Olmutinib in T790M‐positive non–small cell lung cancer after failure of first‐line epidermal growth factor receptor‐tyrosine kinase inhibitor therapy: A global, phase 2 study

Park, Keunchil; Kim, Dong Wan; Han, Ji Youn; Wu, Ming; Lee, Jong Seok; Kang, Jin Hyoung; Lee, Dong Hoon; Cho, Byoung Chul; Yu, Chong Jen; Pang, Yong Kek; Felip, Enriqueta; Kim, Hyun‐Jin; Baek, Eunhye; Noh, Young Su

doi:10.1002/cncr.33385

Cited by 21 publications

(7 citation statements)

References 37 publications

(42 reference statements)

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“…The efficacy of olmutinib against cell lines harboring the T790M mutation has been demonstrated in preclinical studies. The results of clinical trials demonstrated that olmutinib exhibited significant efficacy in patients diagnosed with T790M-positive NSCLC who experienced disease progression following prior TKI therapy, thereby providing a novel treatment option [62]. However, the clinical development of the drug faced challenges due to reports of serious adverse events such as severe skin toxicity and the rare but serious side effect known as Stevens-Johnson syndrome [63].…”

Section: Olmutinibmentioning

confidence: 99%

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy

Wang,

Yang,

Zhang

et al. 2024

Molecules

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The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.

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Section: Olmutinibmentioning

confidence: 99%

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy

Wang,

Yang,

Zhang

et al. 2024

Molecules

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“…On the other hand, the first-line naquotinib resulted in an ORR of 52%, DCR of 94%, and PFS of 11.3 months. However, the phase 3 clinical trial of naquotinib was closed due to limited predicted efficacy and toxicity [ 177 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies

Laface¹,

Maselli²,

Santoro³

et al. 2023

Pharmaceutics

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Almost 17% of Western patients affected by non-small cell lung cancer (NSCLC) have an activating epidermal growth factor receptor (EGFR) gene mutation. Del19 and L858R are the most-common ones; they are positive predictive factors for EGFR tyrosine kinase inhibitors (TKIs). Currently, osimertinib, a third-generation TKI, is the standard first-line therapy for advanced NSCLC patients with common EGFR mutations. This drug is also administered as a second-line treatment for those patients with the T790M EGFR mutation and previously treated with first- (erlotinib, gefitinib) or second- (afatinib) generation TKIs. However, despite the high clinical efficacy, the prognosis remains severe due to intrinsic or acquired resistance to EGRF-TKIs. Various mechanisms of resistance have been reported including the activation of other signalling pathways, the development of secondary mutations, the alteration of the downstream pathways, and phenotypic transformation. However, further data are needed to achieve the goal of overcoming resistance to EGFR-TKIs, hence the necessity of discovering novel genetic targets and developing new-generation drugs. This review aimed to deepen the knowledge of intrinsic and acquired molecular mechanisms of resistance to EGFR-TKIs and the development of new therapeutic strategies to overcome TKIs’ resistance.

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“…In January 2021, the Korean Food and Drug Administration (MFDS) approved the listing of lazertinib for the treatment of patients with locally advanced or metastatic NSCLC positive for EGFR T790M mutations who previously received EGFR-TKI treatment (36). The third-generation EGFR-TKIs olmutinib (37)(38)(39) and nazartinib (40) are also approved in South Korea.…”

Section: Changes In Egfr T790m Mutationmentioning

confidence: 99%

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

et al. 2022

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According to global cancer data, lung cancer was the leading cause of cancer-related death in 2020. With the diversification of treatment strategies, the survival outcomes of patients with advanced lung cancer have improved significantly, but the 5-year overall survival rate remains <20%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for lung adenocarcinoma patients with EGFR-sensitive mutations; however, acquired drug resistance is inevitable. Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation. Unfortunately, acquired drug resistance against third-generation drugs still emerges. The C797s mutation is the primary acquired resistance mechanism against Osimertinib. Research on fourth-generation EGFR-TKI drugs with a C797s mutation is currently at various experimental stages, and no drug has been approved for clinical use. In addition to the resistance mechanisms described above, HER2 amplification, MET amplification, PIK3A mutation, KRAS mutation, BRAF mutation, transformation to small cell lung cancer, transformation to lung squamous cell carcinoma, and EMT have been reported as mechanisms of acquired drug resistance to first-, second-and third-generation EGFR-TKIs. These mechanisms are noted in a relatively high proportion of tumors, but treatment options are limited. In recent years, immunotherapy has made progress in the treatment of several cancers, including advanced EGFR-mutated non-small cell lung cancer (NSCLC). Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

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Olmutinib in T790M‐positive non–small cell lung cancer after failure of first‐line epidermal growth factor receptor‐tyrosine kinase inhibitor therapy: A global, phase 2 study

Cited by 21 publications

References 37 publications

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

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