Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

Gristina, Valerio; Mantia, Maria La; Galvano, Antonio; Cutaia, Sofia; Barraco, Nadia; Castiglia, Marta; Perez, Alessandro; Bono, Marco; Iacono, F.; Greco, M.; Calcara, K.; Calò, Valentina; Rizzo, Sérgio; Incorvaia, Lorena; Lisanti, Maria Chiara; Santanelli, Giulia; Sardo, Delia; Inguglia, Sara; Insalaco, L.; Castellana, Luisa; Cusenza, Stefania; Pantuso, Gianni; Russo, Antonio; Bazan, Viviana

doi:10.3390/jmp2020016

Cited by 16 publications

(13 citation statements)

References 133 publications

(197 reference statements)

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“…EGFR mutation is an important molecular marker of NSCLC. EGFR Exon 21 L858R mutation, a classical activating mutation, is considered related to a better outcome in NSCLC patients, granting a complete blockade of the EGFR signaling pathway by EGFR-TKIs ( 11 ). The 6 months of PFS of the first-line treatment with icotinib and the L858R mutation that disappeared in the second NGS testing after icotinib treatment in our case demonstrated the L858R mutation as a positive predictor of clinical prognosis which responds well to first-generation EGFR-TKI.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Opportunities and Challenges of Immunotherapy in Heavily-Treated EGFR-Mutant Advanced Squamous Cell Lung Carcinoma After Progression on EGFR-TKIs and Chemotherapy

Jin

Wang²,

Wang³

et al. 2022

Front. Oncol.

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BackgroundEpidermal growth factor receptor (EGFR) mutations have a low incidence in squamous cell lung cancer (SqCLC), and the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated SqCLC is far less than that in EGFR-mutated lung adenocarcinoma. The treatment strategy for patients with EGFR-mutated non-small cell lung cancer who are refractory to EGFR TKIs has become a current dilemma and challenge.Case PresentationA case of a 69-year-old male patient suffering from intermittent cough and hemoptysis was diagnosed with EGFR-mutated advanced SqCLC (stage cT2bN2M1). The patient was treated with camrelizumab alone after five courses of different systemic therapies and achieved a partial response, with an eminent progression-free survival of more than 24 months. Grade 1 to 2 reactive cutaneous capillary endothelial proliferation and mild pruritus were observed during the treatment. No other immune-related adverse events were observed.ConclusionMonotherapy of immune-checkpoint inhibitors may be considered as a later-line option for EGFR-mutated advanced SqCLC patients with PD-L1 expression.

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Section: Discussionmentioning

confidence: 99%

Case Report: Opportunities and Challenges of Immunotherapy in Heavily-Treated EGFR-Mutant Advanced Squamous Cell Lung Carcinoma After Progression on EGFR-TKIs and Chemotherapy

Jin

Wang²,

Wang³

et al. 2022

Front. Oncol.

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“…EGFR mutations are particularly common among eastern Asian populations with NSCLC [ 11 – 14 ]. The second-generation TKI afatinib, an irreversible ErbB-family blocker, provides broader inhibition relative to first-generation TKIs, which may delay the development of acquired resistance [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: Final Analysis, with a Focus on Patients Enrolled at Sites in China

Feng

Shi

et al. 2022

Targ Oncol

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Background Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutationpositive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in realworld clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies. Objective To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC. Patients and Methods NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS). Results 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9-15.9), and median PFS was 12.1 months (95% CI 11.0-13.6). Median TTSP (13.8 months, 95% CI 12.7-16.1) and PFS (11.4 months, 95% CI 10.9-13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075). Conclusions Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit. Trial Registration Number and Date of Registration NCT01953913 (1 October 2013).Hai-Yan Tu and Jifeng Feng contributed equally to the article.

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“…Non-small cell lung carcinomas (NSCLC), including adenocarcinomas, constitute around 85%-90% of all lung carcinomas. 1 Around 15%-40% of all lung adenocarcinomas harbour mutations in the epidermal growth factor receptor gene (EGFR); the frequency is higher in Asian non-smoking females than in Caucasians and African-Americans. [1][2][3][4] The most frequent targetable EGFR mutations, accounting for approximately 90% of all the mutations, include the in-frame deletions of exon 19 and point mutation (CTG to CGG) at codon 858 (L858R) in exon 21.…”

Section: Introductionmentioning

confidence: 99%

“…1 Around 15%-40% of all lung adenocarcinomas harbour mutations in the epidermal growth factor receptor gene (EGFR); the frequency is higher in Asian non-smoking females than in Caucasians and African-Americans. [1][2][3][4] The most frequent targetable EGFR mutations, accounting for approximately 90% of all the mutations, include the in-frame deletions of exon 19 and point mutation (CTG to CGG) at codon 858 (L858R) in exon 21. Owing to their high frequency, these two mutations are of great clinical and therapeutic interest in lung adenocarcinomas.…”

Section: Introductionmentioning

confidence: 99%

“…3 Other rare mechanisms include acquired L747S, D761Y, or T854A EGFR mutations, overexpression of the hepatocyte growth factor (HGF) pathway, activation of the insulin-like growth factor-1 (IGF-1) receptor, and very rarely, squamous cell transformation. 1,3,[7][8][9][10][11] These molecular events are unique and experimental studies have found multiple resistance mechanisms in the same patient. These findings indicate complex intra-tumoral molecular heterogeneity leading to treatment failure, metastatic disease, and poor patient survival.…”

Section: Introductionmentioning

confidence: 99%

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Sequential small cell transformation and T790M mutation in an epidermal growth factor‐mutant lung adenocarcinoma: A rare occurrence with significant management implications

Shastri

Gupta

et al. 2022

Cytopathology

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Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor (TKI) resistance may be acquired via genotypic and/or phenotypic transformations. Herein, we report an extremely uncommon case with sequential small cell transformation and EGFR T790M mutation, in an elderly female with EGFR exon 21 L858R-mutant lung adenocarcinoma, following treatment with a first-generation EGFR-TKI.Case: A 67-year-old female never-smoker presented with a cough and dyspnoea of 2 months' duration. Computerised tomography revealed a 39 mm lesion in the upper lobe of the right lung with pleural effusion. Pleural fluid cytology revealed metastatic lung adenocarcinoma, and EGFR testing revealed exon 21 L858R mutation. She was started on gefitinib. After a progression-free survival of 31 months, she presented with disease progression and multiple extra-thoracic metastases. Fine needle aspiration cytology of a chest wall lesion revealed metastatic small cell carcinoma. EGFR testing on this aspirate revealed persistent L858R mutation only. In view of small cell transformation, chemotherapy (etoposide and carboplatin) was administered. After 4 months, ascitic fluid cytology revealed metastatic adenocarcinoma with persistent L858R mutation and an acquired T790M mutation (both detected on liquid biopsy as well) indicating amplification of the adenocarcinoma clone and regression of the small cell carcinoma clone. She was then initiated on osimertinib. Conclusions:The index case highlights the significance of serial EGFR genotyping along with repeated tissue and/or blood sampling in the prompt detection of genetic and phenotypic resistance mechanisms to EGFR-TKIs. Furthermore, it lends evidence in support of the upfront treatment approaches targeting the heterogeneity of acquired EGFR-TKI resistance mechanisms.

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Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

Cited by 16 publications

References 133 publications

Case Report: Opportunities and Challenges of Immunotherapy in Heavily-Treated EGFR-Mutant Advanced Squamous Cell Lung Carcinoma After Progression on EGFR-TKIs and Chemotherapy

Case Report: Opportunities and Challenges of Immunotherapy in Heavily-Treated EGFR-Mutant Advanced Squamous Cell Lung Carcinoma After Progression on EGFR-TKIs and Chemotherapy

A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: Final Analysis, with a Focus on Patients Enrolled at Sites in China

Sequential small cell transformation and T790M mutation in an epidermal growth factor‐mutant lung adenocarcinoma: A rare occurrence with significant management implications

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