Jul 2026· Expert Opinion on Pharmacotherapy· Vol 27, pp. 1125 - 1148· 0 citations· 241 references
Medicine
TL;DR
This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease—specifically TKI combinations with chemotherapy or bispecific antibodies or bispecific antibodies—and emerging post-progression strategies to overcome acquired resistance mechanisms.
Abstract
ABSTRACT Introduction The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies. Areas covered This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease—specifically TKI combinations with chemotherapy (FLAURA2) or bispecific antibodies (MARIPOSA)—and emerging post-progression strategies to overcome acquired resistance mechanisms. A comprehensive literature search (January 2021–March 2026) was conducted via PubMed, and recent major oncology conference proceedings (ASCO, ESMO, WCLC, ELCC) and clinical trial registries for ongoing studies. Expert opinion The therapeutic landscape is shifting from a uniform frontline TKI monotherapy approach toward biomarker-driven, risk-stratified, intensification. High-risk patients (e.g. TP53 co-mutations, L858R) derive significant benefit from combination regimens, whereas mono-TKI remains appropriate for favorable prognostic subgroups. Future progress relies on validating predictive biomarkers—particularly circulating tumor DNA (ctDNA) dynamics—to guide adaptive treatment strategies, balancing efficacy gains against toxicity and costs, while ensuring equitable global access to novel therapies.
Epidermal growth factor receptor (EGFR) activating mutations are pivotal driver alterations in non-small cell lung cancer (NSCLC), with a markedly higher prevalence in Asian populations, female patients, and never-smokers relative to other subgroups. EGFR tyrosine kinase inhibitors (TKIs) have been established as the first-line standard-of-care therapy for EGFR-mutant NSCLC. The third-generation agent osimertinib significantly improves survival outcomes, with a confirmed median progression-free survival (PFS) of 18.9 months in the first-line setting based on the FLAURA pivotal trial. Nevertheless, acquired resistance universally develops within a finite treatment period, and primary resistance occurs in a subset of patients, collectively constituting the major clinical bottleneck limiting durable therapeutic benefits. EGFR-TKI resistance is characterized by substantial complexity and inter- and intra-tumoral heterogeneity, driven by a spectrum of genetic and non-genetic adaptive mechanisms. Notably, distinct resistance mechanisms differ substantially in clinical actionability, defined as the feasibility of clinical detection, availability of targeted therapeutic options, and potential for clinical translation. Existing review studies mainly categorize EGFR-TKI resistance based on genetic mutation types but fail to integrate clinical practicality, resulting in ambiguous hierarchical logic and limited clinical guiding value. To address this gap, the present review systematically reorganizes and classifies EGFR-TKI resistance mechanisms strictly based on clinical actionability and intervention feasibility, constructing a standardized three-tier hierarchical framework: clinically actionable core resistance mechanisms with mature clinical intervention regimens, potentially actionable auxiliary mechanisms with preclinical evidence but limited clinical validation, and refractory primary resistance mechanisms without routine effective intervention strategies. Specifically, core actionable mechanisms include EGFR on-target secondary mutations and compensatory bypass pathway activation, which are well-validated in clinical cohorts and correspond to mature targeted therapies; potentially actionable mechanisms cover tumor phenotypic transformation, metabolic reprogramming, epigenetic modification, autophagy dysregulation, and tumor microenvironment abnormalities, all of which are supported by robust preclinical data but lack large-scale prospective clinical verification; refractory primary resistance is attributed to inherent tumor genetic backgrounds and host individual factors that currently cannot be effectively targeted in routine clinical practice. On the basis of this hierarchical classification, we further correlate each tier of resistance mechanisms with corresponding targeted therapeutic strategies, including next-generation EGFR-TKIs, pathway-specific combination targeted therapy, novel translational therapeutics, metabolic intervention, and traditional Chinese medicine (TCM)-derived natural product adjuvant therapy. This study aims to clarify the hierarchical logical relationship of heterogeneous EGFR-TKI resistance mechanisms, provide evidence-based references for individualized post-resistance clinical decision-making, and offer feasible directions for subsequent translational research and therapeutic optimization.
Yujia Zhai, Xilong Zhou, Weiming Zhao et al.· American Journal of Cancer R...· 0 citations
Simple Summary Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed or mutated in epithelial-derived tumors. In non-small-cell lung cancer (NSCLC), activating EGFR mutations in the cytoplasmic tyrosine kinase domain are important therapeutic targets. EGFR-targeted therapy was among the earliest successful precision-medicine approaches in lung cancer and remains a well-established example of precision oncology, particularly for women, never-smokers, and patients with adenocarcinoma. Between 2014 and 2024, treatment strategies evolved from unselected approaches to EGFR mutation subtype-guided therapies, from advanced unresectable disease to early-stage resected disease, and from monotherapy to combination regimens. The therapeutic armamentarium has expanded beyond small-molecule tyrosine kinase inhibitors to include bispecific antibodies and antibody–drug conjugates. While somatic EGFR mutations guide tumor-directed treatment and resistance assessment, germline EGFR mutations are increasingly recognized for their potential contribution to inherited lung cancer susceptibility and family risk assessment. However, their population prevalence, penetrance, and optimal surveillance remain uncertain. This review summarizes recent advances and future directions in the management of EGFR-mutant NSCLC.
Advanced EGFR-mutant non-small cell lung cancer (NSCLC), specifically tumors harboring classical activating mutations (exon 19 deletions and L858R substitutions, which are the exclusive focus of this review), is no longer a single-treatment landscape. The MARIPOSA and FLAURA2 phase 3 trials have established that combination regimens of amivantamab plus lazertinib and osimertinib plus platinum-pemetrexed, respectively, extend both progression-free and overall survival compared with osimertinib monotherapy. Each carries substantially greater toxicity, treatment complexity, and cost. No validated, prospective framework exists to guide first-line selection between combination and single-agent strategies. Decision-making is currently anchored to trial eligibility criteria and institutional norms rather than individualized risk stratification. This review synthesizes evidence from landmark trials, molecular biomarker analyses, and real-world cohort studies to propose a practical risk-adapted algorithm integrating tumor biology, molecular co-alterations, patient performance status, comorbidities, logistical feasibility, and treatment preference. Patients with biologically high-risk features, including liver metastases, baseline central nervous system (CNS) involvement, circulating tumor DNA (ctDNA) elevation, or heavy disease burden, may derive the greatest absolute benefit from combination therapy. TP53 co-mutation warrants consideration but should be interpreted as a prognostic marker rather than a definitive treatment-selection criterion given conflicting predictive data across trials. The subcutaneous (SC) formulation of amivantamab, demonstrated in PALOMA-3 to reduce infusion-related reactions and administration time relative to the intravenous formulation, may improve the tolerability and logistical feasibility of MARIPOSA-based therapy, though prospective comparative evidence across formulations remains limited. Prospective biomarker-driven trials are needed to validate treatment selection; until that evidence matures, individualized shared decision-making guided by the proposed algorithm is the most defensible clinical approach.
Ashish Sharma, J. Tan, Harendra Kumar et al.· Medical Oncology· 0 citations
Direct KRAS inhibition has transformed KRAS G12C–mutated NSCLC from a previously undruggable subtype into a targetable disease, but durable disease control remains an unmet need.
Kohei Eguchi, Yukito Kajita, Muraoka Suguru et al.· Journal of Clinical Question· 0 citations
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. Targeted monotherapies against the actionable oncogenic drivers, including anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) dysregulation, are well-established for molecularly selected NSCLC patients. However, therapeutic resistance remains a major clinical challenge, and combinatorial strategies targeting distinct signaling pathways may overcome the limitations of single-agent targeted therapies. LR004-VC-MMAE, a novel EGFR-targeting antibody‒drug conjugate (ADC), shows potent antitumor efficacy in multiple EGFR-positive xenografts, yet its therapeutic potential in ALK-rearranged NSCLC remains largely unexplored. Here, we evaluated a novel combinatorial strategy using ALK inhibitors (crizotinib, ceritinib, alectinib, and lorlatinib) in combination with LR004-VC-MMAE in ALK-rearranged NSCLC models. We found that both ALK and cell-surface EGFR were highly expressed in ALK-rearranged NCI-H3122 and NCI-H2228 cell lines but were expressed at low levels in the ALK-wild-type NCI-H460 cell line. All ALK inhibitor-ADC regimens synergistically suppressed proliferation in ALK-rearranged NSCLC cells, while exerting little synergy in ALK wild-type and EGFR-low counterparts. Moreover, crizotinib or ceritinib combined with LR004-VC-MMAE induced significantly greater apoptosis in NCI-H3122 cells compared with either single agent. Mechanistically, the crizotinib-LR004-VC-MMAE combination markedly downregulated ALK and EGFR expression and triggered apoptosis via mitochondrial depolarization-mediated caspase cascade activation and endoplasmic reticulum stress-induced unfolded protein response. In NCI-H3122 xenografts, this combination achieved synergistic tumor inhibition without increased toxicity compared with either treatment alone. Collectively, our findings demonstrate the synergistic antitumor activity of ALK inhibitor plus LR004-VC-MMAE against ALK-rearranged, EGFR-high NSCLC, providing a mechanistic rationale for further clinical development of this combination strategy.
One of the leading causes of death related to cancer worldwide is non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations are one of the most important therapeutic targets. Lazertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI) that is selectively active against EGFR mutations and the T790M resistance mutation, but not against wild-type EGFR. In this paper, we have evaluated the significant role of lazertinib in the treatment of NSCLC, compared with agents, such as osimertinib. We have analyzed the pharmacological benefits, clinical trial evidence, and interactions with the central nervous system (CNS), as well as its active role in first-line therapy beyond acquired resistance. The early-phase results are promising, but queries regarding resistance mechanisms and treatment protocols remain. We have conducted a detailed investigation of lazertinib's therapeutic properties, its role in combination therapies, and its potential to improve treatment outcomes in EGFR-mutant NSCLC. We aimed to highlight both the opportunities and clinical uncertainties associated with lazertinib in cancer care.
Hyma Mandapaka, Surya Kanta De· Anti-Cancer Agents in Medici...· 0 citations
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