Osimertinib Treatment Was Unsuccessful for Lung Adenocarcinoma with G719S, S768I, and T790M Mutations

Nasu, Shingo; Shiroyama, Takayuki; Morita, Satomu; Takata, So; Takada, Hiromune; Masuhiro, Kentaro; Tanaka, Ayako; Morishita, Naoko; Suzuki, Hidekazu; Okamoto, Norio; Hirashima, Tomonori

doi:10.2169/internalmedicine.0923-18

Cited by 9 publications

(7 citation statements)

References 11 publications

(11 reference statements)

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“…Consistent with our study, AURA study observed a relatively lower response rate in patients harboring uncommon sensitive EGFR mutation when comparing with these harboring 19del/L858R [43]. Similarly, several cases found the inferior efficacy of osimertinib in patients harboring uncommon mutations after progression on prior EGFR-TKIs, even in patients with positive T790M mutation [44][45][46], suggesting an alternative more potent anti-cancer strategy is needed for this setting.…”

Section: Discussionsupporting

confidence: 88%

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Yang

Mao

et al. 2020

Lung Cancer

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Section: Discussionsupporting

confidence: 88%

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Yang

Mao

et al. 2020

Lung Cancer

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“…In clinical course and response to osimertinib, our case was similar to the previous case reported by Nasu et al, in which osimertinib was unsuccessful for emergence of the same combination of mutations after gefitinib, erlotinib and afatinib [7]. The main lesions were the progression of primary tumor and pleural effusion and the emergence of brain metastases in the previous case [7], while our case presented with the rapid progression of multiple liver metastases and the sudden emergence of Trousseau syndrome. These two cases suggested that acquired S768I may be refractory to osimertinib and accelerate rapid progression, even if it occurs together with T790M.…”

Section: Discussionsupporting

confidence: 87%

Osimertinib Did Not Respond to a Pulmonary Adenocarcinoma with Triple Mutations of Epidermal Growth Factor Receptor, G719S, T790M and S768I

Minami¹,

Ihara²,

Tanaka³

et al. 2019

Case Rep Oncol

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Uncommon epidermal growth factor receptor (EGFR) gene mutations include G719S, T790M and S768I. T790M gatekeeper mutation is the most frequent mechanism of acquired drug resistance to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib is a specific EGFR-TKI to overcome T790M resistance mutation. However, owing to a new drug and a rare mutation type, it remains unknown whether osimertinib is effective for acquired S768I. Herein, we reported a 76 year-old woman with pulmonary adenocarcinoma, which had acquired EGFR mutations of S768I and T790M in addition to original G719S after long gefitinib treatment. These mutations were detected in biopsy specimen of liver metastases. During two months of osimertinib, multiple liver metastases progressively enlarged. This case suggested that acquired S768I mutation might be resistant to osimeritinib, despite of co-occurrence of T790M.

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“…Furthermore, among the seven NSCLC patients with G719X mutations included in the AURA trial for second-line osimertinib, only one (RR = 14%) showed partial response (PR), three (43%) had SD, and three (43%) displayed progressive disease (PD) [93]. In keeping with that, lack of response to osimertinib and immediate progression have been described in a patient with G719S/T790M co-mutations [92] and another one with co-existing G719S, S768I, and T790M mutations [94]. Collectively, these data seem to indicate that osimertinib, as opposed to afatinib, is less effective in patients with EGFR G719X and other uncommon mutations than in those with classic EGFR -mutants, both in the presence and absence of T790M co-mutation.…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 91%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

117

126

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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Osimertinib Treatment Was Unsuccessful for Lung Adenocarcinoma with G719S, S768I, and T790M Mutations

Cited by 9 publications

References 11 publications

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Osimertinib Did Not Respond to a Pulmonary Adenocarcinoma with Triple Mutations of Epidermal Growth Factor Receptor, G719S, T790M and S768I

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

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