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Recent Results in Cancer Research.... 2018Afatinib (BIBW 2992, US: Gilotrif, other countries: Giotrif©) is an irreversible blocker of the ErbB family, acting at the tyrosine kinases of these proteins. In 2013,... (Review)
Review
Afatinib (BIBW 2992, US: Gilotrif, other countries: Giotrif©) is an irreversible blocker of the ErbB family, acting at the tyrosine kinases of these proteins. In 2013, it was approved by the FDA and the EMA for the treatment of adults with advanced, EGFR mutation-positive non-small-cell lung cancer. Further investigations for the treatment of many other tumors with afatinib, e.g., HNSCC and breast cancer, are ongoing.
Topics: Afatinib; Animals; Antineoplastic Agents; Humans; Neoplasms; Protein Kinase Inhibitors; Quinazolines; Radiation-Sensitizing Agents
PubMed: 30069769
DOI: 10.1007/978-3-319-91442-8_14 -
Annals of Oncology : Official Journal... Dec 2020Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1)... (Review)
Review
Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.
Topics: Afatinib; Biology; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neuregulin-1; Oncogene Proteins, Fusion
PubMed: 32916265
DOI: 10.1016/j.annonc.2020.08.2335 -
The Oncologist Jun 2023The purpose of this analysis was to investigate the effectiveness of afatinib compared to that of osimertinib in patients with non-small cell lung cancer (NSCLC) who... (Review)
Review Meta-Analysis
BACKGROUND
The purpose of this analysis was to investigate the effectiveness of afatinib compared to that of osimertinib in patients with non-small cell lung cancer (NSCLC) who harbored uncommon epidermal growth factor receptor (EGFR) mutations.
METHODS
A PubMed database-based literature review was conducted to retrieve related studies. Patients harboring EGFR mutations besides the deletion in exon 19 (19del) and point mutation of L858R were included in this analysis. The primary outcome events were the objective response rate (ORR) and progression-free survival (PFS). Propensity score matching (PSM) at a ratio of 1:1 was used between afatinib and osimertinib groups to control the confounding factors. Uncommon EGFR mutations were categorized into 4 groups: insertion in exon 20 (ex20ins), non-ex20ins single uncommon EGFR mutations, compound EGFR mutations that with 19del or L858R, and compound EGFR mutations without 19del or L858R.
RESULTS
After PSM, 71 patients in either the afatinib or osimertinib group were matched. The afatinib group had an ORR of 60.6%, slightly higher than the osimertinib group's (50.3%), the difference was not statistically significant (P = .610). However, the afatinib group showed a significantly superior PFS benefit than the osimertinib group (11.0 vs. 7.0 months, P = .044). In addition, patients harboring non-ex20ins single uncommon EGFR mutations yield the best ORR and PFS, following treatment of either afatinib (ORR: 76.7%, mPFS: 14.1 months) or osimertinib (ORR: 68.8%, mPFS: 15.1 months). Moreover, there was no significant difference in terms of ORR or PFS between the cohort of patients treated with afatinib or osimertinib, regardless of whether or not the patients had brain metastases.
CONCLUSIONS
Both afatinib and osimertinib displayed favorable clinical activities toward uncommon EGFR mutations. Afatinib showed a more profound and durable PFS benefit than osimertinib, although no efficacy advantage was observed.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; ErbB Receptors; Mutation; Protein Kinase Inhibitors
PubMed: 37116899
DOI: 10.1093/oncolo/oyad111 -
Journal of Thoracic Oncology : Official... May 2020Limited clinical data are available regarding the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in patients with NSCLC harboring uncommon EGFR mutations. This...
INTRODUCTION
Limited clinical data are available regarding the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in patients with NSCLC harboring uncommon EGFR mutations. This pooled analysis assessed the activity of afatinib in 693 patients with tumors harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate-use and expanded-access programs, phase IIIb trials, noninterventional trials, and case series or studies.
METHODS
Patients had uncommon EGFR mutations, which were categorized as follows: (1) T790M; (2) exon 20 insertions; (3) "major" uncommon mutations (G719X, L861Q, and S768I, with or without any other mutation except T790M or an exon 20 insertion); (4) compound mutations; and (5) other uncommon mutations. Key end points were overall response rate (ORR), duration of response, and time to treatment failure (TTF).
RESULTS
In EGFR TKI-naive patients (n = 315), afatinib demonstrated activity against major uncommon mutations (median TTF = 10.8 mo; 95% confidence interval [CI]: 8.1-16.6; ORR = 60.0%), compound mutations (median TTF = 14.7 mo; 95% CI: 6.8-18.5; ORR = 77.1%), other uncommon mutations (median TTF = 4.5 mo; 95% CI: 2.9-9.7; ORR = 65.2%), and some exon 20 insertions (median TTF = 4.2 mo; 95% CI: 2.8-5.3; ORR = 24.3%). The median duration of response for major uncommon mutations, compound mutations, other uncommon mutations, and some exon 20 insertions was 17.1, 16.6, 9.0, and 11.9 months, respectively. Activity of afatinib was also observed in EGFR TKI-pretreated patients (n = 378). A searchable database of these outcomes by individual genotype was generated.
CONCLUSIONS
Afatinib has clinical activity in NSCLC against major uncommon and compound EGFR mutations. It also has broad activity against other uncommon EGFR mutations and some exon 20 insertions. The data support the use of afatinib in these settings.
Topics: Afatinib; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 31931137
DOI: 10.1016/j.jtho.2019.12.126 -
Current Oncology (Toronto, Ont.) May 2023Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4)... (Review)
Review
Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37366888
DOI: 10.3390/curroncol30060405 -
Expert Opinion on Pharmacotherapy Dec 2018Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its... (Review)
Review
INTRODUCTION
Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its overexpression occurs in more than half the cases. Consequently, many epidermal growth factor receptor (EGFR)-targeted agents have been investigated in patients with SCC.
AREAS COVERED
This review summarizes the potential roles of erlotinib and afatinib in SCC of the lung. The authors explore the rationale of targeting EGFR in SCC and the pharmacological properties of erlotinib and afatinib. Subsequently, they describe the most relevant clinical data involving each agent with regard to their safety profile and antineoplastic activity. Particular focus is given to the LUX-Lung 8 trial, which compared erlotinib and afatinib as a second-line treatment in a population of patients affected by advanced SCC of the lung.
EXPERT OPINION
Despite being overcome by new therapeutic strategies - in particular immune checkpoint inhibitors - afatinib and erlotinib still represent potential treatment options down the line in lung SCC because they have a more manageable toxicity profile compared to chemotherapy.
Topics: Afatinib; Antineoplastic Agents; Carcinoma, Squamous Cell; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Protein Kinase Inhibitors
PubMed: 30392436
DOI: 10.1080/14656566.2018.1540591 -
Journal of Oncology Pharmacy Practice :... Sep 2020Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with mutation-positive (m+) non-small cell lung cancer... (Review)
Review
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with mutation-positive (m+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of m+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with m+ NSCLC.
Topics: Afatinib; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Progression-Free Survival; Protein Kinase Inhibitors
PubMed: 32567494
DOI: 10.1177/1078155220931926 -
Advances in Therapy May 2021Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a standard of care in the first-line treatment of patients with EGFR mutation-positive... (Review)
Review
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a standard of care in the first-line treatment of patients with EGFR mutation-positive metastatic non-small-cell lung cancer (NSCLC). EGFR mutations are relatively common in Asian patients with NSCLC, and there is an increasing number of studies supporting the effectiveness of the second-generation TKI afatinib in routine clinical practice in Asia. This article reviews these real-world studies investigating afatinib as first-line treatment for EGFR mutation-positive NSCLC in Asian patients. Evidence from real-world studies with afatinib in this patient population supports findings from randomized controlled trials (RCTs) showing that afatinib is associated with more favorable outcomes compared with the first-generation EGFR TKIs. The effectiveness of afatinib has also been shown in real-world studies in Asian patients with poor prognostic factors, who are often under-represented or excluded from RCTs, such as those with uncommon EGFR mutations, brain metastases, or poor performance status, and elderly patients. The tolerability profile of afatinib in the real-world setting reflects that seen in RCTs, with no new safety signals reported in real-world studies in Asian patients with EGFR mutation-positive NSCLC. Dose-modification strategies also seem to be effective in the real world, with results of the RealGido study, which included 44% Asian patients, confirming findings from prospective clinical trials showing that tolerability-guided afatinib dose modifications can reduce the incidence of adverse events without adversely affecting clinical outcomes. While further research, including clinical trial data, is needed, real-world data have also demonstrated the feasibility of sequential afatinib followed by the third-generation TKI osimertinib in T790M-positive EGFR mutation-positive patients, which showed longer overall survival. Together, these real-world results demonstrate the real-world clinical effectiveness of afatinib as first-line treatment for patients with EGFR mutation-positive NSCLC.
Topics: Afatinib; Aged; Asia; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 33730350
DOI: 10.1007/s12325-021-01696-9 -
Future Oncology (London, England) Feb 2023EGFR is a protein on cells that helps control their growth and division. Mutations in the gene for EGFR can cause cancer, including some cases of non-small-cell lung... (Review)
Review
WHAT IS EGFR & WHAT IS AFATINIB?
EGFR is a protein on cells that helps control their growth and division. Mutations in the gene for EGFR can cause cancer, including some cases of non-small-cell lung cancer (NSCLC). Afatinib is a medicine that blocks mutated and helps kill cancer cells. Many different types of mutation have been identified in people with NSCLC. Over three quarters of cases are caused by two types of mutation, known as common mutations, but some cases are caused by unusual/uncommon mutations. People with NSCLC who have these unusual/ uncommon mutations are often excluded from clinical trials. Consequently, researchers don't really know how well medicines like afatinib work in these people.
WHAT IS THIS SUMMARY ABOUT?
This is a summary of a study reporting findings from a large database of people with non-small-cell lung cancer (also called NSCLC) who have unusual or uncommon changes in a gene called and who received afatinib. The researchers used the database to see how effective afatinib is in people who have different types of unusual mutation. Afatinib seems to work well in people with NSCLC who have not already been treated. Part of the study also looked at people who had received a similar treatment, called osimertinib, in the past compared to those who had not been treated with this medicine.
WHAT DID THE RESEARCHERS FIND?
The researchers found that afatinib works well in most people with NSCLC who have unusual/uncommon mutations, although it seems to work better against certain types of these mutations than others.
WHAT DO THE RESULTS OF THE STUDY MEAN?
The researchers concluded that afatinib is a treatment option for most people with NSCLC and unusual/uncommon mutations. It is important for doctors to identify the precise type of mutation in a tumor before starting treatment.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 36794564
DOI: 10.2217/fon-2022-0842 -
Clinical Journal of Oncology Nursing Oct 2018Afatinib is an oral, irreversible ErbB family blocker indicated for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with non-resistant... (Review)
Review
BACKGROUND
Afatinib is an oral, irreversible ErbB family blocker indicated for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with non-resistant epidermal growth factor receptor (EGFR) mutations. Afatinib is also approved for the treatment of metastatic squamous NSCLC following progression on platinum-based chemotherapy. Common afatinib-associated toxicities include gastrointestinal and dermatologic events, which can be dose limiting.
OBJECTIVES
In this review, the authors describe clinical trial experiences with afatinib, as well as best practices and practical approaches to the management of afatinib-associated adverse events in EGFR mutation-positive NSCLC.
METHODS
Safety and tolerability data from phase 3 trials of afatinib were reviewed, together with real-life experiences from the authors' clinical practices.
FINDINGS
Patient education, combined with early assessment and effective management of afatinib-related adverse events as well as dose- reduction strategies, allows patients to continue treatment and maximize the clinical benefits of afatinib.
Topics: Adult; Afatinib; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Education, Nursing, Continuing; ErbB Receptors; Female; Humans; Male; Middle Aged; Mutation; Protein Kinase Inhibitors
PubMed: 30239509
DOI: 10.1188/18.CJON.542-548