage likely stems from the improved BBB penetration of TGET, which allows for effective drug delivery to CNS lesions (24). Osimertinib, for example, has demonstrated a CNS penetration rate exceeding 15%, compared to less than 2% for gefitinib or erlotinib. This enhanced penetration enables TGET to achieve therapeutic drug concentrations in the CNS, effectively targeting intracranial lesions and reducing tumor burden (10). Another important finding is the prolonged CNS-DOR with TGET, indicating sustained intracranial disease control once a response is achieved. This is clinically significant, as durable responses reduce the likelihood of CNS progression and the need for additional interventions, such as SRS or WBRT, which carry risks of neurocognitive decline (7). The extended CNS-DOR observed with TGET further highlights their potential to transform the treatment paradigm for EGFR-mutant NSCLC with CNS metastases, shifting the focus from palliative care to long-term disease management (31). The higher CNS-CR and CNS-ORR rates with TGET suggest that these agents not only stabilize disease but also induce meaningful tumor regression, improving patient outcomes. Additionally, the reduced rate of new CNS lesions in the TGET group supports their role in preventing the emergence of intracranial metastases, further reinforcing their value as a first-line therapy.

AEs are critical considerations in the selection of first-line therapy. Our study revealed a lower incidence of grade 3–5 TRAEs with TGET compared to FGET, suggesting a more favorable safety profile. This finding is consistent with previous studies reporting that TGET are better tolerated, particularly in terms of rash and diarrhea, which are common with FGET (32,33). The reduced TRAE rates observed with TGET may be attributed to their more selective inhibition of mutant EGFR while sparing wild-type EGFR, thereby minimizing off-target effects (34). Moreover, the lower incidence of severe AEs with TGET is particularly relevant for patients with CNS metastases, who are often frail and less able to tolerate aggressive treatment regimens. Nevertheless, the overall AE profile of TGET and FGET was broadly similar, indicating that both classes of drugs are generally safe when used in the first-line setting.

Although TGET demonstrated superior CNS efficacy and prolonged CNS disease control compared with FGET, whether these clinical advantages translate into improved cost-effectiveness remains uncertain, as economic outcomes were not assessed in the present meta-analysis. Previous pharmacoeconomic studies evaluating EGFR-TKIs have demonstrated that cost-effectiveness estimates vary substantially according to drug acquisition costs, healthcare systems, willingness-to-pay thresholds, and treatment strategies (35-38). In particular, previous cost-effectiveness analyses of osimertinib and other EGFR-TKIs have reported different conclusions across countries, highlighting that clinical efficacy alone cannot determine economic superiority (35-38). Furthermore, real-world studies have suggested that CNS disease status, treatment patterns, subsequent therapies, and healthcare resource utilization may influence the long-term value of EGFR-TKI therapy (39-41). Therefore, future health economic evaluations incorporating CNS-specific outcomes and real-world evidence are warranted to determine the economic value of TGET, particularly in patients with CNS metastases.

Despite its strengths, this meta-analysis has several limitations. First, the analysis is limited to phase 3 RCTs, which may not capture real-world treatment outcomes. Observational studies and post-marketing data could provide additional insights into the comparative efficacy and safety of TGET and FGET. Second, the heterogeneity in CNS-PFS observed at later time points suggests potential differences in patient populations or study designs across the included RCTs. Third, the lack of individual patient data (IPD) limits our ability to perform subgroup analyses based on key factors such as the presence of baseline brain metastases or the type of EGFR mutation. Fourth, while TGET appear to be more cost-effective in terms of reducing the need for CNS-directed therapies, the economic impact of these agents was not assessed in this study. Fifth, heterogeneity among individual EGFR-TKIs and trial characteristics should be acknowledged, and our findings should therefore be interpreted as a class-level comparison between TGET and FGET rather than a direct comparison of individual agents. Sixth, the limited number of included RCTs reduced the reliability of publication bias assessment; therefore, although no obvious funnel plot asymmetry was observed, potential publication bias cannot be completely excluded. Furthermore, OS interpretation was limited by incomplete reporting across included studies, as only 2 of the 5 phase 3 RCTs provided extractable OS data. Therefore, conclusions regarding OS should be considered hypothesis-generating rather than definitive. Future research should address these gaps to further inform clinical decision-making.

Conclusions

TGET demonstrated superior CNS-PFS and CNS responses compared to FGET in EGFR-mutant NSCLC patients with CNS metastases. The total PFS was significantly improved with TGET, whereas OS showed only a numerical trend favoring TGE, and this finding requires further confirmation. The survival advantage of TGET increased with prolonged survival time. Reduced TRAEs with TGET further highlight their clinical advantage, particularly in patients with poor performance status. Future studies should focus on real-world outcomes and cost-effectiveness analyses to optimize treatment strategies for this challenging patient population.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.