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British Journal of Clinical Pharmacology May 2024We present a 70-year-old female patient diagnosed with epidermal growth factor receptor-mutated metastatic non-small cell lung cancer (T4N2M1a), who developed...
We present a 70-year-old female patient diagnosed with epidermal growth factor receptor-mutated metastatic non-small cell lung cancer (T4N2M1a), who developed afatinib-induced toxic epidermal necrolysis (TEN). We have also performed a PubMed/Medline literature review to detect other possible cases of TEN/Stevens-Johnson syndrome associated with afatinib treatment and found only 5 other cases reported. To our best knowledge, this is the first case of afatinib-induced TEN successfully treated with cyclosporine.
PubMed: 38803188
DOI: 10.1111/bcp.16114 -
Clinical & Translational Oncology :... May 2024The efficacy of afatinib or pyrotinib has been demonstrated in HER2-positive advanced non-small cell lung cancer (NSCLC) patients; however, the efficacy of pyrotinib...
BACKGROUND
The efficacy of afatinib or pyrotinib has been demonstrated in HER2-positive advanced non-small cell lung cancer (NSCLC) patients; however, the efficacy of pyrotinib after afatinib progression has yet to be determined.
METHOD
Patients with HER2 mutated advanced lung adenocarcinoma administered afatinib or pyrotinib monotherapy were enrolled. Those who received pyrotinib after afatinib were further analyzed to determine the efficacy and safety of pyrotinib after progression on afatinib. Survival curves were plotted with the Kaplan-Meier method. A swimming plot was used to describe the specific treatments. Additionally, patient-derived tumor organoids (PDTOs) were established from HER2-amplified NSCLC patient samples to investigate the antitumor activity of pyrotinib in HER2-amplified tumor cells in vitro.
RESULTS
A total of 99 patients were enrolled, 13 of whom were administered pyrotinib after progression on afatinib. No statistical difference in PFS of pyrotinib was observed between patients whether be treated after afatinib progression or not (6.7 months vs. 4.4 months, P = 0.817), thus indicating that progression on afatinib did not affect the efficacy of pyrotinib. Further analysis was conducted on the former patients, which comprising eight patients administered interval chemotherapy after progression on afatinib. Two patients achieved PR after pyrotinib treatment. No independent factors were found to influence the PFS of pyrotinib. PDTOs confirmed the anti-tumor activity of pyrotinib in NSCLC tumor cells with HER2 amplification.
CONCLUSIONS
Progression after prior afatinib treatment does not influence the efficacy of pyrotinib treatment. Pyrotinib may be a salvage option for patients with HER2 mutation who have experienced progression on afatinib.
PubMed: 38795256
DOI: 10.1007/s12094-024-03482-9 -
Lung Cancer (Auckland, N.Z.) 2024Afatinib, a second-generation covalent EGFR TKI, has been approved for the treatment of the three "uncommon" mutations (G719X, S768I, and L861Q) based on one pooled...
Afatinib, a second-generation covalent EGFR TKI, has been approved for the treatment of the three "uncommon" mutations (G719X, S768I, and L861Q) based on one pooled retrospective analysis of three prospective trials (LUX-Lung 2, 3 and 6). The confirmed overall response rate, as assessed by independent radiology review, was 66% (95% confidence interval: 47-81). Among the 21 responders, the proportion of patients with response duration of ≥12 months was 52% and the proportion with response durations of ≥18 months was 33%. Of note, all patients received afatinib at 40 or 50 mg once daily which is higher than the approved dose of 40 mg once daily and the usual 30 mg once daily starting dose by most thoracic oncologists. Given the approval of afatinib for "uncommon" mutations was based on the limited number of patients analyzed, the retrospective nature of the analysis, lack of randomized phase 2 or 3 trial, there remains uncertainty as to whether afatinib, chemotherapy or other next-generation EGFR TKIs is the optimal treatment. This uncertainty also hinders the development of future treatment of these "uncommon" mutations because of the uncertainty that afatinib is the optimal treatment and hence should be the standard of care control arm in future randomized trials. Finally, the ACHILLES/TORG1834 provided us with the first randomized trial result that afatinib achieved superior progression-free survival over platinum-based chemotherapy (10.6 months vs 5.7 months, HR = 0.42; 95% CI: 0.256-0.694; P = 0.0007). However, ACHILLES should mostly be considered as phase 2 trial given the limited number (N = 109) of patients enrolled. Furthermore, the PFS benefit seemed to be with the 40 mg daily dose (HR = 0.128; 95% CI: 0.050-0.327) and not with the 30 mg daily dose (HR = 0.704; 95% CI: 0.352-1.406). Further investigation of the 30 once daily dosing for the treatment of uncommon mutations is needed.
PubMed: 38784059
DOI: 10.2147/LCTT.S461758 -
Respiratory Investigation Jul 2024MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted... (Review)
Review
Unfavorable response to capmatinib for MET exon14 skipping after first-line osimertinib in a patient with EGFR-mutated lung adenocarcinoma: A case report and literature review.
MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted therapy against METex14s emerging after osimertinib resistance is uncertain. Herein, we report a case of EGFR-mutated metastatic lung adenocarcinoma in which METex14 was detected in a re-biopsy upon first-line osimertinib resistance. The patient received capmatinib monotherapy as third-line therapy, which was ineffective, followed by an exceptional response to salvage therapy with afatinib. This report highlights the heterogeneity of EGFR-TKI resistance and that targeting rare resistance mechanisms remains challenging.
Topics: Humans; Acrylamides; Aniline Compounds; ErbB Receptors; Lung Neoplasms; Exons; Mutation; Proto-Oncogene Proteins c-met; Adenocarcinoma of Lung; Drug Resistance, Neoplasm; Benzamides; Protein Kinase Inhibitors; Triazines; Afatinib; Male; Middle Aged; Female; Antineoplastic Agents; Salvage Therapy; Aged; Imidazoles; Indoles; Pyrimidines
PubMed: 38776647
DOI: 10.1016/j.resinv.2024.05.009 -
Chinese Medical Journal Jun 2024
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Cyclin-Dependent Kinase 4; ErbB Receptors; Female; Middle Aged; Lung Neoplasms; Quinazolines; Male; Mutation; Aged
PubMed: 38775179
DOI: 10.1097/CM9.0000000000003136 -
Theranostics 2024: Small molecule drugs such as tyrosine kinase inhibitors (TKIs) targeting tumoral molecular dependencies have become standard of care for numerous cancer types....
: Small molecule drugs such as tyrosine kinase inhibitors (TKIs) targeting tumoral molecular dependencies have become standard of care for numerous cancer types. Notably, epidermal growth factor receptor (EGFR) TKIs (e.g., erlotinib, afatinib, osimertinib) are the current first-line treatment for non-small cell lung cancer (NSCLC) due to their improved therapeutic outcomes for EGFR mutated and overexpressing disease over traditional platinum-based chemotherapy. However, many NSCLC tumors develop resistance to EGFR TKI therapy causing disease progression. Currently, the relationship between drug target availability (DTA), local protein expression and therapeutic response cannot be accurately assessed using existing analytical tools despite being crucial to understanding the mechanism of therapeutic efficacy. : We have previously reported development of our fluorescence imaging platform termed TRIPODD (herapeutic esponse maging through roteomic and ptical rug istribution) that is capable of simultaneous quantification of single-cell DTA and protein expression with preserved spatial context within a tumor. TRIPODD combines two complementary fluorescence imaging techniques: intracellular paired agent imaging (iPAI) to measure DTA and cyclic immunofluorescence (cyCIF), which utilizes oligonucleotide conjugated antibodies (Ab-oligos) for spatial proteomic expression profiling on tissue samples. Herein, TRIPODD was modified and optimized to provide a downstream analysis of therapeutic response through single-cell DTA and proteomic response imaging. : We successfully performed sequential imaging of iPAI and cyCIF resulting in high dimensional imaging and biomarker assessment to quantify single-cell DTA and local protein expression on erlotinib treated NSCLC models. Pharmacodynamic and pharmacokinetic studies of the erlotinib iPAI probes revealed that administration of 2.5 mg/kg each of the targeted and untargeted probe 4 h prior to tumor collection enabled calculation of DTA values with high Pearson correlation to EGFR, the erlotinib molecular target, expression in the tumors. Analysis of single-cell biomarker expression revealed that a single erlotinib dose was insufficient to enact a measurable decrease in the EGFR signaling cascade protein expression, where only the DTA metric detected the presence of bound erlotinib. : We demonstrated the capability of TRIPODD to evaluate therapeutic response imaging to erlotinib treatment as it relates to signaling inhibition, DTA, proliferation, and apoptosis with preserved spatial context.
Topics: Humans; Optical Imaging; Carcinoma, Non-Small-Cell Lung; Single-Cell Analysis; Lung Neoplasms; Animals; Cell Line, Tumor; ErbB Receptors; Mice; Protein Kinase Inhibitors; Antineoplastic Agents; Erlotinib Hydrochloride; Female
PubMed: 38773974
DOI: 10.7150/thno.93256 -
Journal of Hepatocellular Carcinoma 2024Immunogenic cell death (ICD) can enhance the potency of immunotherapy in cancer treatment. Nevertheless, it is ambiguous how ICD-related genes (ICDRGs) contribute to...
INTRODUCTION
Immunogenic cell death (ICD) can enhance the potency of immunotherapy in cancer treatment. Nevertheless, it is ambiguous how ICD-related genes (ICDRGs) contribute to hepatocellular carcinoma (HCC).
METHODS
Single-cell RNA sequencing (scRNA-seq) data were used to distinguish malignant cells from normal cells in the HCC tumor microenvironment(TME). Bulk RNA sequencing data was employed to acquire the landscape of the 33 ICDRGs. Unsupervised clustering identified two ICD molecular subtypes. The cellular infiltration characteristics and biological behavior in different subtypes were analyzed by ssGSEA. Subsequently, differentially expressed genes (DEGs) between the two subtypes were determined, based on which patients were classified into three gene clusters. Then, the prognostic model was constructed by Lasso-Cox analysis. Finally, we investigated the expression of risk genes in cancer cell line encyclopedia (CCLE) and validated the function of NKX3-2 in vitro experiments.
RESULTS
ICD scores and ICDRGs expression in malignant cells were significantly lower than in normal cells by scRNA-seq analysis. ICD-high subtype was characterized by ICD-related gene overexpression and high levels of immune infiltration abundance and immune checkpoints; Three DEGs-related gene clusters were likewise strongly linked to stromal and immunological activation. In the ICD-related prognostic model consisting of NKX3-2, CHODL, MMP1, NR0B1, and CTSV, the low-risk group patients had a better endpoint and displayed increased susceptibility to immunotherapy and chemotherapeutic drugs like 5-Fluorouracil, afatinib, bortezomib, cediratinib, lapatinib, dasatinib, gefitinib and crizotinib. Moreover, NKX3-2 amplification in HCC samples has been verified by experiments, and its disruption suppressed the proliferation and invasion of tumor cells.
CONCLUSION
Our study highlighted the potential of the ICDRGs risk score as a prognostic indicator to aid in the accurate diagnosis and immunotherapy sensitivity of HCC.
PubMed: 38770169
DOI: 10.2147/JHC.S449419 -
Frontiers in Oncology 2024Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable mutation-positive (m+) non-small cell...
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable mutation-positive (m+) non-small cell lung cancer (NSCLC). However, 10-20% of patients with m+ NSCLC have uncommon variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel :: gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon mutations, with or without co-mutations, may be sensitive to afatinib.
PubMed: 38769948
DOI: 10.3389/fonc.2024.1347742 -
Clinical Cancer Research : An Official... May 2024In the realm of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) therapy with tyrosine kinase inhibitors (TKIs), addressing...
In the realm of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) therapy with tyrosine kinase inhibitors (TKIs), addressing optimal treatment for uncommon EGFR mutations like G719X in exon 18, S768I in exon 20, and L861Q in exon 21 remains a pivotal yet challenging frontier. Contrary to the well-established efficacy of EGFR-TKIs in common EGFR mutations, these uncommon alterations pose unmet medical needs due to a lack of comprehensive evidence. While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. Recent developments include multiple clinical trials investigating the efficacy of both second and third-generation EGFR-TKIs in patients with uncommon EGFR mutations. A noteworthy example is a prospective phase II trial of osimertinib including the landmark UNICORN study, which has shown promising results in treating uncommon EGFR mutations. Despite various reports on the efficacy of afatinib and osimertinib in treating uncommon EGFR mutations, the appropriate use of these TKIs remains unclear. This review aims to consolidate the findings from the latest clinical trials focused on uncommon EGFR mutations, outlining variations in the therapeutic efficacy of these TKIs based on the specific genetic mutation. By synthesizing these findings, we aim to guide oncologists towards more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.
PubMed: 38767589
DOI: 10.1158/1078-0432.CCR-23-4035 -
BioRxiv : the Preprint Server For... May 2024Acrylamides are the most commonly used warheads of targeted covalent inhibitors (TCIs) directed at cysteines; however, the reaction mechanisms of acrylamides in proteins...
Acrylamides are the most commonly used warheads of targeted covalent inhibitors (TCIs) directed at cysteines; however, the reaction mechanisms of acrylamides in proteins remain controversial, particularly for those involving protonated or unreactive cysteines. Using the combined semiempirical quantum mechanics (QM)/molecular mechanics (MM) free energy simulations, we investigated the reaction between afatinib, the first TCI drug for cancer treatment, and Cys797 in the EGFR kinase. Afatinib contains a -dimethylaminomethyl (-DMAM) substitution which has been shown to enhance the intrinsic reactivity and potency against EGFR for related inhibitors. Two hypothesized reaction mechanisms were tested. Our data suggest that Cys797 becomes deprotonated in the presence of afatinib and the reaction proceeds via a classical Michael addition mechanism, with Asp800 stabilizing the ion-pair reactant state -DMAM/C797 and the transition state of the nucleophilic attack. Our work elucidates an important structure-activity relationship of acrylamides in proteins.
PubMed: 38766221
DOI: 10.1101/2024.02.18.580887