The resistance landscape of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer: molecular mechanisms and novel therapeutic strategies

Introduction

Lung cancer continues to be the leading cause of global cancer-related deaths, with distant metastases detected in 57% of patients at initial diagnosis, correlating with a stark five-year survival rate of just 5% (1). Among all categories of lung cancer, non-small cell lung cancer (NSCLC) is a common subtype, constituting 85% of lung cancer cases (2-5). NSCLC is typically diagnosed at advanced stages, rendering most patients ineligible for surgical intervention. For decades, platinum-based doublet chemotherapy served as the first-line standard, yet yielded a modest 5-year survival rate of just 15% (6). Epidermal growth factor receptor (EGFR) is a key oncogenic driver in cancer development, and EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have become extensively researched and clinically utilized therapeutic agents (7). EGFR mutations are observed in over half of the NSCLC patients (8), and first-generation EGFR-TKIs and second-generation EGFR-TKIs have been proved to have great impacts on these patients (9). EGFR-TKIs have demonstrated superior efficacy compared to conventional chemotherapy in EGFR-mutant NSCLC patients, achieving response rates of 62–83% while significantly extending progression-free survival (PFS) and enhancing quality of life outcomes (10).

The EGFR signaling pathway, which is located on the cell membrane to bind to its corresponding ligands, plays a critical role in regulating key cellular processes including proliferation, differentiation, migration, and survival (11). The most common mutations of EGFR are ex19del and L858R, with approximately 20% of EGFR-mutant patients harboring them (12). These two classic EGFR mutations respond effectively to first- and second-generation TKIs. However, targeted therapy inevitably leads to acquired resistance: 50–60% of patients develop the T790M gatekeeper mutation (13,14), while others exhibit activation of bypass signaling pathways (15).

First-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) act as reversible competitive antagonists of the EGFR kinase domain, binding at the ATP pocket to temporarily block tyrosine kinase activity (16). The phase III Iressa Pan-Asia Study compared first-line gefitinib vs. carboplatin-paclitaxel in East Asian patients with advanced NSCLC, demonstrating significantly improved PFS specifically in the EGFR mutation-positive subgroup, while showing no benefit in EGFR wild-type cases (17). Gefitinib gained U.S. regulatory clearance in 2015 specifically for treatment-naïve advanced NSCLC patients exhibiting EGFR-activating mutations (18).

Unlike first-generation EGFR-TKIs, second-generation inhibitors like afatinib and dacomitinib function as irreversible covalent binders, designed to overcome acquired resistance to earlier agents through permanent kinase domain inhibition (19). Afatinib serves as a dual EGFR/HER2 irreversible inhibitor, while dacomitinib acts as a pan-HER family blocker. Compared to first-generation gefitinib, these second-generation TKIs—validated in the LUX-Lung 7 and ARCHER 1050 trials—demonstrated clinically significant progression-free and overall survival (OS) advantages in treatment-naïve EGFR-mutant NSCLC, securing their position as first-line therapeutic options (20,21). Clinical data indicate that second-generation EGFR-TKIs exhibit a lower maximum tolerated dose and more pronounced skin/gastrointestinal toxicity compared to first-generation agents, often requiring dose modifications in practice. These pharmacological challenges, combined with sustained EGFR inhibition, create selective pressure that frequently leads to the emergence of the T790M gatekeeper mutation in exon 20—observed in 50–60% of resistant cases across both TKI generations (22-24).

The T790M ‘gatekeeper’ mutation exerts dual mechanistic effects that compromise TKI efficacy: it enhances steric hindrance at the drug-binding site while simultaneously increasing EGFR’s ATP affinity, thereby reducing the therapeutic activity of both first- and second-generation EGFR-TKIs (22). Third-generation EGFR-TKIs like osimertinib demonstrate dual advantages for T790M-positive NSCLC: superior target inhibition against the gatekeeper mutation and an improved safety profile compared to earlier agents. The AURA3 study established osimertinib’s superiority over platinum chemotherapy in this setting, with striking PFS benefits [10.1 vs. 4.4 months; hazard ratio (HR) =0.30] and significant OS improvement (26.8 vs. 22.5 months; HR =0.69) for patients progressing on first-line TKIs (24). Research has characterized both genetic and non-genetic mechanisms underlying EGFR-TKI resistance. Key molecular drivers include mesenchymal-epithelial transition (MET) factor amplification, decreased EGFR activating mutations, gene fusion, and PTEN deletion, alongside non-genetic processes such as histologic transformation, epithelial-mesenchymal transition (EMT), epigenetic modifications, and tumor microenvironment adaptation. However, the biological basis remains undetermined in 18–20% of resistant cases (25). This comprehensive review systematically examines: the molecular mechanisms of EGFR downstream signaling pathways, the classification and clinical application of targeted therapies against these pathways, and the diverse array of resistance mechanisms that limit treatment efficacy. Furthermore, it critically analyzes current therapeutic challenges and proposes potential strategies to overcome these limitations in clinical practice.

EGFR-TKIs, mutations, and signaling pathways

History and mechanism of approved EFGR-TKIs

The two primary EGFR driver mutations—exon 19 deletions (ex19del) and L858R point mutations—constitutively activate EGFR signaling, promoting uncontrolled tumor cell proliferation and differentiation. This discovery paved the way for precision oncology when gefitinib became the first EGFR-TKI approved by the U.S. Food and Drug Administration (FDA) in 2003 for NSCLC patients harboring these EGFR-activating mutations, revolutionizing targeted cancer treatment paradigms (26). Following gefitinib’s approval, several additional EGFR-TKIs—including erlotinib, lapatinib, and icotinib—were subsequently introduced into clinical practice for treating NSCLC patients with EGFR mutations, expanding the therapeutic arsenal against this genetically defined cancer subtype (27-29). However, first-generation TKIs like gefitinib and erlotinib ultimately faced therapeutic limitations due to their reversible binding mechanism and narrow spectrum of efficacy (restricted primarily to ex19del and L858R mutations) (30). Due to these reasons, patients undergoing first-generation treatment gained acquired resistance and only had 9 to 15 PFS (31). Against this resistance backdrop, second-generation EGFR-TKIs—afatinib, dacomitinib, and neratinib (21,32,33)—were developed as irreversible inhibitors targeting Cys797 (C797) through covalent binding (19). Despite their irreversible binding mechanism, second-generation TKIs ultimately failed to overcome T790M-mediated resistance due to its big size and the mutation’s dual effects on ATP affinity and steric hindrance, necessitating the development of third-generation inhibitors specifically designed to target T790M-positive tumors.

Against the limitations of second-generation TKIs, researchers developed third-generation EGFR inhibitors—including osimertinib, rociletinib, olmutinib, and nazartinib (34-37)—featuring optimized molecular structures that irreversibly target C797 while maintaining compact dimensions. This strategic design enables faster and more efficient penetration of the ATP-binding pocket, effectively circumventing the steric hindrance imposed by the T790M mutation and establishing a new standard for overcoming T790M-mediated resistance (19). Furthermore, osimertinib demonstrates a superior safety profile compared to first- and second-generation TKIs, with clinically significant reductions in the incidence and severity of treatment-related adverse events, enhancing both tolerability and treatment adherence in EGFR-mutant NSCLC patients (21,34). According to the LAURA trial, osimertinib has promising effect on patients who suffer unresectable stage 3 EGFR-mutated NSCLC (38). Clinical trial data demonstrate osimertinib’s robust efficacy in EGFR-mutant NSCLC, with a median PFS of 20.1 months [95% confidence interval (CI): 17.1–22.1] and OS reaching 42 months (95% CI: 37.7–48.4), establishing it as a benchmark for targeted therapy outcomes in this population (39). The emergence of the C797S mutation has introduced a new therapeutic challenge, as this cysteine-to-serine substitution at residue 797 prevents the covalent binding essential for third-generation TKIs like osimertinib to exert their inhibitory effects, thereby significantly compromising their clinical efficacy against resistant tumors.

Beyond the predominant L858R and ex19del mutations, approximately 15% of EGFR mutations in NSCLC are classified as uncommon variants, with the following distribution: exon 20 insertions (ex20ins) account for 5.8%, G719X mutations for 3%, S768I for 1%, L861Q for 1%, exon 19 insertions (19ins) for 0.6%, exon 18 deletions (18del) for 0.3%, E709X for 0.3%, and other rare mutations collectively representing 3% of cases (40). The figure below illustrates the structures of different generations of TKIs and the historical development of therapeutic strategies for EGFR-mutant NSCLC patients, covering studies before 2023 (including 2023) (41-43), 2024 (44,45) and 2025 (46,47).

The evolution of these EGFR-TKIs is fundamentally rooted in precision design targeting key mutations within the EGFR kinase domain. Therefore, a deep understanding of how these mutations impact drug binding and drive tumorigenesis requires first delineating the core components and activation mechanism of the EGFR signaling pathway (Figures 1,2).

Figure 1 Illustration of the key milestones in the development of EGFR TKIs for NSCLC. This timeline chronicles the evolution from foundational discoveries, beginning with the identification of EGFR in 1978, to the latest clinical advancements. It highlights major breakthroughs, including the initial link between EGFR mutations and TKI sensitivity, the subsequent FDA approvals of first- (e.g., gefitinib), second- (e.g., afatinib), and third-generation (osimertinib) agents, and the ongoing development of fourth-generation TKIs. A central theme is the continuous effort to overcome drug resistance, illustrated by the discovery of resistance mechanisms like T790M and the testing of novel strategies such as drug combinations (e.g., osimertinib + bevacizumab) and newer agents like amivantamab, tracing the progression of targeted therapy from initial efficacy to managing resistance. CTC, circulating tumor cell; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; PFS, progression-free survival; SCLC, small cell lung cancer; TKI, tyrosine kinase inhibitor.

Figure 2 Presentation of the chemical structures of representative first-, second-, and third-generation EGFR TKIs. The image illustrates the chemical structures of TKIs across three generations. First-generation TKIs, such as gefitinib, icotinib, and erlotinib, feature basic structures with nitrogen, oxygen atoms, and polycyclic aromatic hydrocarbons. Second-generation TKIs, like afatinib and dacomitinib, have more complex structures with various cyclic groups. Third-generation TKIs, including rociletinib, avitinib, nazartinib, olmutinib, alfutinib, almonertinib, lazertinib, osimertinib, and naquotinib, exhibit even more intricate configurations with multiple rings and long-chain groups. These structural evolutions are designed to enhance the efficacy and selectivity of targeted therapies. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

EGFR signaling pathway

EGFR is one of the most common genes which are to blame for NSCLC. EGFR belongs to the HER/ErbB family—a subtype of receptor tyrosine kinase (RTK)—which plays a significant role in tumor cell proliferation, differentiation, migration and survival (48). EGFR, a 170 kDa RTK, comprises three functional domains: an extracellular ligand-binding region with four EGF-interacting subdomains, a 23-amino-acid transmembrane segment, and an intracellular tyrosine kinase domain. This domain, divided into N and C lobes, contains the critical ATP-binding site where trans-autophosphorylation triggers downstream signaling cascades upon receptor dimerization (49-51) (Figure 3). EGFR signaling mainly activates three canonical downstream pathways: the MAPK/ERK, PI3K/AKT/mTOR, and STAT/JAK cascades (52). Their activation endows tumor cells with core oncogenic traits—uncontrolled proliferation, aberrant differentiation, metastatic potential, and immune evasion—that collectively drive cancer progression and therapy resistance.

Figure 3 Illustration of the structure of the EGFR protein and its corresponding gene, mapping key domains to specific exons and highlighting common mutational sites. The diagram is divided into two main sections for clear comparison. The left side depicts the EGFR protein structure, detailing extracellular domains (L1, CR1, L2, CR2), the TM region, and the intracellular tyrosine kinase domain (with N-lobe, ATP-binding site, and C-lobe), followed by the C-terminal tail. The right side shows the gene structure with exons 1–28, explicitly indicating which exons code for which protein domains. Furthermore, the figure annotates common oncogenic mutations—such as E709X, L718Q, G719X, S768I, T790M, and L858R—directly onto the gene and protein diagrams, providing an integrated view of how genetic alterations impact the protein’s functional regions. This layout effectively correlates genetic information with structural and functional consequences. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; TM, transmembrane.

MAPK/ERK signaling pathway

The MAPK (mitogen-activated protein kinase) family plays a pivotal role in converting extracellular signals into nuclear transcriptional responses via three canonical members: the ERK (ERK1/2), JNK (JNK1-3), and p38 (p38α/β/γ) subfamilies, which mediate core cellular processes in both physiological and pathological contexts (53). As the central signaling hub, the MAPK/ERK pathway functions through a sequential kinase cascade, in which signals are amplified by tiered phosphorylation—from cell-surface RTKs through RAS (MAP4K), RAF (MAP3K), MEK (MAPKK), and finally ERK (MAPK) (54,55). This cascade is initiated by ligand-bound RTK autophosphorylation, which recruits the GRB2/SHC/SOS adaptor complex to the membrane and drives RAS GDP-to-GTP exchange. GTP-bound RAS activates RAF kinases via membrane localization and dimerization; activated RAF phosphorylates MEK and subsequently ERK. Phosphorylated ERK translocates to the nucleus, regulating oncogenic transcription factors (e.g., FOS) and driving tumor cell proliferation, differentiation, and immune evasion (53).

PIK3/Akt/mTOR signaling pathway

Similar to the MAPK/ERK cascade, the PI3K/AKT/mTOR pathway acts as a central regulator of cellular homeostasis, controlling key processes including autophagy, cell cycle progression, inflammation, and (56). The PI3K/AKT/mTOR pathway consists of key components: PI3K (phosphoinositide 3-kinase), AKT (protein kinase B), mTOR (mammalian target of rapamycin), and the lipid mediators PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate) (57). According to Lindsay et al. (58), PIP2 and PIP3 localize to the nucleus but occupy distinct subnuclear locations. We indicate that PIP3 may be generated from PIP2 (59). The PI3K/AKT/mTOR pathway is activated via a tightly regulated cascade initiated by ligand-bound RTKs, which recruit and activate PI3K at the membrane. Activated PI3K converts PIP2 to PIP3, a critical second messenger that promotes AKT activation through PH domain binding; full AKT phosphorylation requires PDK1 and mTORC2 as co-activators. In contrast to this linear cascade, mTOR activation is indirectly controlled: AKT phosphorylates and inhibits the TSC1/2 complex, thereby relieving mTOR suppression (60,61). The activated PI3K/AKT/mTOR pathway impairs antitumor immunity through two mechanisms: mTOR-mediated inhibition of autophagy and PI3K-driven reduction in immune cell cytotoxicity, which together establish an immunosuppressive tumor microenvironment that promotes cancer cell survival and immune evasion (56).

JAK/STAT3 signaling pathway

The JAK/STAT3 pathway plays a pivotal role in tumor biology by regulating key processes such as cancer progression, metastasis, inflammation (62), apoptosis, autophagy, and angiogenesis (63). Beyond these cell-autonomous effects, it shapes the tumor microenvironment by recruiting immunosuppressive M2-type tumor-associated macrophages and regulatory T cells (Tregs), fostering an immune-tolerant niche that supports tumor immune evasion and growth. The Janus kinase (JAK) family acts as a critical intracellular kinase, while signal transducer and activator of transcription (STAT) proteins function as both signal transducers and nuclear transcription activators (62). Among STAT family members, STAT2 mediates antiviral immunity, whereas STAT5A/B isoforms specifically promote tumor invasion and metastasis through oncogenic transcriptional programs (64). GP130 is an essential protein that binds to IL-6R, forming the IL-6/IL-6R/GP130 trimeric complex (65).

The JAK/STAT3 pathway functions via a concise activation cascade: ligand binding to EGFR triggers receptor dimerization and autophosphorylation, which recruits and activates JAK kinases to phosphorylate STAT3, enabling its dimerization, nuclear translocation, and transcriptional activity (66). Emerging evidence demonstrates bidirectional crosstalk between IL-6 and EGFR signaling: EGFR activation upregulates IL-6 expression (67), which in turn stimulates JAK/STAT3 signaling, forming a synergistic loop amplifying oncogenic functions including cell proliferation, differentiation, and survival. The IL-6 signaling cascade begins when IL-6 binds to its receptor (IL-6R), forming a GP130-recruiting complex. Two such trimeric complexes dimerize via their D1 domains, activating JAK kinases and inducing phosphorylation of specific GP130 tyrosine residues (65). These phosphotyrosines serve as docking sites for the STAT3 SH2 domain, enabling JAK-mediated STAT3 phosphorylation triggering STAT3 homodimerization and nuclear translocation (62). Activated STAT3 dimers translocate to the nucleus, bind cognate DNA response elements, and initiate target gene transcription—including STAT3 itself—forming a positive feedback loop amplifying and sustaining oncogenic signaling (64).

Taken together, the MAPK/ERK, PI3K/AKT/mTOR, and JAK/STAT3 pathways constitute core signaling networks that convert extracellular stimuli into intracellular responses. Via coordinated phosphorylation cascades, these pathways relay signals from the plasma membrane to the nucleus, thereby tightly regulating gene expression programs governing essential cellular processes including proliferation, differentiation, and metabolic homeostasis (Figure 4).

Figure 4 A comprehensive overview of the three primary downstream signaling pathways activated by EGFR. The diagram visually summarizes how ligand-bound EGFR initiates parallel signaling cascades. The central RAS-RAF-MEK-ERK (MAPK) pathway drives proliferation, while the adjacent PI3K-AKT-mTOR pathway primarily regulates cell survival and metabolism. A key feature illustrated is the crosstalk between EGFR and the JAK-STAT pathway, notably showing how IL-6 can activate phosphorylated EGFR, leading to STAT3 phosphorylation and nuclear translocation to regulate target genes like FOS. The figure effectively uses spatial organization, placing the nucleus at the center to represent the convergent point for all three pathways, which ultimately coordinate to control critical cellular processes such as gene transcription, cell cycle progression (G1/S phase), and apoptosis. This integrated view highlights the complex network through which EGFR signaling influences cell fate. EGFR, epidermal growth factor receptor; IL, interleukin.

Drug resistance

Based on the temporal sequence of resistance onset and molecular mechanistic characteristics, EGFR-TKI resistance can be categorized into primary resistance and acquired resistance. Primary resistance refers to the intrinsic insensitivity of tumors present at the initial stage of treatment, whereas acquired resistance describes the adaptive evolution of tumor cells during treatment, driven by genetic mutations or signaling pathway remodeling.

Primary resistance mechanism

Primary resistance is generally defined as disease progression within 3 months of initiating EGFR-TKI therapy, or a best overall response of progressive disease. Such mechanisms are primarily related to the structural heterogeneity of distinct EGFR-mutant variants or the coexistence of other oncogenic drivers (43).

Ex20ins

Ex20ins is the most common primary resistance mutation in clinical practice, accounting for 5–10% of all EGFR mutations. It shows a slightly higher incidence in Asian populations (7.2%), reflecting the ethnic heterogeneity of EGFR mutations (68). Ex20ins induces C-helix displacement in the EGFR kinase domain, enlarging the ATP pocket and blocking first- and second-generation TKIs binding through steric hindrance (69). Patients with ex20ins have a median survival of 16.5 months, markedly shorter than those with classical EGFR mutations (33 months) (70). Ex20ins confers poor sensitivity to first- and second-generation EGFR-TKIs, requiring alternative therapies for this subgroup. Amivantamab, an EGFR/MET bispecific antibody, overcomes ex20ins-mediated resistance by binding EGFR’s extracellular domain to bypass the mutated ATP pocket and inhibit EGFR signaling (71). The CHRYSALIS phase I trial demonstrated Amivantamab’s robust clinical activity in ex20ins-mutated NSCLC, achieving a 40% objective response rate (ORR) with median duration of response (DOR) of 11.1 months, alongside significant improvements over chemotherapy in PFS (8.3 vs. 4.2 months) and OS (22.8 vs. 13.1 months) (72). This efficacy profile is complemented by other ex20ins-targeted agents like mobocertinib (ORR 28%, PFS 7.3 months) (73) and poziotinib (ORR 27% but with notable toxicity concerns) (74), collectively establishing a new therapeutic paradigm for this previously treatment-resistant mutation subset.

PACC mutation

PACC (P-loop and αC-helix compressed) mutation represent a category of primary resistance mechanisms systematically classified in recent years. These mutations occur in the EGFR kinase domain and cause spatial compression of the P-loop and αC-helix, thereby increasing ATP affinity and impairing TKI binding. According to MD Anderson, PACC mutation comprises 10–15% of EGFR mutations, including G719X, S768I, L861Q, E709-T710 delinsD mutation (75). It is shown that 1st- and 3rd-generation TKIs offer low efficacy in this mutation, while 2nd-generation TKI show satisfactory response rate ranging from 47.8–72.3% (76). Notably, the identification and classification of PACC mutations are continuously evolving, and their incidence and clinical significance warrant validation in larger-scale studies.

Other primary resistance mechanisms

In addition to structural abnormalities of the EGFR itself, a variety of pre-existing molecular and genetic alterations also mediate primary resistance to EGFR-TKIs. Among these, baseline co-existing genetic alterations in bypass signaling pathways—including MET amplification and HER2 amplification—can sustain the growth and survival of tumor cells independently of EGFR signaling (77). PTEN deficiency and phosphatidylinositol-3-kinase catalytic α (PIK3CA) mutations abrogate the inhibition of the EGFR downstream PI3K-AKT pathway and lead to its constitutive activation, whereas pre-existing co-mutations in cell cycle-related genes including CCND1/2, CCNE1, and CDK4/6 also contribute to the establishment of intrinsic resistance (78,79). A germline deletion polymorphism in intron 2 of the BIM gene reduces the activity of the key pro-apoptotic protein, thereby decreasing the sensitivity of tumors to osimertinib (80).

Acquired resistance mechanism

Acquired resistance is generally defined as disease progression that occurs after an initial effective treatment response (objective response or stable disease) lasting for more than 6 months (81). These mechanisms encompass on-target secondary mutations, bypass signaling activation, downstream pathway alterations, histological transformation, and other related processes.

C797S mutation

The acquired EGFR C797S mutation is an on-target resistance mechanism that arises following treatment with irreversible EGFR-TKIs, and is frequently reported in the setting of second- and later-line osimertinib therapy. This mutation is caused by a missense mutation in exon 20 of the EGFR gene, which results in the substitution of cysteine at position 797 with serine within the ATP-binding pocket of the EGFR kinase domain. This amino acid change eliminates the free sulfhydryl group required for the formation of irreversible covalent bonds between third-generation EGFR-TKIs and the target protein, markedly reducing the binding affinity of the drug to EGFR. Consequently, the agent can no longer effectively suppress EGFR kinase activity and the activation of downstream oncogenic signaling cascades, including the RAS-MAPK and PI3K-AKT pathways, which ultimately drives the development of resistance to targeted therapy (82). An analysis of the cohort of patients treated with second-line osimertinib in the phase III AURA3 clinical trial revealed that acquired EGFR C797S mutations developed in 14% of patients (83). In contrast, in the first-line treatment setting, several studies have reported that acquired EGFR C797S mutations are detected in only approximately 5% of patients (84,85). The EGFR C797S resistance mutation is more prevalent in patients with EGFR T790M-positive disease treated with later-line EGFR-TKIs, and has been demonstrated to be a late-occurring resistance event in the second-line osimertinib setting, suggesting that EGFR C797S represents a late-onset resistance mechanism (85).

T790M mutation

The T790M mutation is one of the most predominant acquired resistance mechanisms to first- and second-generation EGFR-TKIs. The T790M mutation occurs in the EGFR ATP-binding pocket, changing the amino acid at position 790 from threonine to methionine. This increases ATP affinity by 5-fold and significantly increases steric hindrance, thus reducing the efficacy of first- and second-generation TKIs (30). The T790M mutation exerts dual resistance mechanisms: it allosterically stabilizes EGFR’s active kinase conformation while sterically hindering drug binding, collectively diminishing the efficacy of first- and second-generation TKIs (86). This mutation accounts for 50–60% of acquired resistance cases, with a slightly higher prevalence in Asian (54.3%) vs. European (49.8%) populations, reflecting potential ethnic differences in resistance evolution (87). Compounding the therapeutic challenge, the T790M mutation frequently co-occurs (~30% prevalence) with other driver mutations such as L858R in resistant tumors, creating complex mutational profiles that significantly complicate treatment strategies and often necessitate combination therapeutic approaches. Due to the high incidence of the T790M mutation and its low sensitivity to first- and second-generation TKIs, third-generation TKIs have been developed. They form irreversible covalent bonds with the C797 residue, thus overcoming the increased ATP affinity conferred by the T790M mutation (19). The FLAURA trial established the superiority of osimertinib over first-generation TKIs, demonstrating significantly prolonged PFS (18.9 vs. 10.2 months) and OS (38.6 vs. 31.8 months) (34). Similarly, the AENEAS trial revealed the exceptional clinical benefit of aumolertinib, with centrally confirmed PFS and DOR both reaching 29.0 months, compared with 8.3 months for gefitinib (88). These findings were further corroborated by the FURLONG trial, in which furmonertinib outperformed gefitinib with a nearly doubled median PFS (20.8 vs. 11.1 months) while maintaining comparable OS rates (84% vs. 82%) (89).

Histological transformation

Histologic transformation from NSCLC to small cell lung cancer (SCLC) occurs in 4–15% of cases and represents a clinically significant resistance mechanism to both first- and third-generation EGFR-TKIs, including osimertinib, with substantial prognostic implications (90-93). Emerging clinical evidence confirms that histologic transformation to SCLC represents a consistent resistance mechanism across multiple generations of EGFR-TKIs therapy, including third-line osimertinib treatment (94-96). Lee and colleagues identified RB1 and TP53 tumor suppressor genes as key drivers of NSCLC-to-SCLC transformation, with their complete functional loss being essential throughout this histologic conversion process (97). Monitoring plasma circulating tumor DNA (ctDNA) for RB1/TP53 mutations and measuring neuron-specific enolase levels during osimertinib progression may help detect emerging SCLC transformation (90).

Recent studies have documented that NSCLC patients developing resistance to EGFR-TKIs (including both gefitinib and osimertinib) frequently exhibit molecular and phenotypic hallmarks of EMT. This resistance-associated transition is characterized by a consistent downregulation of epithelial markers (notably E-cadherin) coupled with upregulated mesenchymal markers (particularly vimentin), loss of polarity and cell-contacts, occurring independently of secondary EGFR mutations (98-100). Emerging research has linked osimertinib resistance in EGFR-mutant NSCLC to upregulated TWIST-1, a master regulator of EMT, prompting ongoing development of targeted inhibitors against this transcription factor as a potential therapeutic strategy (101). Besides, evidence shows that EMT may be associated with AXL regulation. The activation of EMT transcriptional programs, particularly through vimentin upregulation, appears to contribute to AXL overexpression in EGFR-TKI-resistant, EGFR-mutant lung cancer cells (102).

Aberrant bypassing activation

MET amplification

MET factor, a tyrosine kinase receptor belonging to the hepatocyte growth factor receptor (HGFR) family, shares mechanistic parallels with EGFR. Upon HGF binding, MET undergoes dimerization and autophosphorylation, initiating downstream signaling through both the MAPK/ERK and PI3K/AKT pathways—thereby bypassing EGFR-dependent signaling and establishing an alternative growth-promoting cascade (103,104). The AURA3 trial revealed that 19% (14/73) of patients developed MET amplification following second-line osimertinib treatment, establishing it as the second most prevalent resistance mechanism after C797S mutations in this clinical context (83). The FLAURA trial identified MET amplification in 15% of patients following first-line osimertinib treatment, confirming its role as a clinically significant resistance mechanism to third-generation EGFR-TKIs (105). These findings strongly suggest that MET amplification represents a major resistance mechanism across third-generation EGFR-TKIs, also emerging in 15% of first-line osimertinib-treated patients (FLAURA trial) and 8–26% of rociletinib-treated cases, positioning it as one of the most prevalent on-target resistance patterns following frontline TKI therapy (19).

AXL pathway aberrant activation

AXL, an RTK, binds GAS6 to activate downstream signaling cascades that regulate cell proliferation, survival, migration, angiogenesis, and natural killer (NK) cell development (106,107,108). Taniguchi et al. demonstrated that increased AXL expression is associated with diminished therapeutic response to osimertinib, indicating its potential utility as a predictive biomarker for acquired resistance in EGFR-mutant NSCLC (109). Emerging evidence indicates that EGFR-AXL crosstalk generates quantitatively greater and qualitatively more complex downstream signaling outputs compared to EGFR activation alone, creating an amplified oncogenic signaling network that enhances tumor survival and progression (102,110). The SAKK trial revealed a clinically significant association between elevated AXL expression and increased CD34/bcl-2 levels, with this molecular signature correlating with poorer PFS and OS outcomes in the studied cohort (111). Furthermore, genomic analysis identified AXL amplification in patients who developed resistance to abivertinib therapy (112), highlighting that both mutation and amplification of AXL are potential reasons for third-generation EGFR-TKIs resistance. Current clinical trials have demonstrated efficacy for multiple AXL-targeted regimens including Cabozantinib monotherapy (median PFS 5.2 months), osimertinib-cabozantinib combinations, cabozantinib-nivolumab-ipilimumab triplets (57% 12-month PFS rate), and cabozantinib-atezolizumab pairings (median PFS/OS 4.6/10.7 months), collectively validating AXL inhibition as a viable strategy against resistant tumors through diverse therapeutic approaches (113-118).

HER2 amplification

HER2, a member of the HER receptor family, significantly modulates both the PI3K/AKT/mTOR and MAPK signaling cascades downstream of EGFR. Its amplification drives constitutive activation of these pathways, thereby fostering resistance to third-generation EGFR-TKIs through sustained pro-survival signaling (119). Unlike HER1 (EGFR), which binds extracellular ligands such as EGF, HER2 operates through a distinct mechanism—it cannot bind any known extracellular proteins. Instead, HER2 exerts its oncogenic effects primarily by forming heterodimers with other ErbB family members (HER1/3/4), thereby amplifying their downstream signaling cascades. This unique dimerization-dependent activation enables HER2 to serve as a potent signaling amplifier in the ErbB network (120). The AURA3 trial revealed HER2 amplification in 6% of osimertinib-resistant patients receiving second-line therapy (83), a finding consistent with the 10% prevalence reported by Le et al. (82) in their investigation of resistance mechanisms. Notably, the FLAURA study demonstrated a lower 2% incidence of HER2 amplification among patients developing resistance to first-line osimertinib treatment, suggesting potential line-of-therapy differences in resistance patterns (105).

Aberrant fibroblast growth factor receptor (FGFR) signaling pathway activation

The FGFR signaling pathway regulates cell proliferation, metabolism, and invasion through key downstream effectors like MAPK and PI3K/AKT/mTOR. Its dysregulation drives cancer progression and therapy resistance, making it an important therapeutic target (121). Kim et al. demonstrated that elevated FGFR1 amplification and FGF2 overexpression were observed in osimertinib-resistant patients, indicating a potential role of the FGF2-FGFR1 autocrine signaling axis in mediating acquired resistance to this third-generation EGFR-TKIs (95). Analysis of ctDNA in plasma samples identified coexisting FGFR3-TACC3 fusion mutations in T790M-positive patients, with subsequent disease progression observed following treatment with both osimertinib and naquotinib, suggesting a potential resistance mechanism mediated by FGFR3-driven bypass signaling (122). These findings implicate dysregulated FGFR pathway activity as a potential mediator of resistance to third-generation EGFR-TKIs.

Aberrant IGF1R activation

Transcriptomic profiling of resistant cell line models revealed that IGFBP3 and IGFBP4—known negative regulators of IGF signaling that competitively inhibit IGF/IGF1R binding while possessing intrinsic IGF-independent growth suppressive properties—were responsible for IGF1R-mediated drug resistance (123,124). As IGFBP3 and IGFBP4 are negative regulators, while EGFR-TKIs decrease EGF concentration, IGFBP3/4 are downregulated and IGF successfully binds with IGF1R, thus continuously activating PI3K/AKT/mTOR pathway in order to confront the EGFR-TKIs blockade (123). What’s more, recent research by Zhou and colleagues demonstrated that activation of the IGF1R signaling pathway promotes acquired resistance to EGFR-TKIs in NSCLC cells, primarily through induction of EMT mediated by upregulation of Snail and downregulation of E-cadherin expression (125). Clinical studies demonstrate that ganitumab significantly extends median OS to 16.0 vs. 6.8 months with placebo in patients exhibiting high IGF1/IGFBP3 expression, validating its therapeutic efficacy for this biomarker-defined subgroup (126).

Aberrant downstream pathway activation

PIK3CA mutation

PIK3CA mutation and amplification influence PI3K/AKT/mTOR signaling pathway, thus enhancing tumor infiltration and migration. PIK3CA amplification is highly relevant to third-generation EGFR-TKIs resistance, especially osimertinib. Different clinical studies have shown relevant outcomes. In the FLAURA trial, PIK3CA mutations were detected at varying frequencies, with E545K being the most prevalent (4%), followed by E453K (1%) and H1047R (1%) (105). Oxnard and colleagues identified PIK3CA gene amplification in approximately 10% (4 out of 41) of cases exhibiting resistance to osimertinib therapy, highlighting this genomic alteration as a clinically relevant resistance mechanism (127). Till now, a variety of PIK3CA-relevant drugs are undergoing clinical research. A phase III trial demonstrated that the inavolisib-palbociclib-fulvestrant combination achieves superior efficacy with a PFS of 15.0 months and an ORR of 58.4%, while maintaining a favorable safety profile compared to alternative treatments (128). Besides, according to phase III SOLAR-1 trial, in the PIK3CA-mutated patients with liver metastasis, median OS are 39.3 and 37.2 months, respectively (129). Both these two innovative drugs have shown exceptionally promising prospect, demonstrating both strong efficacy and favorable safety profiles. The IPATunity130 phase III trial revealed that the ipatasertib-paclitaxel combination demonstrated comparable PFS, OS and overall grade ≥3 adverse event rates to placebo-paclitaxel, though with increased incidence of grade ≥3 diarrhea (11.3% vs. 1.0%) and higher rates of dose reductions (34% vs. 9%) in the experimental arm (130).

Loss of PTEN gene

As a tumor suppressor gene, PTEN plays a crucial protective role in preventing normal cells transformation into malignant tumor cells (131,132). Research has demonstrated that even minor reductions in PTEN expression can elevate cellular transformation risk, with tumor progression markedly accelerating when PTEN levels fall below 50% of the normal threshold (133). PTEN mediates the conversion of PIP3 back to PIP2 (134,135), thereby suppressing the PI3K/AKT signaling pathway, as evidenced by significantly reduced AKT phosphorylation levels (136). Mechanistically, the transcription factor EGR1 regulates PTEN expression through nuclear translocation, where it directly binds to the PTEN promoter to activate its transcription. This EGR1-mediated upregulation of PTEN serves as a critical tumor suppressive mechanism (137). However, this regulatory mechanism was observed to be significantly attenuated in drug-resistant cell models, while showing restoration of function in revertant models, indicating a dynamic, resistance-associated modulation of the EGR1-PTEN tumor suppressive axis (136). To sum up, it is clear that EGR1 downregulation transcriptionally suppresses PTEN expression.

KRAS and BRAF mutations

The RAS-RAF signaling cascade, a canonical EGFR downstream pathway that regulates diverse cellular processes, has KRAS and BRAF as core members of the RAS and RAF kinase families, respectively. KRAS and BRAF alterations are rare acquired resistance mechanisms to osimertinib: the phase III AURA3 trial detected KRAS G12D and BRAF V600E mutations in only 1% and 3% of cases, respectively (83), consistent with findings from the FLAURA trial, which reported a 3% incidence of BRAF V600E and 1% prevalence for each KRAS variant (A146T, G12C, G12D) (105). Rarer events including KRAS Q61K mutation and ESYT2-BRAF gene fusion have also been documented in other studies (127). Sotorasib is a specific, irreversible inhibitor of the GTPase protein of KRAS G12C. According to phase III trial NCT04303780, sotorasib shows satisfactory PFS compared with conventional docetaxel, 5.6 vs. 4.5 months, respectively (138). The phase III CodeBreaK 200 trial showed that patients suffer less side effects when treated with sotorasib, compared with docetaxel, highlighting the higher safety profile of sotorasib (139). Another clinical study ICECREAM demonstrates how to deal with KRAS G12D more effectively. Cetuximab plus irinotecan shows longer 6 months PFS rate, 23% vs. 10%, compared with cetuximab alone. What’s more, stable disease rate also proves combination therapy better, 70% vs. 58%, respectively (140). In another phase III study, statistics also show that using bevacizumab significantly prolongs PFS in both wild type patients and KRAS-mutant patients (141). Several clinical studies also offer considerable drugs for BRAF mutation: atezolizumab, vemurafenib, dabrafenib plus trametinib (142-144). These 3 medications demonstrate substantial therapeutic efficacy coupled with favorable safety profiles and prognostic outcomes.

Gene fusion

Oncogenic fusion events have been detected in 3–10% of second-line osimertinib resistance cases, functioning as driver alterations that may coexist with other resistance mechanisms including EGFR C797S mutations, BRAF mutations, and MET amplification (83). Key oncogenic fusions implicated in second-line osimertinib resistance include FGFR3-TACC3 and RET-ERCC1, along with several other recurrent alterations such as CCDC6-RET, NTRK1-TPM3, NCOA4-RET, GOPC-ROS1, AGK-BRAF, and ESYT2-BRAF (82,127,145,146). Notably, dual targeting of EGFR and RET using osimertinib combined with the selective RET inhibitor BLU-667 (pralsetinib) demonstrated clinical efficacy in overcoming CCDC6-RET fusion-mediated resistance (145). Recent research has revealed that RTK and BRAF kinase fusions, though rare, can drive TKI resistance in advanced NSCLC. Notably, a previously unreported PLEKHA7-ALK fusion emerged following osimertinib therapy, expanding the spectrum of known resistance mechanisms (147). A confirmed EML4-ALK fusion emerging after second-line osimertinib failure demonstrated clinical significance when sequential therapy combining osimertinib with the ALK inhibitor crizotinib achieved disease stabilization (148).

Drug-tolerant cell

Recent research has discovered a special group of cancer cells in EGFR-mutant lung cancer that can survive targeted drug treatment (149,150). These “tolerant cells” grow more slowly and are harder to kill with current therapies, which helps explain why tumors eventually come back after initially responding well to treatment, resulting in disease progression (151-153). Emerging evidence indicates that epigenetic modifications are pivotal in facilitating cancer cell adaptation to treatment, allowing them to survive therapy (154,155). Additionally, the tumor microenvironment, particularly cancer-associated fibroblasts, has been shown to actively support the formation and maintenance of these drug-resistant persister cell populations (150) (Table 1).

Taken together, the mechanisms underlying resistance to EGFR-TKIs exhibit extraordinary complexity and heterogeneity. Primary resistance is mainly driven by the structural diversity of EGFR-mutant subtypes (e.g., ex20ins mutations and PACC mutations) as well as concurrent pre-existing genetic aberrations. In contrast, acquired resistance encompasses a broad spectrum of mechanisms, including on-target secondary mutations in EGFR itself (such as T790M and C797S), bypass pathway activation (e.g., aberrations in MET, HER2, and AXL), alterations of downstream signaling pathways (involving PI3K, PTEN, KRAS, and BRAF), histological transformation (including SCLC transformation and EMT), and oncogenic gene fusions. Distinct resistance mechanisms can coexist in the same patient, even within a single tumor lesion, and undergo clonal selection and the evolution of clonal dominance under therapeutic pressure. The recently characterized drug-tolerant persister (DTP) cells have further revealed the fundamental roles of epigenetic modifications and the tumor microenvironment in resistance evolution. Looking forward, it is imperative to conduct in-depth dissection of the coexistence and evolutionary patterns of resistant clones based on dynamic molecular monitoring, and explore combined targeted strategies to address the interplay of multiple concurrent resistance mechanisms, thereby advancing the continuous optimization of individualized treatment regimens (Figure 5).

Figure 5 A complex network of cell signaling pathways and genetic alterations associated with cancer cell growth and proliferation. It highlights key receptors such as EGFR, FGFR1, and IGF1R, activated by their corresponding ligands, leading to downstream signaling via pathways like RAS-RAF-MEK-ERK and PI3K-AKT-mTOR. Various gene mutations and amplifications, such as EGFR mutations and HER2 amplifications, result in abnormal signaling activity. The figure also covers processes related to cancer, including gene fusions, transcriptions, and the histological transformation of NSCLC to other types, involving EMT. Additionally, it outlines interactions between molecules, highlighting activation and inhibition dynamics, which are influenced by factors like AXL activation and PTEN loss. EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; NSCLC, non-small cell lung cancer.

Approaches to overcome drug-resistance

Despite osimertinib’s efficacy in EGFR-mutant NSCLC, therapeutic resistance inevitably arises due to tumor heterogeneity and selection pressure. This complex resistance landscape features coexisting mechanisms that evolve spatially (across tumor sites) and temporally (during treatment), creating significant challenges for durable response. The dynamic clonal evolution drives diverse resistance patterns, including secondary mutations and bypass signaling, underscoring the need for comprehensive molecular profiling and tailored combination strategies (156). Several methods to overcome osimertinib resistance are included in the following text.

Fourth-generation EGFR-TKIs

Given that the C797S mutation represents the predominant resistance mutation to osimertinib, the development of therapeutic strategies targeting this mutational site has emerged as a major research focus, and clinical trials of fourth-generation EGFR-TKIs have been progressively advanced in this context. It encompasses multiple categories: next-generation allosteric small-molecule inhibitors that target mutant EGFR independently of covalent binding to the C797 site; bispecific or multispecific antibodies against EGFR and bypass receptors such as MET; and rational combination regimens designed to overcome or delay resistance (157). From the perspective of drug structural evolution, the development of EGFR-TKIs follows a distinct iterative pattern: first- and second-generation inhibitors are built on a quinazoline core scaffold (e.g., gefitinib, erlotinib) (158); third-generation agents shift to pyrimidine derivatives (e.g., osimertinib) (159); while fourth-generation compounds undergo further structural optimization based on existing frameworks, with some exerting dual ALK/EGFR inhibitory activity (e.g., brigatinib). Such an iterative scaffold-optimization strategy provides important theoretical support for the development of fourth-generation EGFR-TKIs (160,161). Fourth-generation EGFR-TKIs currently under preclinical and early clinical development can be classified according to their mechanisms of action. These agents differ in their inhibitory potency against osimertinib-resistant mutations, applicable mutational subtypes, and clinical implications.

Allosteric inhibitors of fourth-generation EGFR-TKIs

Represented by EAI045 and its derivatives, this class of agents exerts its core mechanism by targeting the allosteric binding pocket of EGFR, with major activity against the L858R/T790M/C797S triple mutation. However, their inhibitory activity is dependent on the conformational state of EGFR. As the first allosteric inhibitor targeting EGFR with the T790M/C797S double mutation, EAI045 requires combination with the anti-EGFR antibody cetuximab to achieve selective inhibition: cetuximab blocks ligand-dependent EGFR dimerization, thereby facilitating the targeting of dimerization-deficient EGFR-mutants by EAI045 (162,163). EAI045 was developed on the basis of the compound EAI001, which was identified in high throughput screening. EAI001 exhibits inhibitory activity against L858R/T790M-mutant EGFR with a half maximal inhibitory concentration (IC₅₀) of 24 nM, whereas its optimized derivative EAI045 demonstrates significantly enhanced potency (IC₅₀ =3 nM) against the same target, reflecting an 8-fold improvement in binding affinity through structural refinement. What’s more, EAI045 shows outstanding efficacy in animal models. However, EAI045 demonstrated limited clinical potential due to poor antitumor activity and incomplete suppression of EGFR autophosphorylation in cellular models (164). Structural studies reveal that this stems from fundamental differences in wild-type vs. mutant EGFR dimer activation: in EGFR^WT, asymmetric dimerization induces a C-helix “in” conformation only in the receiver subunit, while mutant EGFR (e.g., L858R/T790M) activates both subunits symmetrically (164). Since EAI045 binds only one subunit per dimer, it fails to fully block downstream signaling in mutant-driven tumors—a critical limitation explaining its partial efficacy (164).

Through iterative structural optimization of EAI001 analogs, researchers developed JBJ-04-125-02, a novel allosteric inhibitor that binds the C-helix-out conformation of EGFR similarly to EAI045 but induces a unique A-loop conformation stabilized by a hydrogen bond between its piperazine group and Glu865 (165). Unlike EAI045, JBJ-04-125-02 demonstrates single-agent cytotoxicity against L858R, L858R/T790M, and L858R/T790M/C797S mutants without requiring cetuximab coadministration, though it remains ineffective against EGFR^WT and Ex19del variants (165). Intriguingly, osimertinib may potentiate JBJ-04-125-02’s binding to EGFR, suggesting combination strategies could enhance antitumor efficacy (165). The subsequently identified allosteric inhibitor JBJ-09-063 exerts potent single-agent activity in vitro and in vivo against multiple osimertinib-resistant mutations including C797S, while demonstrating high selectivity for mutant EGFR. However, homodimerization or heterodimerization of the ERBB family (which can be induced by ligand stimulation or forced dimerization) compromises its efficacy, and combination therapy with osimertinib results in synergistic antitumor effects. Nonetheless, this compound still requires further structural and pharmacological optimization to advance into a clinical candidate (166).

While these allosteric inhibitors represent promising approaches for overcoming resistance to third-generation EGFR-TKIs in L858R-based mutants, no compound addresses resistance driven by Ex19del/T790M/C797S triple mutations (164,165).

ATP-competitive inhibitors of fourth-generation EGFR‑TKIs

Represented by CH7233163, this class of agents exerts its inhibitory effects by directly binding to the ATP-binding pocket of EGFR. A key advantage is that they cover multiple osimertinib-resistant triple mutations, and particularly overcome the inactivity of allosteric inhibitors against the Ex19del/T790M/C797S mutation. Unlike wild-type EGFR, CH7233163 selectively targets mutant variants (L858R/T790M, Ex19del/T790M, Ex19del, and L858R), exhibiting significant antitumor effects in cellular models (167). Structural analysis reveals that CH7233163 binds the ATP-binding pocket through hydrogen bonds and CH/π interactions, bypassing Ser797—a key distinction from osimertinib (167). Additionally, CH7233163 engages the P-loop, hinge region, and Met790, enhancing its binding affinity. Unlike EAI001, CH7233163 stabilizes the C-helix conformation of EGFR, enabling effective inhibition of the Ex19del/T790M/C797S mutation (167).

In addition, multi-target inhibitors and novel compounds have been incorporated into the research and development pipeline of fourth-generation EGFR-TKIs, further expanding the therapeutic options for osimertinib resistance.

Brigatinib, originally developed as a next-generation ALK inhibitor, has demonstrated dual ALK/EGFR inhibitory activity with particular efficacy against the C797S/T790M/Ex19del triple-mutant EGFR variant. Preclinical studies confirm its ability to suppress proliferation in both cellular models (in vitro) and animal studies (in vivo) harboring this resistant mutation profile, positioning it as a potential therapeutic option for patients progressing on third-generation EGFR-TKIs (168-170).

TQB3804 and BBT-176, as two novel fourth-generation EGFR-TKIs, have both exhibited potent inhibitory activity against two types of EGFR triple mutations, namely Ex19del/T790M/C797S and L858R/T790M/C797S, in preclinical studies. Among them, preclinical studies of TQB3804 have shown that its IC₅₀ values against wild-type EGFR (EGFR^WT) and EGFR L858R/T790M/C797S are 7.92 and 0.218 nM, respectively. This drug can inhibit the growth of xenograft tumors by targeting EGFR triple mutations and downregulating the expression of phosphorylated EGFR (p-EGFR), phosphorylated AKT (p-AKT), and phosphorylated extracellular signal-regulated kinase (p-ERK) (171). The phase I clinical trial of TQB3804 (NCT04128085) was initiated in November 2019, and no relevant data on the safety and efficacy in patients with C797S mutation-resistant cancer have been reported to date.

BBT-176 is a reversible ATP-competitive EGFR inhibitor that exerts potent inhibitory effects on both Ex19del/T790M/C797S and L858R/T790M/C797S triple mutations, and can significantly suppress tumor growth and induce tumor regression in animal models. However, the clinical results announced in 2023 were unsatisfactory: only 1 of 18 treated patients achieved a partial response (PR), and the relevant clinical trial has been suspended or terminated (172,173).

Similarly, BLU-945, another fourth-generation EGFR-TKI targeting EGFR T790M/C797S, exhibits potent inhibitory activity against the aforementioned resistant mutants and is highly selective for EGFR^WT. In vivo studies further confirmed that BLU-945, either as monotherapy or in combination with osimertinib/gefitinib, can effectively inhibit tumor growth in cell-derived xenograft and patient-derived xenograft models harboring the Ex19del/T790M/C797S mutation (171,174). Nevertheless, the results of its phase II clinical study showed that 2 patients in the high-dose BLU-945 monotherapy group achieved a PR; 10 patients in the BLU-945 plus osimertinib group achieved PR, of which 4 were confirmed PR. However, 12 cases of dose-limiting toxicities occurred in the high-dose group, mainly attributed to liver dysfunction; the effective dose of the combination therapy exceeded the toxicity threshold, and the relevant clinical trial has been suspended or terminated (175).

BDTX-1535 is a fourth-generation irreversible covalent EGFR inhibitor with favorable brain penetration. Data from the 2024 AACR meeting showed that it achieved an ORR of 55% in patients with osimertinib-resistant cancer, with no dose-limiting toxicities observed at low doses, while related toxicities occurred at high doses (176).

ES-072 is a fourth-generation irreversible covalent EGFR inhibitor with inhibitory activity against EGFR triple mutation-harboring cells. Zheng et al. completed the phase I clinical trial of this drug (CTR20180074) in patients with NSCLC carrying the EGFR T790M mutation. The results demonstrated that ES-072 had favorable safety and tolerability, with the incidence rates of rash and diarrhea being 15.8% and 10.5%, respectively, indicating its higher selectivity for mutant EGFR. However, ES-072 presents significant cardiotoxicity, with a high incidence (57.9%) of QT interval prolongation, so monitoring of cardiac function parameters should be strengthened in subsequent clinical trials (177).

JIN-A02 is a novel oral fourth-generation EGFR-TKI. It exerts a significant antiproliferative effect on cells harboring the Del19/T790M/C797S triple mutation, with an IC₅₀ of 92.1 nM. In patient-derived cancer (PDC) models, once-daily administration of 50 and 60 mg/kg doses significantly inhibited tumor growth in mice, with tumor growth inhibition (TGI) rates of 91.7% and 95.7%, respectively. Preliminary dose-finding results from the phase I clinical study showed that JIN-A02 could induce shrinkage of tumors and brain metastases, with no reported cases of rash, diarrhea, or cardiotoxicity. At present, the phase II clinical trial of this drug (NCT05394831) is underway to evaluate its safety, tolerability, pharmacokinetics, and antitumor activity in patients with EGFR-mutant advanced NSCLC, and the results have not yet been published (178) (Table 2).

Combination therapy

Despite the potent initial efficacy of EGFR-TKIs, the inevitable emergence of resistance has prompted clinical investigations into first-line combination therapies to prolong treatment response.

EGFR-TKIs combined with chemotherapy

The NEJ009 trial (UMIN000006340) and Noronha et al.’s study demonstrated that adding 4–6 cycles of chemotherapy to gefitinib treatment led to significant improvements in both first-line PFS and subsequent PFS2 (defined as time from randomization until progression after both platinum-based chemotherapy and gefitinib), although this combination regimen was associated with increased toxicity (179,180). Although OS benefits were observed in the two clinical trials, extended follow-up data from NEJ009 revealed that this OS advantage did not reach statistical significance (181).

The global FLAURA2 trial (NCT04035486) investigated osimertinib combined with carboplatin/pemetrexed (4 cycles) followed by pemetrexed/osimertinib maintenance vs. osimertinib monotherapy. The combination demonstrated significantly prolonged PFS vs. monotherapy (median 25.5 vs. 16.7 months; HR =0.62, 95% CI: 0.49–0.79) (182). However, the combination therapy demonstrated a significantly higher incidence of grade ≥3 adverse events compared to monotherapy (64% vs. 27%). These increased toxicities primarily reflected classic chemotherapy-related side effects, particularly hematologic adverse events (183). The combination regimen showed promising central nervous system (CNS) efficacy, demonstrating a 42% reduction in risk of CNS progression compared to osimertinib monotherapy (HR =0.58, 95% CI: 0.33–1.01), though the CI marginally crossed unity (184). For patients with baseline brain metastases, the chemotherapy combination showed significant PFS improvement (median 24.9 vs. 13.8 months; HR =0.47, 95% CI: 0.33–0.66). This contrasted with expectations given chemotherapy’s historically limited intracranial efficacy compared to third-generation EGFR-TKIs. Notably, while first-line chemo-TKI combination extended PFS by 8 months, second-line chemotherapy alone achieved only 4.2–4.4 months median PFS (24,185).

EGFR-TKIs combined with EGFR-MET bispecific antibodies

The MARIPOSA trial (NCT04487080) investigated first-line amivantamab (an EGFR-MET bispecific antibody) combined with lazertinib vs. osimertinib or lazertinib monotherapy in metastatic NSCLC with EGFR mutations, using a 2:2:1 randomization. The combination demonstrated superior efficacy over osimertinib alone, with significantly prolonged median PFS (23.7 vs. 16.6 months; HR =0.70, 95% CI: 0.58–0.85), while lazertinib monotherapy showed comparable PFS to osimertinib (186). The updated analysis revealed that the amivantamab-lazertinib combination achieved a clinically meaningful OS advantage compared to control therapy (median OS not reached vs. 36.7 months; HR =0.75, 95% CI: 0.61–0.92) (187). The MARIPOSA trial design prohibited crossover to amivantamab-containing regimens (like MARIPOSA-2, NCT04988295) for the control group upon progression. The amivantamab-lazertinib combination showed substantially higher toxicity than osimertinib monotherapy, with grade ≥3 adverse events occurring in 75% vs. 43% of patients. The most frequent toxicities included paronychia, rash, and infusion reactions, while thromboembolic events were markedly more common with the combination (37% vs. 9%), predominantly occurring within the first 4 months—prompting FDA-mandated prophylactic anticoagulation during this period in subsequent trials. Notably, the combination demonstrated particular efficacy in high-risk subgroups, including patients with CNS/liver metastases, TP53 co-mutations, or persistent ctDNA after two treatment cycles (188). The MARIPOSA trial employed a rigorous brain magnetic resonance imaging (MRI) monitoring protocol, requiring scans every 8 weeks for the first 30 months (then every 12 weeks) for patients with baseline brain metastases and every 24 weeks for those without, potentially enabling earlier CNS progression detection compared to trials with less frequent imaging.

In the PALOMA-3 trial (NCT05388669), subcutaneous amivantamab combined with lazertinib demonstrated non-inferior pharmacokinetics and ORR compared to intravenous administration while showing substantially lower rates of infusion reactions (13% vs. 66%) and thromboembolic events (9% vs. 14%), with 81% of patients receiving prophylactic anticoagulation. The subcutaneous formulation reduced administration time from approximately 5 hours to 5 minutes, significantly improving patient and provider experience. Notably, subcutaneous administration was associated with superior DOR and OS (HR =0.62, 95% CI: 0.42–0.92), suggesting potential immunological advantages through subcutaneous tissue interactions, while its improved safety profile may facilitate future home-based treatment administration (189,190).

EGFR-TKIs combined with anti-angiogenic agents

Multiple clinical investigations have explored anti-angiogenic strategies in EGFR-mutant NSCLC. Two pivotal phase III trials demonstrated that adding bevacizumab (a VEGF-targeting monoclonal antibody) to first-line erlotinib significantly prolonged PFS compared to erlotinib monotherapy—with median PFS improvements of 17.9 vs. 11.2 months (HR =0.55, 95% CI 0.41–0.73) (191) and 16.9 vs. 13.3 months (HR =0.605, 95% CI: 0.42–0.88) (192), respectively. The erlotinib-ramucirumab combination, targeting VEGF pathway inhibition, demonstrated comparable efficacy with a median PFS of 19.4 vs. 12.4 months for erlotinib alone (HR =0.59, 95% CI: 0.46–0.76), reinforcing the therapeutic value of dual EGFR/VEGF blockade in this population (193). Current evidence consistently shows no OS benefit and increased toxicity when combining anti-VEGF agents with EGFR-TKIs. The role of adding these agents to third-generation TKIs like osimertinib remains uncertain, supported only by phase II studies without phase III validation. Conflicting PFS results were observed across trials: while WJOG9717L (UMIN000030206) and OSIRAM (UMIN2080224085) showed no benefit from adding bevacizumab (194) or ramucirumab (195) to osimertinib, the RAMOSE trial (46) (NCT03909334) demonstrated improved PFS (24.8 vs. 15.6 months; HR =0.55, 95% CI: 0.32–0.93) at the cost of higher grade ≥3 adverse events (53% vs. 41%) (196). These collective findings do not support routine use of anti-VEGF combinations with first-line osimertinib (Table 3).

Consolidative local therapies

Local ablative therapies for residual disease in EGFR-TKI responders target drug-persistent tumor cells, potentially delaying resistance. This approach is particularly relevant for EGFR-mutant NSCLC, which often progresses at original disease sites. Combining local treatments with continued TKI therapy may extend disease control by eliminating residual foci before resistant clones emerge (197). Two randomized trials have investigated radiotherapy combined with EGFR-TKIs for oligometastatic NSCLC. The phase II SINDAS trial (NCT02893332) evaluated first-generation EGFR-TKIs with or without stereotactic radiotherapy in patients with ≤5 metastatic lesions (198). The addition of radiotherapy significantly improved both PFS (median PFS 20.2 vs. 12.5 months; HR =0.22, 95% CI: 0.17–0.46) and OS (median OS 25.5 vs. 17.6 months; HR =0.44, 95% CI: 0.28–0.68) in the SINDAS trial. However, the study’s applicability is limited by its focus on bone metastases (excluding brain lesions) and high screen-failure rate, indicating a highly selected population. A separate phase III trial evaluated icotinib with or without thoracic radiotherapy in treatment-naive oligometastatic patients, though results are pending (199). Patients receiving thoracic radiotherapy with TKIs showed improved outcomes (median PFS 17.1 vs. 10.6 months, HR =0.57, P=0.004; median OS 34.4 vs. 26.2 months, HR =0.62, P=0.029) compared to TKI alone, though with increased grade ≥3 adverse events (11.9% vs. 5.1%). Notably, combining osimertinib with thoracic radiation may elevate severe pneumonitis risk. Radiotherapy to other metastatic sites was permitted per clinician judgment (200). Based on current evidence, we recommend temporarily pausing osimertinib during thoracic radiotherapy to mitigate pneumonitis risk, while limiting the interruption duration to prevent disease flare (observed in 23% of patients within a median of 8 days post-cessation) or progression at untreated sites (201). For oligometastatic EGFR-mutant NSCLC, consolidative radiotherapy to residual disease sites may be considered in select patients demonstrating response to first-line EGFR-TKIs, though current evidence lacks clear guidance on optimal response duration or depth required for this intervention.

Biomarker-selected treatment

Treatment strategies for EGFR-mutant NSCLC with secondary resistance mutations should be mutation-specific: third-generation osimertinib for T790M, second-generation afatinib for G724S/L718Q/V (202,203), and first-generation gefitinib showing superior sensitivity for C797S compared to later-generation agents (204).

For EGFR-mutant NSCLC patients developing MET amplification-mediated resistance, clinical trials have demonstrated the efficacy of osimertinib-savolitinib combinations, with the SAVANNAH (205) (NCT03778229) and ORCHARD (206) (NCT03944772) trials reporting ORRs of 32% (95% CI: 26–39%) and 41% (80% CI: 25–59%) respectively. Response rates correlated strongly with MET expression levels, reaching 56% (95% CI: 39–59%) in tumors with high MET amplification (GCN ≥10) or overexpression [immunohistochemistry (IHC) 3+ in ≥90% cells] vs. just 9% (95% CI: 4–18%) in less amplified tumors (205,207). The phase III SACHI trial (NCT05015608) further confirmed the regimen’s superiority over chemotherapy in this population, while savolitinib monotherapy’s inferior response (ORR 16%, 95% CI: 5–36%) underscores the necessity of concurrent EGFR inhibition (208). Interestingly, the INSIGHT-2 trial revealed that patients with concurrent resistance mechanisms (e.g., BRAF, ALK, or RAS alterations) showed no response to combination therapy, underscoring the critical need for comprehensive molecular profiling at disease progression to identify all clinically relevant resistance pathways (209).

Given the limited evidence supporting combination therapies targeting bypass resistance mechanisms with osimertinib, enrollment in biomarker-driven clinical trials should be prioritized when available (210). Several case reports and series have documented the combination of selpercatinib or pralsetinib with osimertinib for patients developing RET fusion-mediated resistance to EGFR-targeted therapy (145,148,211). The combination of osimertinib with alectinib has been explored in cases of acquired ALK fusion-mediated resistance, while osimertinib paired with BRAF/MEK inhibitors has been investigated for BRAF mutation-driven resistance in EGFR-mutant NSCLC (212-214). Emerging preclinical and early clinical evidence suggests potential strategies for overcoming specific resistance mechanisms in EGFR-mutant NSCLC: capivasertib combined with osimertinib may address PI3K pathway-driven resistance, while CDK4/6 inhibitors paired with osimertinib show promise against cell cycle alterations (215,216). Besides, the TRAEMOS trial (NCT03784599) demonstrated limited efficacy of osimertinib plus trastuzumab emtansine in addressing HER2-mediated resistance (217). To sum up, facing osimertinib resistance, it is essential to utilize comprehensive molecular testing to “know the enemy and know yourself”, then tailor the most targeted combination therapy strategy based on the specific resistance mechanism, while actively exploring future directions through clinical trials.

Conclusions

Currently, the therapeutic landscape of advanced EGFR-mutant NSCLC is in a transitional phase, which has witnessed breakthrough advances while facing numerous persistent challenges that urgently need to be addressed. The high complexity and dynamic evolutionary characteristics of osimertinib resistance mechanisms represent the fundamental bottleneck restricting further improvement of clinical efficacy. Such complexity is mainly manifested in multiple dimensions: first, on-target and off-target resistance mechanisms show a dynamic shifting pattern, and the resistance spectrum differs significantly across treatment lines—in second-line osimertinib therapy for T790M-positive patients, the incidence of the on-target C797S mutation is approximately 14%, and the incidence of off-target MET amplification is about 19% (218). Analyses based on the FLAURA study demonstrated that in the first-line treatment setting, MET amplification (15%) emerged as the most predominant resistance mechanism, the incidence of the C797S mutation decreased to approximately 7%, and the T790M mutation was extremely rare (219). Second, unknown resistance mechanisms predominate. Analyses of ctDNA data from the FLAURA2 study have revealed a critical trend: following treatment with osimertinib plus chemotherapy, the detection rates of known resistance mutations (such as C797S mutation and MET amplification) decreased markedly, with C797S mutation dropping from 12% to 4% and MET amplification from 14% to 9%, whereas the proportion of unknown resistance mechanisms surged from 49% to 75% (81). This indicates that although combination therapy can effectively suppress known dominant resistant clones, it may reshape the selective pressure on tumor cells and give rise to cryptic resistance mechanisms beyond the current scope of detection technologies or understanding, posing a severe challenge to existing single-gene, single-dimensional biomarker detection strategies. Third, resistance mechanisms are characterized by coexistence and dynamic evolution, among which the allelic configuration of C797S and T790M mutations is decisive for the selection of therapeutic strategies—when C797S and T790M mutations are expressed in trans, tumors may be sensitive to the combination of first- and third-generation TKIs; whereas when the two mutations are present in cis on the same chromosome, tumors exhibit resistance to all currently available TKIs (220). Such refined molecular typing imposes higher requirements on the technical resolution of liquid biopsy and tissue biopsy. Fourth, the challenges posed by non-genomic resistance mechanisms have become increasingly prominent. Histological transformations include EMT and transformation to SCLC; the latter occurs at an incidence of approximately 3–10% and is highly associated with concurrent RB1/TP53 mutations (221,222). These non-genomic mechanisms cannot be detected by conventional next-generation sequencing (NGS) and are readily missed by ctDNA monitoring.

Beyond the complexity of resistance mechanisms, the development of fourthgeneration EGFR-TKIs has also been fraught with difficulties. The core mechanism of action of fourth-generation TKIs is to alter the conformation of EGFR by binding to its allosteric site, thereby circumventing the C797S mutation in the ATP-binding pocket (164). However, the lack of single-agent efficacy of the pioneering drug EAI045 revealed that even molecules with high target selectivity may have their single‑agent activity completely neutralized in the face of complex cellular signaling networks (e.g., the regulation of EGFR dimerization). Clinically, the development of fourth‑generation EGFR-TKIs remains at an early stage and has not yet achieved the expected efficacy in early-phase clinical trials. The phase I/II SYMPHONY trial (NCT04862780) evaluated the efficacy and safety of BLU-945 monotherapy or in combination with osimertinib in 133 heavily pretreated patients with EGFR-mutant NSCLC. The results demonstrated favorable tolerability but insufficient clinical activity; even with observed ctDNA clearance, the durability of patient response was poor. This finding strongly indicates that for tumors subjected to multiple lines of therapy, their high genomic heterogeneity and polyclonal resistance characteristics (e.g., concurrent MET amplification, KRAS mutation, etc.) make it difficult for single allosteric inhibitors to deliver durable clinical benefit.

In the face of numerous dilemmas associated with monotherapy, combination therapeutic strategies have emerged as the mainstream approach to delay resistance and enhance clinical efficacy, yet they have also introduced new therapeutic complexities. In terms of therapeutic breakthroughs, the value of chemotherapycombination strategies has been validated by the FLAURA2 study: osimertinib combined with chemotherapy not only yielded dual benefits in PFS (HR 0.62) and OS (HR 0.77), but also verified the feasibility of eliminating DTP cells via chemotherapy (182). Major breakthroughs have also been achieved with bispecific antibody combination strategies. The MARIPOSA study showed that the median PFS of first-line amivantamab plus lazertinib (23.7 months) was significantly superior to that of osimertinib monotherapy (16.6 months). Moreover, this combination regimen was the first to demonstrate an OS benefit over third-generation TKI monotherapy (HR 0.75) in a phase III clinical trial. This finding validated the value of simultaneous blockade of the EGFR and MET pathways in preventing bypass signaling activation and delaying resistance (186).

However, the accompanying challenges of combination therapy cannot be overlooked. On the one hand, the toxicity profile of treatment is significantly complicated. In the MARIPOSA-2 study, although the median PFS in patients receiving amivantamab plus lazertinib and chemotherapy (8.3 months) and amivantamab plus chemotherapy (6.3 months) was improved compared with chemotherapy alone (4.2 months), the incidence rates of grade ≥3 adverse events were 92% and 72%, respectively, which were much higher than the 48% in the chemotherapy group (185). In the FLAURA2 study, the incidence rate of grade ≥3 adverse events in the osimertinib plus chemotherapy group also reached 70% (182). This suggests that the improved efficacy of combination therapy comes at the cost of increased treatment toxicity and more complex clinical management (e.g., prophylactic anticoagulation, management of cutaneous adverse reactions, etc.). On the other hand, resistance mechanisms have become increasingly complex. As mentioned above, while combination therapy reduces the incidence of known resistance mechanisms, it significantly increases the proportion of unknown resistance mechanisms, which brings great uncertainty to the selection of subsequent treatment options after disease progression in patients. The success of first-line combination therapies (such as the regimens in the FLAURA2 and MARIPOSA studies) may give rise to a brand-new, currently unrecognized resistance spectrum, forcing researchers to continuously keep pace with tumor evolution.

In summary, the treatment of EGFR-mutant NSCLC is standing at a new historical juncture, and the field is gradually transitioning from monotherapy with the third-generation TKI osimertinib to a comprehensive therapy integrating combination therapy, dynamic monitoring and precision intervention. The tortuous development process of fourth-generation allosteric inhibitors has profoundly revealed that, in the face of high tumor heterogeneity and strong evolutionary adaptability, it is difficult for any single, static targeted therapeutic strategy to independently achieve durable clinical benefit.

Looking ahead, the future of EGFR-mutant NSCLC treatment hinges on several key advancements. First, the development of more comprehensive resistance profiling tools—including single-cell sequencing and spatial transcriptomics—will enable real-time tracking of clonal evolution. Second, novel therapeutic strategies, such as covalent EGFR degraders or triple-action kinase inhibitors, may overcome existing resistance barriers. Third, the integration of artificial intelligence in treatment planning could optimize sequencing and combination strategies based on dynamic risk assessment. Ultimately, the goal is to shift from reactive resistance management to proactive, precision-based approaches. By leveraging emerging technologies, refining biomarker-driven therapies, and prioritizing patient-centric trial designs, we may transform EGFR-mutant NSCLC into a chronically manageable disease. The path forward requires collaboration across disciplines, with a focus on translating mechanistic insights into clinically actionable solutions that balance efficacy, safety, and accessibility.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1380/prf

Funding: This study was financially supported by project grants from the National Natural Science Foundation of China (Nos. 82271875 and 12405391), Natural Science Foundation of Sichuan Province (No. 2024NSFSC1913), and “Qimingxing” Youth Talent Research Startup Fund of West China Hospital (Nos. HXQMX0032 and HXQMX0114).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1380/coif). The authors have no conflicts of interest to declare.

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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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