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Neoplasia (New York, N.Y.) Sep 2023Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of...
Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-2 as GLP-2 receptor inhibitor. In conclusion, sitagliptin exhibits promising potential as a therapeutic option for managing afatinib-induced diarrhea. Taken together, our study provides valuable insights into alleviating afatinib-induced diarrhea through both afatinib medication adjustment and sitagliptin combination therapy.
Topics: Rats; Animals; Afatinib; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Sitagliptin Phosphate; Quality of Life; ErbB Receptors; Diarrhea
PubMed: 37567055
DOI: 10.1016/j.neo.2023.100922 -
Frontiers in Oncology 2023HER2-targeted therapy provides survival benefits to -mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of...
BACKGROUND
HER2-targeted therapy provides survival benefits to -mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of treatment-naïve -positive NSCLC, as well as the efficacy of and resistance to HER2-targeted therapy in -altered NSCLC, could promote further improvement of HER2 targeted therapy.
METHODS
-altered NSCLC patients was retrospectively included and their genomic profiles were performed by next-generation sequencing. The clinical outcomes included overall response rate, disease control rate and progression-free survival.
RESULTS
Among 176 treatment-naïve patients with alterations, 64.8% harbored mutations with/without amplification, and 35.2% carried amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with oncogenic mutations showed a higher prevalence of mutations and a higher tumor mutation burden. However, this correlation was not found in patients with amplification only. Twenty-one patients with alterations treated with pyrotinib or afatinib were retrospectively enrolled. Pyrotinib yielded a longer median progression-free survival than afatinib (5.9 [95% CI, 3.8-13.0] vs. 4.0 months [95% CI, 1.9-6.3], = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified copy number gain and G518W mutation, as well as mutations involving DNA damage repair signaling, SWI-SNF complex, and epigenetic regulations as potential resistance mechanisms.
CONCLUSION
-mutant NSCLC had different molecular features from -amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in -altered NSCLC, although larger cohorts are warranted to validate it. -dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.
PubMed: 37077822
DOI: 10.3389/fonc.2023.1121708 -
European Journal of Cancer (Oxford,... Jul 2023This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.
AIM
This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.
METHODS
The dose-finding part enroled patients (2-<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m/d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1-<18 years) had tumours fulfilling ≥2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score>150); HER2 membrane staining (H-score>0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response.
RESULTS
Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled ≥2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (-81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14-38).
CONCLUSION
Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (>3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion.
Topics: Child; Humans; Afatinib; Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors; Neoplasms; Child, Preschool; Adolescent
PubMed: 37178647
DOI: 10.1016/j.ejca.2023.04.007 -
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 -
Cellular & Molecular Biology Letters Jul 2023Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was...
BACKGROUND
Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways.
METHOD
The expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation.
RESULT
EFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon.
CONCLUSION
EFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells.
Topics: Female; Humans; B7-H1 Antigen; Cell Line, Tumor; ErbB Receptors; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Ovarian Neoplasms; Signal Transduction; Extracellular Matrix Proteins
PubMed: 37420173
DOI: 10.1186/s11658-023-00471-8 -
Translational Cancer Research Dec 2019Invasive mucinous adenocarcinoma (IMA) is a unique histological subtype of adenocarcinoma. Due to its low incidence rates, survival data for IMA is scarce and often... (Review)
Review
Invasive mucinous adenocarcinoma (IMA) is a unique histological subtype of adenocarcinoma. Due to its low incidence rates, survival data for IMA is scarce and often contradictory. The clinical manifestations of IMA are not precise as compared to other adenocarcinomas, with some patients having bronchial mucus overflow. Difference in immunohistochemical expression levels is present in IMA and invasive non-mucinous adenocarcinomas (INMA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are more frequent in IMAs, while epidermal growth factor receptor (EGFR) mutations are relatively rare. This makes it distinct from the other more common adenocarcinomas. Neuregulin 1 (NRG1) gene fusions are considered important therapeutic targets for IMA, suggesting that Afatinib may be an effective drug to treat IMA. However, IMA prognosis remains controversial.
PubMed: 35117050
DOI: 10.21037/tcr.2019.11.02 -
OncoTargets and Therapy 2019The discovery that mutations in the gene are present in up to 50% of patients with lung adenocarcinoma, and the development of highly efficacious EGFR tyrosine kinase... (Review)
Review
The discovery that mutations in the gene are present in up to 50% of patients with lung adenocarcinoma, and the development of highly efficacious EGFR tyrosine kinase inhibitors (TKIs), has revolutionized the way this common malignancy is treated. Three generations of EGFR TKIs are now approved for use in mutation-positive non-small cell lung cancer (NSCLC); the first-generation agents erlotinib, gefitinib, and icotinib; the second-generation ErbB family blockers afatinib and dacomitinib; and most recently, osimertinib, a third-generation EGFR TKI. The second-generation agents have demonstrated impressive efficacy relative to both standard platinum-based chemotherapy and first-generation EGFR TKIs, significantly improving response and progression-free and overall survival. Data from real-world studies suggest that afatinib is as effective and well tolerated in routine clinical practice as it is in clinical studies and is effective in patients with certain uncommon mutations, patients with brain metastases, and older patients. Few real-world data are available for dacomitinib in the first-line setting. Afatinib and dacomitinib have similar safety profiles, with acne/skin dryzness, diarrhea, stomatitis, and paronychia the most common adverse events (AEs) reported in clinical and real-world studies. Numerous studies have shown that tolerability-guided dose reductions can help manage afatinib-related AEs without reducing efficacy. As the number of therapeutic options for advanced NSCLC increases, the optimal choice for first-line treatment will be determined by considering patient factors such as the presence of brain metastases, the type of mutation, tolerability, and subsequent therapy options for long-term treatment.
PubMed: 31496745
DOI: 10.2147/OTT.S198945 -
Cancers Sep 2022Several new drugs and combination strategies can be used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma in the second-line... (Review)
Review
Comparison of Second-Line Treatments for Patients with Platinum-Resistant Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Bayesian Network Meta-Analysis.
Several new drugs and combination strategies can be used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma in the second-line treatment. Questions regarding the relative efficacy and safety of any two of the multiple second-line treatment strategies have emerged. This study aims to compare second-line treatments for patients with platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify relevant articles. Direct and indirect evidence in terms of the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events grade ≥ 3 (grade ≥ 3 trAE) were analyzed in this Bayesian network meta-analysis. A total of twenty-three trials involving 5039 patients were included. These studies compared 20 different treatments, including the standard of care (SOC: docetaxel, methotrexate, or cetuximab), PD-1 inhibitors (nivolumab or pembrolizumab), durvalumab, tremelimumab, durvalumab + tremelimumab, palbociclib + SOC, tivantinib + SOC, sorafenib + SOC, EMD1201081 + SOC, vandetanib + SOC, PX-866 + SOC, 5-fluorouracil + SOC, cixutumumab + SOC, gefitinib + SOC, cabazitaxel, nolatrexed, duligotuzumab, zalutumumab, gefitinib, and afatinib. Among the currently available treatment options, compared to the standard of care (SOC: docetaxel, methotrexate, or cetuximab), the PD inhibitor significantly improved OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS. In conclusion, compared to the SOC, the PD-1 inhibitor significantly improved the OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS.
PubMed: 36139631
DOI: 10.3390/cancers14184472 -
Clinical Cancer Research : An Official... Apr 2022EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen...
PURPOSE
EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment.
PATIENTS AND METHODS
The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx.
RESULTS
From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy.
CONCLUSIONS
Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.
Topics: Afatinib; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; ErbB Receptors; Head and Neck Neoplasms; Humans; Neoplasm Recurrence, Local; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment
PubMed: 35046059
DOI: 10.1158/1078-0432.CCR-21-3025 -
Lung Cancer (Amsterdam, Netherlands) Dec 2021Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However,...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.
METHODS
In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).
RESULTS
At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.
CONCLUSION
Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
Topics: Acrylamides; Afatinib; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors
PubMed: 34649106
DOI: 10.1016/j.lungcan.2021.09.009