Non-small cell lung cancer research: advances and persistent challenges.

1
Introduction
Lung cancer remains a leading cause of cancer-related mortality worldwide, driving extensive research into novel therapeutic strategies and precision medicine approaches (1). The treatment landscape for non-small cell lung cancer (NSCLC) has rapidly expanded beyond traditional chemotherapy and initial targeted therapies. Current investigations are focused on overcoming resistance mechanisms, exploiting new molecular targets, refining immunotherapy applications, and addressing the unique needs of specific patient subgroups (2).
Significant progress has been made across multiple fronts. Antibody-drug conjugates (ADCs), such as those targeting trophoblastic cell surface antigen 2 (TROP-2), represent a promising frontier for refractory disease (3, 4). Simultaneously, next-generation TKIs for oncogenic drivers like ALK, ROS1, MET, and KRAS G12C offer improved efficacy (5–7). Diagnostic modalities are also evolving, with liquid biopsy for circulating tumor DNA (ctDNA) analysis and artificial intelligence (AI) applied to histopathology enhancing prognostic accuracy and personalization (8–10). Furthermore, comprehensive genomic profiling (CGP) is increasingly advocated to detect a broader range of actionable targets (11).
However, these advances are matched by persistent and multifaceted challenges. Acquired resistance to targeted agents and immunotherapies remains a fundamental biological hurdle (12). Biomarker validation, including for PD-L1, ctDNA dynamics, and mutations in STK11/KEAP1, lags behind therapeutic innovation (8, 10, 13). The clinical implementation of precision oncology faces systemic barriers, such as inconsistent access to testing, reimbursement issues, and workflow complexities, with only a minority of eligible patients receiving matched therapies (11, 14). Furthermore, robust data for special populations, including older adults and those with rare subtypes, remain scarce (15, 16).
To synthesize these developments and challenges critically, this review is structured around three interconnected thematic axes: (1) Therapeutic innovations and resistance mechanisms, examining novel agents, their efficacy-toxicity profiles, and strategies to overcome resistance; (2) Diagnostic and biomarker advances, evaluating the integration and validation of tools like CGP, ctDNA, and AI; and (3) Implementation and equity challenges, addressing systemic barriers and evidence gaps in special populations. This reorganization aims to streamline the narrative, reduce redundancy, and provide a more analytical framework. Additionally, new algorithms and tables are incorporated to contextualize emerging therapies within current treatment paradigms and molecular testing workflows. By integrating this critical appraisal, the review aims to highlight actionable priorities for future research and clinical practice, guiding efforts to translate innovation into equitable improvements in NSCLC management. Figure 1; Tables 1, 2.

2
Therapeutic innovations and resistance mechanisms in NSCLC
The therapeutic landscape of NSCLC is being reshaped by several innovative platforms that enhance precision and combat resistance. Antibody-drug conjugates (ADCs) exemplify this progress, with agents like HER3-DXd delivering cytotoxic payloads to EGFR-TKI resistant tumors and T-DXd combined with nivolumab showing promise in HER2-altered cancers (32, 33). These ADCs merge targeted delivery with potent cytotoxicity, offering new options where standard therapies fail. However, their distinct and sometimes notable toxicity profiles, such as the hematologic and gastrointestinal events seen with TROP-2-targeting ADCs or the interstitial lung disease risk with HER2-targeting agents, require careful management and influence their position in treatment sequences (3, 4, 32). Complementing ADCs, next-generation tyrosine kinase inhibitors (TKIs) continue to advance. Agents like lorlatinib for ALK-positive disease achieve unprecedented progression-free survival, including superior intracranial control, while selective inhibitors for MET exon 14 skipping (tepotinib) and KRAS G12C (glecirasib, divarasib) validate once “undruggable” targets (3, 19, 22). Yet, each TKI class carries a distinct toxicity spectrum, from lipid abnormalities with lorlatinib to edema with MET inhibitors, necessitating vigilant monitoring and affecting their suitability for combination strategies (5, 26, 34). Beyond traditional pharmacotherapy, novel modalities are emerging. Oligonucleotide therapies, such as FOXP3-targeting antisense oligonucleotides (ASOs), aim to modulate the immunosuppressive tumor microenvironment (TME), while nanoparticle systems seek to improve drug bioavailability (35, 36). Concurrently, T-cell engineering via therapies like afami-cel demonstrates the potential of cellular immunotherapy in specific solid tumors (17). The critical appraisal of these innovations must balance their promising efficacy against the practical challenges of their toxicity profiles, the optimal timing of their use within treatment algorithms, and their potential for synergistic combination.
2.1
Molecular profiling techniques and biomarker advances
Accurate patient stratification is the cornerstone of precision oncology, driven by advances in molecular profiling. CGP using next-generation sequencing (NGS) detects actionable genomic alterations in a significant proportion of advanced solid tumors, expanding therapeutic opportunities beyond routine testing (37, 38). Liquid biopsy, particularly circulating tumor DNA (ctDNA) analysis, offers a non-invasive alternative for genotyping, resistance monitoring, and dynamic assessment of treatment response (39–41). The prognostic value of ctDNA dynamics, where clearance or early reduction correlates with improved outcomes, is a compelling advancement for real-time adaptation (10, 41). However, significant limitations impede universal implementation. The sensitivity of ctDNA assays is not absolute, and tissue-based profiling remains the gold standard for initial comprehensive assessment (39, 40). Furthermore, the clinical utility of CGP, while clear in increasing target detection, requires further validation regarding its definitive impact on survival outcomes and cost-effectiveness compared to standard testing algorithms (11, 12). Beyond genomics, transcriptomic and proteomic profiling are revealing predictive immune signatures and metabolic biomarkers, such as T-cell infiltration and circulating L-arginine levels, which may better predict immunotherapy response (42, 43). AI applied to histopathology shows nascent promise in predicting genetic mutations from routine tissue sections, potentially circumventing costly testing (9). Yet, its current performance is suboptimal for clinical adoption, lacking robust external validation across diverse populations and seamless integration into pathology workflows (11). These diagnostic tools, while powerful, face the dual challenges of rigorous biomarker validation and the creation of standardized, accessible clinical pathways (42). Figure 2.

2.2
Actionable genomic targets and overcoming therapeutic resistance
The expansion of actionable targets directly informs therapeutic strategy. For EGFR-mutant NSCLC, osimertinib is the established standard, with combinations like osimertinib plus ramucirumab showing further progression-free survival (PFS) benefit (18, 20). In ALK-positive cancer, lorlatinib sets a new benchmark for long-term disease control (3, 20). Targets such as KRAS G12C, METex14, and NTRK fusions now have effective inhibitors, enabling tumor-agnostic treatment approaches in some cases (28, 44). However, the durability of these responses is universally challenged by acquired resistance. Primary and secondary resistance arises through on-target mutations (EGFR C797S, ALK G1202R), off-target bypass pathway activation (MET, HER2, AXL amplification), and phenotypic transformation (NSCLC-to-SCLC transition) (26, 28). Immunotherapy resistance is driven by an immunosuppressive TME, with mutations in STK11/KEAP1 or metabolic alterations like low L-arginine contributing to immune evasion (29, 30, 43).
Overcoming this resistance requires innovative strategies. Next-generation TKIs are designed to target specific resistance mutations, as seen with ficonalkib for ALK G1202R (26). ADCs offer a potent strategy against tumors with bypass resistance by delivering payloads independently of the original signaling pathway (32, 33). Proactive combination therapies, such as osimertinib with ramucirumab or divarasib with cetuximab, aim to delay resistance by simultaneously blocking primary targets and escape routes (18, 44). Emerging approaches include bispecific antibodies (targeting EGFR/c-MET), synthetic lethality strategies (PARP inhibitors in homologous recombination-deficient tumors), and autologous T-cell therapies designed to overcome antigen loss (17, 45, 46). A critical component of managing resistance is longitudinal monitoring via ctDNA, which can detect molecular relapse ahead of clinical progression and guide adaptive intervention (28, 40, 41). The future of NSCLC therapy lies in deepening the molecular characterization of resistance and deploying these sequential and combinatorial strategies within a framework of dynamic biomarker monitoring (47). Table 3; Figure 3.

3
Diagnostic, biomarker, and implementation advances in NSCLC
The translation of therapeutic innovation into clinical benefit is governed by diagnostic pathways, biomarker validation, and the realities of healthcare delivery. This section examines the integration of molecular testing into clinical algorithms, the challenges of implementation, and strategies to optimize management across diverse care contexts.
3.1
Molecular testing workflows and stage-directed treatment algorithms
Precision oncology in NSCLC is initiated through structured molecular testing workflows. For newly diagnosed advanced NSCLC, current guidelines mandate comprehensive biomarker testing to guide first-line therapy. This includes assessment of EGFR, ALK, ROS1, BRAF, NTRK, METex14, RET, and KRAS G12C mutations, alongside PD-L1 expression. The integration of NGS, either via tissue-based CGP or liquid biopsy, is increasingly advocated to efficiently identify these and other rare actionable targets (11, 37, 38). As illustrated in a proposed molecular testing workflow (see Figure 2), the choice between tissue and plasma-based testing is influenced by tissue availability, tumor burden, and urgency for results, with reflex to the alternative modality following an inconclusive initial result (39, 40, 52).
This biomarker data directly informs stage-specific treatment algorithms. For early-stage resectable disease, the standard of care involves surgery with or without adjuvant therapy, though neoadjuvant and perioperative immunotherapy combinations are now emerging as new standards, with their efficacy potentially modulated by specific actionable genomic alterations (53, 54). The management of unresectable stage III disease has been revolutionized by consolidative durvalumab following chemoradiation, establishing a benchmark against which novel combinations are being tested (50). For stage IV disease, treatment selection is stratified by driver mutation status and PD-L1 expression, as summarized in a biomarker-directed first-line therapy (see Table 2). Notably, the positioning of emerging agents is continuously evolving within these sequences. For instance, ADCs such as HER3-DXd are specifically under investigation for patients with EGFR-mutant NSCLC who have developed acquired resistance to EGFR TKIs (33). Similarly, T-DXd combined with immunotherapy is being evaluated in patients with HER2-mutant or HER2-overexpressing advanced NSCLC (32), and TROP-2-targeting ADCs like datopotamab deruxtecan are being developed for advanced, refractory non-oncogene-addicted NSCLC (3, 4). Next-generation TKIs, such as lorlatinib for ALK-positive disease, are firmly established in the first-line setting for their respective molecular subsets (3, 20). Understanding this algorithmic context and the precise indications for novel therapies is essential for evaluating where they may fill unmet needs or displace current standards.

3.2
Clinical implementation challenges and access disparities
Despite established guidelines, the implementation of precision medicine faces profound systemic challenges. Access to comprehensive molecular testing remains inconsistent; in some real-world cohorts, only about half of advanced NSCLC patients receive complete biomarker profiling (52). Restricted gene panels miss a significant proportion of actionable alterations compared to broader CGP, potentially denying patients effective therapies (55, 56). While liquid biopsy can mitigate tissue scarcity issues, its sensitivity is not perfect, and it may fail to detect alterations present in tissue (39, 40).
Therapeutic access is further hindered by reimbursement barriers and infrastructural limitations. Even when actionable alterations are identified, a staggering proportion of patients; estimated at 66-89%, do not receive a genomically matched therapy due to drug access issues, restrictive clinical trial eligibility, or clinical deterioration (38, 56, 57). Molecular tumor boards (MTBs) have been established to interpret complex genomic data and recommend therapies, succeeding in doing so for 19-61% of cases (39, 58). However, MTBs face operational hurdles, including lengthy turnaround times for CGP reports, variant interpretation challenges, and integration into busy clinical workflows. Furthermore, the added cost of CGP (€1.5K-€3.9K per patient) and a lack of NGS infrastructure in resource-limited settings create significant geographic and socioeconomic disparities in care (56, 57, 59). These barriers collectively ensure that the promise of precision oncology remains unrealized for a majority of eligible patients, underscoring an urgent need for standardized, cost-effective, and equitable implementation models (55). Table 4.

3.3
Optimizing care for special populations and future directions
Optimizing NSCLC management requires tailored approaches for special populations often underrepresented in clinical trials. Elderly patients, who constitute a large proportion of the NSCLC population, require careful assessment beyond chronological age. Comprehensive geriatric assessments evaluating functional status, comorbidities, polypharmacy, and social support are crucial for determining fitness for therapy. Evidence suggests that while TKIs like osimertinib are effective and tolerable in older adults with EGFR mutations, combination regimens may incur excessive toxicity, favoring monotherapy approaches (13). Similarly, for patients with active central nervous system metastases, selecting agents with high central nervous system penetration (lorlatinib, osimertinib) is a critical component of treatment planning (3, 31, 49).
Ethnic and regional genetic differences also influence disease management. The higher prevalence of EGFR mutations in Asian populations (40-55%) compared to Caucasians (10-15%) justifies different empirical treatment approaches and trial designs (50, 51). Furthermore, research on rare histological subtypes (hepatoid adenocarcinoma) is inherently limited, often relying on retrospective data to inform management, which typically involves surgery for localized disease and platinum-based chemotherapy with or without immunotherapy for advanced stages (14).
Future directions must address these multifaceted challenges through convergent strategies. Diagnostically, efforts should focus on validating and standardizing dynamic biomarkers like ctDNA for minimal residual disease detection and early progression (27, 52). Therapeutically, the development of novel platforms, such as bispecific antibodies, next-generation ADCs, and cellular therapies, must be coupled with pragmatic combination and sequencing studies (17, 21, 39). Operationally, deploying cost-effective NGS panels, expanding MTB access, and developing equitable reimbursement models are essential to democratize precision medicine (24, 26). Finally, dedicated research initiatives incorporating geriatric assessments and international registries for rare subtypes are needed to generate robust evidence for all patient subgroups. By integrating these advances in diagnostics, therapeutics, and health systems, the field can progress toward more personalized, effective, and equitable NSCLC care for every patient (41, 53). Table 5, Figure 4.

4
Conclusion
NSCLC research stands at a pivotal inflection point, marked by unprecedented therapeutic innovation yet challenged by persistent implementation gaps. The treatment landscape has expanded dramatically beyond chemotherapy and initial targeted agents, driven by breakthroughs in ADCs such as TROP-2-targeting sacituzumab govitecan and datopotamab deruxtecan, as well as HER3-DXd, which deliver potent cytotoxic payloads to refractory tumors, including EGFR-TKI-resistant and non-oncogene-addicted disease. Simultaneously, highly selective next-generation TKIs such as lorlatinib, tepotinib/savolitinib, and glecirasib/divarasib offer superior efficacy and central nervous system control, redefining standards of care for oncogene-driven subsets. Immunotherapy continues to evolve beyond PD-1/PD-L1, exploring novel targets such as CD47-SIRPα blockade and metabolic modulation such as L-arginine supplementation to overcome immunosuppressive TME.
However, this remarkable progress is counterbalanced by significant, multifaceted limitations. Acquired resistance to targeted therapies, driven by on-target mutations such as EGFR C797S and ALK G1202R, bypass pathway activation, or lineage plasticity, remains a fundamental biological hurdle. While strategies such as proactive combination therapies and next-generation ADCs show promise in circumventing resistance, their long-term durability and optimal sequencing require further validation. Biomarker development lags behind therapeutic innovation. PD-L1 expression is an imperfect predictor, and validated biomarkers for newer agents and immunotherapy resistance are urgently needed. The integration of liquid biopsy for ctDNA dynamics offers a powerful non-invasive tool for real-time monitoring, early progression detection, and minimal residual disease assessment, but its prognostic utility demands prospective validation in diverse clinical pathways.
Crucially, translating research advances into equitable patient benefit faces substantial systemic barriers. Robust data for special populations, particularly older adults and those with rare subtypes such as hepatoid adenocarcinoma of the lung, remain scarce, necessitating dedicated trials incorporating geriatric assessments. While CGP detects a broader range of actionable targets, its real-world clinical utility and cost-effectiveness are hampered by inconsistent access, reimbursement hurdles, lengthy turnaround times, and complex interpretation. Only 11-34% of eligible patients ultimately receive matched targeted therapies, with disparities exacerbated in resource-limited settings. Molecular tumor boards improve target identification but face operational challenges. Furthermore, the toxicity profiles of newer agents and novel combinations necessitate careful management and longer-term safety data.
Looking ahead, the future of NSCLC management hinges on several converging strategies. First, overcoming resistance requires deepening the molecular characterization of relapse mechanisms and developing effective sequential or combinatorial regimens leveraging ADCs, bispecific antibodies, and cellular therapies. Second, biomarker refinement is essential, utilizing AI-driven multi-omics integration to discover predictive signatures and validating ctDNA dynamics for real-time adaptation. Third, pragmatic implementation must address accessibility by streamlining CGP workflows, developing cost-effective panels, establishing equitable reimbursement models, and expanding liquid biopsy use globally. Fourth, dedicated research must focus on special populations through geriatric-focused trials and international registries for rare subtypes. Finally, tumor-agnostic approaches and interception strategies hold promise for expanding treatable populations.
In essence, while the therapeutic arsenal for NSCLC has never been more potent or precise, realizing its full potential demands a concerted effort to dismantle biological, technological, and systemic barriers. Success will depend on integrating deep molecular science with pragmatic solutions for biomarker validation, accessible profiling, tailored toxicity management, and inclusive trial design. By bridging these gaps, the field can transform current momentum into sustained, equitable improvements in survival and quality of life for all NSCLC patients. The path forward is complex, but the foundation for transformative progress is firmly established.