Afatinib in the first-line treatment of patients with non-small cell lung cancer: clinical evidence and experience

Ricciuti, Biagio; Baglivo, Sara; Giglio, Andrea De; Chiari, Rita

doi:10.1177/1753466618808659

Cited by 24 publications

(11 citation statements)

References 65 publications

(121 reference statements)

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“…Since, EGFR p.T790M is still the most common mechanism of resistance to afatinib, similar to reversible EGFR TKI, a comparison of patients´prognosis and form of disease upon basis of the mutational profile should be made. Previously, patients were shown to have a better prognosis and more indolent form of disease progression upon the presence of an EGFR exon 19 deletion [31][32][33][34]. Matsuo and co-workers investigated whether there was an association of the (primary) EGFR driver mutation with the occurrence and frequency of EGFR p.T790M and the period of response to EGFR TKI.…”

Section: Discussionmentioning

confidence: 99%

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

et al. 2020

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Background: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1stgeneration (reversible) EGFR TKI and later the 2nd-generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI. Methods: Rebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification. Results: One hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib-vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M. Conclusions: The EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

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Section: Discussionmentioning

confidence: 99%

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

et al. 2020

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“…In metastatic colorectal cancers the use of EGFR inhibitors in combination with conventional chemotherapy significantly improved survival [9,10]. Furthermore, afatinib and osimertinib have recently been approved for the treatment of EGFR mutated non-small cell lung cancers [11,12], while the combination of BRAF and MEK inhibitors improve overall survival in melanoma [13]. However, the presence of mutations in proteins other than the intended therapeutic target can affect the response to a particular therapy.…”

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confidence: 99%

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

et al. 2020

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Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

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“…Afatinib is a good and irreversible EGFR TKI, and recently, many clinical trials have proved that it can effectively prolong the median PFS and OS time in NSCLC patients when compared to the first-generation EGFR TKIs [19]. However, severe side effects and newer mutations induced acquired resistance, limiting its use clinically, and 13 Disease Markers so some patients who acquired resistance to the first generation TKIs directly jumped to the third generation EGFR TKI treatment like osimertinib [20,21].…”

Section: Discussionmentioning

confidence: 99%

Ethacrynic Acid Enhances the Antitumor Effects of Afatinib in EGFR/T790M-Mutated NSCLC by Inhibiting WNT/Beta-Catenin Pathway Activation

et al. 2021

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Background. Despite afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion or other rare EGFR-mutation patients, the acquired resistance or toxic effects associated with it limited its use clinically. The controlling of acquired resistance or optimization of the afatinib dosage in EGFR/T790M mutation-positive non-small-cell lung cancer (NSCLC) is still an important fundamental problem. Ethacrynic acid (EA) has been proved as a dual inhibitor of GST and WNT, and the α, β-unsaturated-keto structure of it is similar to that of irreversible tyrosine kinase inhibitors (TKIs). However, these beneficial effects of EA combined with afatinib have never been reported in NSCLC. Therefore, the antitumor effects of afatinib combined with EA in EGFR L858R/T790M-mutated NSCLC cells and related mechanisms were analyzed. Our in vitro and in vivo results showed that EA has strong synergistic antitumor effects with afatinib in EGFR L858R/T790M-mutated NSCLC cells, but has no cytotoxic effects in NSCLC cells when used it alone, i.e., the cytotoxic effects of afatinib (IC30) plus EA (IC30) were stronger than the effects of afatinib (IC50) alone. Our functional studies found that the antitumor mechanisms of afatinib when combined with EA mainly occurred by inhibiting WNT/β-catenin pathway activation and suppression of the secretion of anti-inflammatory factors. These results revealed that combination of afatinib with EA derivatives not only provided a new therapeutic approach for EGFR/T790M-mutated NSCLC patients but also offered a new idea for developing new drugs or optimizing the dose of afatinib in clinical use in future antitumor therapy.

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Afatinib in the first-line treatment of patients with non-small cell lung cancer: clinical evidence and experience

Cited by 24 publications

References 65 publications

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

Ethacrynic Acid Enhances the Antitumor Effects of Afatinib in EGFR/T790M-Mutated NSCLC by Inhibiting WNT/Beta-Catenin Pathway Activation

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