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Clinical Cancer Research : An Official... Jun 2020Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC)....
PURPOSE
Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.
EXPERIMENTAL DESIGN
We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied and for efficacy and safety.
RESULTS
Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient-derived HNSCCs. Finally, toxicity studies in -deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters.
CONCLUSIONS
Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Fanconi Anemia; Female; Gefitinib; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 32005748
DOI: 10.1158/1078-0432.CCR-19-1625 -
Translational Lung Cancer Research Jun 2023Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for -mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against -dependent resistance after osimertinib treatment, although these have not been prospectively investigated.
METHODS
The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023.
DISCUSSION
The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established.
REGISTRATION
UMIN Clinical Trial Registry: UMIN000049225.
PubMed: 37425417
DOI: 10.21037/tlcr-23-12 -
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 -
OncoTargets and Therapy 2022Two recent non-interventional trials, GioTag and UpSwinG, demonstrated encouraging time-to-treatment failure (TTF) and overall survival (OS) in patients with epidermal...
Sequential Afatinib and Osimertinib in Asian Patients with Mutation-Positive Non-Small Cell Lung Cancer and Acquired T790M: Combined Analysis of Two Global Non-Interventional Studies.
OBJECTIVE
Two recent non-interventional trials, GioTag and UpSwinG, demonstrated encouraging time-to-treatment failure (TTF) and overall survival (OS) in patients with epidermal growth factor receptor ( mutation-positive non-small cell lung cancer (NSCLC) (Del19 or L858R) who received sequential afatinib/osimertinib, especially in Asians. Here, we have undertaken a combined analysis of Asian patients from both studies.
MATERIALS AND METHODS
Existing medical/electronic records were identified for consecutive EGFR-tyrosine kinase inhibitor (TKI)-naïve patients who received first-line afatinib/second-line osimertinib in "real-world" practice (all T790M-positive). Patients with active brain metastases were excluded. The primary objective was TTF. OS was a key secondary objective.
RESULTS
One hundred and sixty-eight patients were analyzed. Most patients were recruited from South Korea or Japan (52/21%). At the start of afatinib, median age (range) was 61.5 years (35-88), 58% were female, Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0/1/≥2) was 29/62/9%, 17% had brain metastases, and mutation status (Del19/L858R) was 65/35%. At the start of osimertinib, ECOG PS (0/1/≥2) was 22/61/17% and 14% had brain metastases. Median TTF and OS were 30.0 months (95% CI: 24.5-32.5) and 45.2 months (95% CI: 41.7-71.1), respectively. Median OS was 63.5 months in patients with a Del19 mutation. Median OS in patients with brain metastases or ECOG PS ≥2 was 26.4 and 33.1 months, respectively.
CONCLUSION
Sequential afatinib/osimertinib showed encouraging activity in Asian patients with mutation-positive NSCLC and T790M-mediated acquired resistance, especially those with Del19-positive disease. Activity was observed across "real-world" patients including those with poor ECOG PS and/or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib.
PubMed: 36033903
DOI: 10.2147/OTT.S362535 -
Scientific Reports Nov 2023Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along...
Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients' outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99-1.48]; p = 0.053), ECOG PS 0-1 (HR 0.71 [95% CI 0.54-0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66-0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0-1 (HR 0.41 [95% CI 0.31-0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13-1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02-4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12-0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28-1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Erlotinib Hydrochloride; Gefitinib; ErbB Receptors; Lung Neoplasms; Protein Kinase Inhibitors; Mutation; Treatment Outcome; Brain Neoplasms
PubMed: 37989860
DOI: 10.1038/s41598-023-45815-8 -
Anticancer Research Nov 2019Trastuzumab is the only clinically approved targeted therapy for HER2 gene-amplified gastric cancer at present. However, the clinical significance of multi-targeting...
BACKGROUND/AIM
Trastuzumab is the only clinically approved targeted therapy for HER2 gene-amplified gastric cancer at present. However, the clinical significance of multi-targeting tyrosine kinase inhibitors (TKIs) in HER2-positive gastric cancer remains unclear.
MATERIALS AND METHODS
We examined the anti-tumor activity of lapatinib and afatinib, that are reversible and irreversible TKIs, in HER2 gene-amplified trastuzumab-sensitive and - resistant gastric cancer cells (GLM-1 and GLM-1HerR2) in vitro and in vivo.
RESULTS
Afatinib inhibited the growth of GLM-1 and GLM-1HerR2 cells in vitro more efficiently than lapatinib by inducing G cell-cycle arrest and apoptosis. Preclinical studies in mice revealed that afatinib inhibited growth of intraperitoneal GLM-1 and subcutaneous GLM-1HerR2 tumor more strongly than lapatinib. Afatinib was more effective than lapatinib in blocking PI3K/Akt and MAPK signaling in both GLM-1 and GLM-1HerR2 cells.
CONCLUSION
Afatinib could be a potential new molecular-targeted therapy for trastuzumab-sensitive and trastuzumab-resistant HER2 gene-amplified gastric cancers.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Gene Amplification; Humans; Lapatinib; Male; Mice; Mice, Nude; Receptor, ErbB-2; Signal Transduction; Stomach Neoplasms; Trastuzumab; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 31704817
DOI: 10.21873/anticanres.13797 -
Pharmacology 2022A simple, sensitive, rapid, and practical 2-dimensional liquid chromatography (2D-LC) method was developed and validated for the quantification of a 500-μL afatinib...
INTRODUCTION
A simple, sensitive, rapid, and practical 2-dimensional liquid chromatography (2D-LC) method was developed and validated for the quantification of a 500-μL afatinib sample extracted from human plasma.
METHODS
The plasma samples were pretreated with acetonitrile for protein precipitation. The mobile phase consisted of a first-dimensional mobile phase (acetonitrile, methanol, and 25 mmol/L ammonium phosphate in a ratio of 25:25:50, V/V/V) and a second-dimensional mobile phase (acetonitrile and 10 mmol/L ammonium phosphate in a ratio of 25:75, V/V). The average recovery of the plasma samples was stable and reproducible (98.56%-100.02%).
RESULTS
The analyte was sufficiently stable for handling and analysis. The calibration curve was linear, ranging from 10.93 to 277.25 ng/mL with regression equation y = 804.60 x - 4,169.87 (R2 = 0.999). The relative standard deviations for accuracy and precision studies were within ±2.30% and <3.41%, respectively (intra- and interday). Finally, the validated method was successfully employed to determine the drug levels in plasma from the patients treated with afatinib. In clinical assessment, the patients with gastric cancer were orally administered with 30 or 40 mg per day of afatinib, which resulted in large plasma concentrations, ranging from 5.52 to 45.16 ng/mL.
CONCLUSION
The results indicated that this method was useful for the therapeutic drug monitoring of afatinib and suitable for the assessment of the risks and benefits of chemotherapy in patients with non-small cell lung cancer.
Topics: Acetonitriles; Afatinib; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Lung Neoplasms; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 35086096
DOI: 10.1159/000521181 -
The Oncologist Jan 2021Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an...
BACKGROUND
Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.
PATIENTS AND METHODS
This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.
RESULTS
The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.
CONCLUSION
This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.
KEY POINTS
NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.
Topics: Adult; Afatinib; Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neuregulin-1; Oncogene Proteins, Fusion; Protein Kinase Inhibitors
PubMed: 32852072
DOI: 10.1634/theoncologist.2020-0379 -
Journal of Investigative Medicine : the... Jun 2023Owing to the high rates of relapse and migration, ovarian cancer (OC) has been recognized as the most lethal gynecological malignancy worldwide. The activity of the...
Owing to the high rates of relapse and migration, ovarian cancer (OC) has been recognized as the most lethal gynecological malignancy worldwide. The activity of the epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with OC cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in OC patients failed to achieve satisfactory therapeutic effects. In this study, we identified that bruceine D (BD) and EGFR inhibitor, afatinib, combination resulted in synergistic anti-OC effects. The results indicated that compared with one of both drugs alone, the combination of BD and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of BD and afatinib possessed a stronger ability to inhibit the OC cell adhesion and migration than treatment with BD or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against OC treatment. The results support the potential of BD and afatinib combination as a therapeutic strategy for OC patients.
Topics: Humans; Female; Afatinib; ErbB Receptors; Neoplasm Recurrence, Local; Cell Proliferation; Ovarian Neoplasms; DNA Damage; Cell Line, Tumor; Lung Neoplasms
PubMed: 36859802
DOI: 10.1177/10815589231158043 -
Analytical Biochemistry May 2023Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used to treat advanced non-small cell lung cancer (NSCLC). A rapid and reliable...
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used to treat advanced non-small cell lung cancer (NSCLC). A rapid and reliable method for measuring plasma and cerebrospinal fluid (CSF) concentrations of EGFR-TKIs is needed for therapeutic drug monitoring. By using UHPLC‒MS/MS with multiple reaction monitoring mode, we developed a method for rapidly determining the plasma and CSF concentrations of gefitinib, erlotinib, afatinib, and osimertinib. Protein precipitation was employed to remove protein interference for plasma and CSF matrix. The LC‒MS/MS assay was validated to be satisfactory in terms of linearity, precision, and accuracy. This method was successfully applied to measure plasma (n = 44) and CSF (n = 6) concentrations of EGFR-TKIs in NSCLC patients. The chromatographic separation was achieved by a Hypersil Gold aQ column within 3 min. The median plasma concentrations were 325.76, 1981.50, 42.62, 40.27, and 340.92 ng/ml for gefitinib erlotinib, afatinib 30 mg/day, afatinib 40 mg/day, and osimertinib, respectively. The CSF penetration rates were 2.15% for the patients receiving erlotinib therapy, 0.59% for afatinib, 0.08-1.12% for osimertinib 80 mg/day, and 2.18% for those receiving osimertinib 160 mg/day. This assay helps to predict the effectiveness and toxicities of EGFR-TKIs in the pursuit of precision medicine for lung cancer patients.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Afatinib; Erlotinib Hydrochloride; Gefitinib; Tandem Mass Spectrometry; Chromatography, Liquid; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 36931580
DOI: 10.1016/j.ab.2023.115115