Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non–Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study

Hosomi, Yukio; Morita, Satoshi; Sugawara, Shunichi; Kato, Terufumi; Fukuhara, Tatsuro; Gemma, Akihiko; Takahashi, Kazuhisa; Fujita, Yuka; Harada, Toshiyuki; Minato, Koichi; Takamura, Kei; Hagiwara, Koichi; Kobayashi, Kunihiko; Nukiwa, Toshihiro; Inoue, Akira

doi:10.1200/jco.19.01488

Cited by 385 publications

(355 citation statements)

References 19 publications

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“…Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed significantly prolonged the median OS (50.9 v 38.8 months) in EGFR-mutated NSCLC patients, which was the best OS benefit so far [45]. Moreover, erlotinib plus bevacizumab was associated with the best PFS (19.5 months) in patients with the 21-L858R mutation [46].…”

Section: Discussionmentioning

confidence: 91%

Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial

Zhang

Jiang

et al. 2020

Clinical Cancer Research

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are employees of Betta Pharmaceuticals which provided partial funding for the study. Other authors declared no conflict of interests. Word count: 4147 Tables/figures: 3 figures, 3 tables, 1 supplemental figures. Statement of translational relevance Non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 21 L858R mutation is considered less sensitive to EGFR tyrosine kinase inhibitors, and new strategies are anticipated to improve the efficacy of targeted therapies among this patient population. This multicenter phase II randomized clinical trial provides an analysis of progression-free survival (PFS) in treatment-naïve EGFR-mutant NSCLC patients on high-dose Research.

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Section: Discussionmentioning

confidence: 91%

Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial

Zhang

Jiang

et al. 2020

Clinical Cancer Research

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“…67 Despite the comparably low rate of third-generation EGFR-TKI treatment (22%), the PFS (20.9 months) and OS (50.9 months) in the NEJ009 phase III trial is unprecedented. 66 Whether the infrequent application of third-generation EGFR-TKIs in the above mention trials might be explained by a different mutational spectrum at progression is still an open question. It will be also important to answer if co-mutations or certain mutational profiles will be able to identify patients who are able to obtain an extraordinary benefit through the addition of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Meisel

Prof

2020

healthbook TIMES Onco Hema

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Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A) 1 , which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B). 2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed 1,3,4 , but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype. 5-7 The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). 5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades. 5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/ RAF/MEK and PI3K/AKT pathways, among others. 5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients. 5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling. 8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C). 9 Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety. 10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance. 11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation. 12 Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progressionfree survival (PFS) relative to those treated with first-generation EGFR-TKIs. 13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first-and second-generation EGFR-TKIs. 15 Although the treatment landscape of advanced NSCLC has dramatically ch...

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“…The second-generation EGFR-TKIs, afatinib and dacomitinib, also showed superior efficacy to first-generation EGFR-TKIs [34,35]. Importantly, gefitinib combined with carboplatin plus pemetrexed showed a significant superior median PFS (20.9 vs. 11.9 months; HR = 0:49, p < 0:001) and median OS (50.9 vs. 38.8 months; HR = 0:722, p = 0:021) compared to gefitinib alone with an acceptable toxicity profile in a recent phase III NEJ 009 study [36]. Although the authors mentioned that the OS benefit requires further validation, an OS of over 50 months is a remarkable result.…”

Section: Case Reports In Oncological Medicinementioning

confidence: 98%

Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy

Ameku¹,

Higa

2020

Case Reports in Oncological Medicine

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Osimertinib has demonstrated efficacy against stable or asymptomatic central nervous system (CNS) metastases of epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in phase 2 and 3 clinical trials that allowed prior CNS radiotherapy. However, the efficacy of osimertinib only or the optimal treatment combination or sequence of radiotherapy has not been investigated. A 74-year-old woman diagnosed with T4N1M1c Stage IVB lung adenocarcinoma with EGFR mutation presented with a left upper lobe mass and multiple bilateral lung metastases. A total of more than 20 asymptomatic multiple brain metastases with a maximum diameter of 12 mm were diagnosed simultaneously. Osimertinib was administered as first-line treatment. Whole brain radiotherapy was deferred because she had no neurological symptoms. After 5 weeks, the multiple brain metastases disappeared completely, together with the response in the lung lesions. This case demonstrated that first-line treatment with osimertinib could even achieve complete remission of multiple brain metastases comprising as many as twenty lesions of EGFR-mutated NSCLC without radiation therapy. Radiation therapy for brain metastases can be deferred or even withheld. A new treatment strategy for EGFR mutated NSCLC with CNS metastases should be investigated using osimertinib, especially regarding optimal combination or sequence of radiotherapy.

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Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non–Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study

Cited by 385 publications

References 19 publications

Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial

Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy

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