Towards better outcomes for epidermal growth factor receptor L858R+ lung cancer patients: mutant-selective allosteric inhibitors and the potential for double-drugging.
Aug 2026· Philosophical transactions of the Royal Society of London. Series B, Biological sciences· Vol 381 1957· 1 citation· 94 references
Medicine
TL;DR
Next-generation EGFR inhibitors with a particular focus on allosteric inhibitors developed for L858R-mutant NSCLC are surveyed, offering the possibility of double-drugging the mutant receptor to achieve deeper and more durable responses for EGFR L858R+ patients.
Abstract
Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a frequent cause of non-small cell lung cancer (NSCLC). Osimertinib, a third-generation tyrosine kinase inhibitor (TKI) that is selective for mutant EGFR, is standard of care for patients with the classical exon 19 deletion variants and the L858R point mutation. Although osimertinib and a recently developed therapy that combines TKI lazertinib with the antibody amivantamab improve outcomes for these patients, resistance limits the durability of response to these agents. Additionally, patients with the L858R mutation do not respond as well as those with exon 19 deletions, highlighting the need for more effective therapies for these patients and for those with brain metastases, a common complication of these cancers. In this review, we survey the development of next-generation EGFR inhibitors with a particular focus on allosteric inhibitors developed for L858R-mutant NSCLC. EAI-432 and other allosteric EGFR inhibitors can co-bind with osimertinib, offering the possibility of double-drugging the mutant receptor to achieve deeper and more durable responses for EGFR L858R+ patients. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.
Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations, and osimertinib is now established as first-line therapy for NSCLCs. Combination therapies (e.g., osimertininb plus chemotherapy; lazertinib plus amivantamab) have been shown to improve median progression-free survival (mPFS) and median overall survival (mOS) relative to monotherapy. However, due to several resistance mechanisms, patients experience disease progression following EGFR TKI treatment. On-target resistance mechanisms include additional mutations (e.g., C797S/G/N, L718Q, L844V, G724X). Within the heterogeneous group of off-target resistance mechanisms, human epidermal growth factor receptor 2 (HER2) amplifications, mesenchymal-epithelial transition factor (MET) alterations, oncogenic fusions (e.g., BRAF, FGFR, RET), histological changes, epithelial-mesenchymal transitions, and alterations of the RAS/MEK/ERK and the PI3K/AKT/mTOR signal transduction pathways are critical and can confer resistance to EGFR TKIs. Several drugs have been identified to inhibit these pathways, with some of them already approved for clinical use. Most fourth-generation EGFR TKIs are orally bioavailable and are mainly allosteric thiazole amide-based reversible inhibitors. Their activity results from selective binding to an allosteric site, which can alter the EGFR protein conformation, allowing them to bypass C797X. A recommendation for the optimal treatment strategy and sequence for NSCLC patients with acquired EGFR TKI-resistant tumours still cannot be given. An improved understanding of the underlying resistance mechanisms will help to pave the way for the development of innovative and highly specific drugs for the therapy of osimertinib-resistant NSCLCs. The putative clinical relevance of fourth-generation EGFR TKIs for NSCLC patients needs to be defined, and many development hurdles need to be cleared before victory can be declared.
W. Dempke, K. Fenchel, Loretta Sullivan et al.· Cancer Drug Resistance· 0 citations
EGFR-mutant lung cancer represents a major subtype of non-small cell lung cancer in Asia, with particularly high prevalence in never-smokers, women, and patients with adenocarcinoma histology. Although this clinicopathologic enrichment has been recognized for more than two decades, the mechanisms underlying the excess frequency of EGFR-mutant disease in Asian populations remain only partially understood. Accumulating evidence suggests a multifactorial basis involving host genetic susceptibility and diversity, endogenous mutational processes and exogenous exposures such as ambient particulate matter. In particular, recent genomic and experimental studies support a tumour-promotion framework in which inflammatory microenvironmental cues may facilitate the outgrowth of pre-existing oncogenic clones, while mutational signatures provide genomic footprints of these processes. In parallel, the treatment landscape for EGFR-mutant non-small cell lung cancer has evolved substantially with successive generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs), leading to marked improvements in survival. However, acquired resistance remains inevitable in most patients with advanced disease and is driven by both genetic and non-genetic mechanisms, including secondary EGFR alterations, bypass pathway activation, TP53-associated genomic instability, adaptive mutagenesis, and drug-tolerant persister states. These insights have provided a strong rationale for combination strategies beyond EGFR-TKI monotherapy. In this review, we summarize current understanding of the epidemiology and biological basis of EGFR-mutant lung cancer in Asia and discuss the preclinical rationale and emerging clinical evidence supporting combination approaches with chemotherapy, anti-angiogenic agents, and EGFR/MET-directed therapies.
N. Sunaga, Yoshinori Hasegawa, M. Sato· Respirology (Carlton South....· 0 citations
A number of lead candidates with strong EGFR inhibitory potential, promising pharmacokinetic profiles, and mutant selectivity were successfully identified by the integrated computational approach.
M. Kendre, S. S. Bhusari, Pravin S. Wakte· Journal of Pharmaceutical In...· 0 citations
Abstract Background The standard first-line treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC) is EGFR tyrosine kinase inhibitors. However, concurrent mutations facilitate resistance evolution in EGFR-mutant lung adenocarcinoma and combination therapies may offer a superior approach. This study explores the efficacy and safety of osimertinib plus anlotinib as first-line treatment for advanced NSCLC with EGFR co-mutations. Materials and Methods This study prospectively enrolled patients with advanced NSCLC harboring EGFR (19Del/21L858R) mutations and ≥1 mutation in TP53, PIK3CA, or RB1, who had not undergone systemic treatment. Kaplan-Meier survival analysis tested the differences among patients with different concurrent mutations. ctDNA test was administered before and after treatment and its correlation with efficacy. Results A total of 38 patients were enrolled, with co-mutations in TP53 (76.3%), PIK3CA (26.3%), and RB1 (2.6%). With a median follow-up of 25.6 months, the median progression-free survival (PFS) was 29.0 months (95% CI, 18.6-NR), and 1-year PFS rate was 85% (95% CI, 70.4%-94.5%). Objective response rate was 73.7% (95% CI, 56.9%-86.3%), and disease control rate was 100.0% (95% CI, 90.7%-100.0%). Adverse events of any grade occurred in all patients. Seven (18.4%) patients experienced grade 3 treatment-related adverse events (TRAEs), with no grade 4 TRAEs or treatment-related deaths. Conclusion Osimertinib plus anlotinib shows promising efficacy and manageable toxicity as first-line treatment for advanced NSCLC with EGFR co-mutations (ChiCTR2300070023). Clinical trial registration This study was registered in the Chinese Clinical Trial Registry (ChiCTR) under the registration number ChiCTR2300070023 on March 31, 2023 (https://www.chictr.org.cn).
Xiao-Jun Yang, Qin-Quan Tan, Shi-Yuan Chen et al.· The Oncologist· 0 citations
Epidermal growth factor receptor exon 20 insertion mutations is a genetically and structurally distinct class of oncogenic drivers in non-small cell lung cancer, historically characterized by marked insensitivity to classical first-, second-, and third-generation tyrosine kinase inhibitors. The clinical management of this disease has radically changed following the introduction of targeted modalities specifically engineered to overcome the steric hindrance imposed by αC-helix and loop insertions within the ATP-binding cleft. Sunvozertinib is an orally bioavailable, irreversible, rationalized small-molecule tyrosine kinase inhibitor exhibiting selective, nanomolar potency against a wide spectrum of exon 20 insertion variants while preserving wild-type receptor margins. Clinical trial evaluations across the multi-cohort WU-KONG program have established confirmed objective response rates ranging from 46% to 62% in platinum-pretreated advanced disease, alongside robust intracranial activity and prolonged response duration. Regulatory approvals in China and the United States validate its role as a pivotal oral targeted option in second-line settings. Nevertheless, clinical utility is eventually challenged by acquired resistance pathways, including secondary receptor alterations such as the C797S covalent binding site disruption, MET and ERBB2 bypass amplification, downstream pathway reactivation, and histological lineage plasticity. Ongoing phase III investigations explore frontline positioning against systemic chemo-immunotherapy combinations, while companion biomarker discovery aims to define individualized treatment sequencing. Sunvozertinib provides a compelling pharmacological option that bridges long-standing unmet needs in precision thoracic oncology.
I. Kumar, N. Sharma, Sonia Sharma et al.· Journal of Pharma Insights a...· 0 citations
SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ≥ 3) occurred in 99.6%/57.2% of patients. Common grade ≥3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.
Zi-Ming Li, Zhen Zhou, Zhi-Yong He et al.· Cancer Cell· 0 citations
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