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Cancer Medicine Aug 2023The efficacy of definite for non-small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations has been preliminarily demonstrated....
BACKGROUND
The efficacy of definite for non-small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations has been preliminarily demonstrated. However, there is a paucity of data with which to compare the efficacy and safety of second- and third-generation TKIs in patients with NSCLC carrying uncommon EGFR mutations.
METHODS
We compared the efficacy and safety of second- and third-generation TKIs in all NSCLC patients in whom next-generation sequencing confirmed uncommon EGFR mutations, including G719X, S768I, and L861Q. The parameters analyzed included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The rate of treatment-related adverse events (AEs) reflected the safety of these TKIs.
RESULTS
Eighty-four NSCLC patients with uncommon EGFR mutations were enrolled between April 2016 and May 2022 at Zhejiang Cancer Hospital, including 63 treated with second-generation TKIs and 21 treated with third-generation TKIs. The ORR for all patients receiving TKIs was 47.6%, and the DCR was 86.9%. The median PFS for NSCLC patients with uncommon EGFR mutations receiving TKIs was 11.9 months and OS was 30.6 months. There was no significant difference in PFS after treatment with second- or third-generation TKIs (13.3 vs. 11.0 months, respectively, P = 0.910) or in OS (30.6 vs. 24.6 months, respectively P = 0.623). The third-generation TKIs showed no severe toxicity.
CONCLUSIONS
The efficacy of second- and third-generation TKIs for NSCLC with uncommon EGFR mutations does not differ, and so can be used to treat NSCLC patients with these mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein Kinase Inhibitors; Treatment Outcome; ErbB Receptors; Mutation
PubMed: 37306192
DOI: 10.1002/cam4.6229 -
Aging Nov 2023Recent years have seen a sharp rise in the amount of research on the connection between oxidative stress, autophagy, and cancer cells. However, the significant functions...
Recent years have seen a sharp rise in the amount of research on the connection between oxidative stress, autophagy, and cancer cells. However, the significant functions of oxidative stress and autophagy-related genes (OARGs) in gastric cancer (GC) are yet to be investigated integrally. Therefore, it will be a new and promising concept to search for novel OARG-related biomarkers to predict the prognosis and treatment response of GC. First, we assessed changes in prognosis and tumor microenvironment (TME) characteristics across the various oxidative stress and autophagy-related modification patterns based on a detailed analysis of 17 OARGs with prognostic significance of 808 GC samples. We identified three distinct OARG alteration patterns which displayed unique biological characteristics and immune cell infiltration features. Using principal component analysis methods, the OARGscore was developed to evaluate the OARG modification patterns of certain tumors. The negative connection between OARGscore and immune cells was statistically significant. Increased survival, a higher incidence of mutations, and a better response to immunotherapy were all predicted to be related to patients' high-OARGscore. In addition, the candidate chemotherapeutic drugs were predicted using the oncoPredict program. The low-OARGscore group was predicted to benefit more from Ribociclib, Alisertib, Niraparib, Epirubicin, Olaparib, and Axitinib, while patients in the high-OARGscore group were predicted to benefit more from Afatinib, Oxaliplatin, Paclitaxel, 5-Fluorouracil, Dabrafenib and Lapatinib. Our findings offer a specific method for predicting a patient's prognosis and susceptibility to immunotherapy, as well as a promising insight of oxidative stress and autophagy in GC.
Topics: Humans; Stomach Neoplasms; Tumor Microenvironment; Autophagy; Fluorouracil; Afatinib; Prognosis
PubMed: 37950729
DOI: 10.18632/aging.205194 -
NPJ Precision Oncology Oct 2023Most patients with advanced ovarian cancer (OC) relapse and progress despite systemic therapy, pointing to the need for improved and tailored therapy options. Functional...
Most patients with advanced ovarian cancer (OC) relapse and progress despite systemic therapy, pointing to the need for improved and tailored therapy options. Functional precision medicine can help to identify effective therapies for individual patients in a clinically relevant timeframe. Here, we present a scalable functional precision medicine platform: DET3Ct (Drug Efficacy Testing in 3D Cultures), where the response of patient cells to drugs and drug combinations are quantified with live-cell imaging. We demonstrate the delivery of individual drug sensitivity profiles in 20 samples from 16 patients with ovarian cancer in both 2D and 3D culture formats, achieving over 90% success rate in providing results six days after operation. In this cohort all patients received carboplatin. The carboplatin sensitivity scores were significantly different for patients with a progression free interval (PFI) less than or equal to 12 months and those with more than 12 months (p < 0.05). We find that the 3D culture format better retains proliferation and characteristics of the in vivo setting. Using the DET3Ct platform we evaluate 27 tailored combinations with results available 10 days after operation. Notably, carboplatin and A-1331852 (Bcl-xL inhibitor) showed an additive effect in four of eight OC samples tested, while afatinib and A-1331852 led to synergy in five of seven OC models. In conclusion, our 3D DET3Ct platform can rapidly define potential, clinically relevant data on efficacy of existing drugs in OC for precision medicine purposes, as well as provide insights on emerging drugs and drug combinations that warrant testing in clinical trials.
PubMed: 37907613
DOI: 10.1038/s41698-023-00463-z -
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 -
Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants.Nature Communications Mar 2024The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different...
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
Topics: Humans; Glioblastoma; Protein Kinase Inhibitors; ErbB Receptors; Lung Neoplasms; Mutation
PubMed: 38548752
DOI: 10.1038/s41467-024-45594-4 -
Frontiers in Cell and Developmental... 2023Poor outcomes and chemotherapy resistance for patients with pancreatic adenocarcinoma (PAAD) are a challenge worldwide, and new or improved prognostic biomarkers are...
Poor outcomes and chemotherapy resistance for patients with pancreatic adenocarcinoma (PAAD) are a challenge worldwide, and new or improved prognostic biomarkers are urgently required. Individual laminin family members have been established as cancer-associated markers, predicting patient outcomes in many cancer types, including PAAD. Here, we used multiple modalities including RNAseq and gene chip, and genomic and proteomic data to examine the relationships of all laminin genes in PAAD with clinical outcomes. These analyses identified that LAMA3, LAMB3, and LAMC2 expression levels are increased at the mRNA and protein levels in PAAD tumours with evidence of co-regulation. Increased expression of all three genes was associated with decreased promoter methylation status, TP53 mutations, and altered receptor tyrosine kinase (RTK) pathways. Clinically, high LAMA3, LAMB3, and LAMC2 transcript abundance was each related to an advanced histological grade. Moreover, high expression of these genes individually predicted poor patient survival, while a signature of combined high expression of LAMA3, LAMB3, and LAMC2 was a stronger predictor of patient outcomes than each gene alone. Interestingly, cell lines with high expression of LM332 chains were not sensitive to the commonly used PAAD chemotherapy drugs paclitaxel and gemcitabine; however, increased sensitivity was evident for erlotinib, afatinib, gefitinib, and cetuximab epidermal growth factor (EGFR) RTK inhibitors. To explore possible mechanisms, we investigated co-expressed genes, identifying eight hub genes, namely, , , , , , , , and , which are co-expressed with all three of LAMA3, LAMB3, and LAMC2. Of these, only SERPINB5 provided a stronger predictive value than the laminin-encoding genes. Together, these multiple integrated analyses suggest that the combined expression of LM332 is a useful prognostic biomarker for PAAD and could help patient stratification and therapeutic selection.
PubMed: 37779898
DOI: 10.3389/fcell.2023.1242706 -
Taiwan Journal of Ophthalmology 2024This case discussed a significant ocular side effect, bilateral keratitis, which could be induced by afatinib, an irreversible epidermal growth factor receptor-tyrosine...
This case discussed a significant ocular side effect, bilateral keratitis, which could be induced by afatinib, an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We explored the disease progression of a 52-year-old, stage IV nasopharyngeal carcinoma male patient, who was under afatinib treatment and had experienced progressive bilateral eye dryness and tenderness on increasing afatinib from 40 mg every other day to 40 mg daily. Clinical examination noted bilateral visual acuity reduction, diffuse superficial punctate keratopathy in the right eye, and a central epithelial defect in the left eye. Seidel test results were negative for both eyes, with no corneal infiltration, lagophthalmos, anterior chamber cell precipitation, or retinal lesion. Symptoms subsequently resolved after reducing the frequency of afatinib used, along with intensive ocular hydration. In summary, this case highlighted afatinib's potential link to bilateral keratitis, and early afatinib dose adjustment with supportive medication could significantly reverse the condition.
PubMed: 38654991
DOI: 10.4103/tjo.TJO-D-24-00003 -
Thoracic Cancer Nov 2023Despite the well-established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), there... (Meta-Analysis)
Meta-Analysis
Do patient characteristics affect EGFR tyrosine kinase inhibitor treatment outcomes? A network meta-analysis of real-world survival outcomes of East Asian patients with advanced non-small cell lung cancer treated with first-line EGFR-TKIs.
BACKGROUND
Despite the well-established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), there is limited real-world evidence comparing their effectiveness according to patients' clinical characteristics. This network meta-analysis (NMA) compared survival outcomes among first-line EGFR-TKIs in different subgroups of East Asian patients with advanced NSCLC.
METHODS
This NMA included real-world observational studies reporting outcomes with TKIs in patients aged >65 years, with baseline brain metastasis, with different Eastern Cooperative Oncology Group (ECOG) statuses, or with different common EGFR mutation types.
RESULTS
In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression-free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46-0.75) and gefitinib (HR: 0.41, 95% CI: 0.32-0.53). Similarly, in patients with the EGFR Del19 mutation, afatinib and erlotinib resulted in significantly longer PFS than gefitinib (HR: 0.48 with 95% CI: 0.33-0.71 and HR: 0.54 with 95% CI: 0.36-0.80, respectively). Moreover, afatinib resulted in significantly longer PFS than gefitinib in patients with brain metastasis (HR: 0.53, 95% CI: 0.33-0.87) or ECOG status 0-1 (HR: 0.37, 95% CI: 0.23-0.59).
CONCLUSION
This NMA suggests that afatinib results in similar PFS to erlotinib and superior PFS than gefitinib in patients with Del19 mutant NSCLC, aged ≥65 years, with ECOG scores of 0-1, and with baseline brain metastasis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Gefitinib; Erlotinib Hydrochloride; Afatinib; Tyrosine Kinase Inhibitors; Lung Neoplasms; East Asian People; Network Meta-Analysis; Protein Kinase Inhibitors; Mutation; Treatment Outcome; ErbB Receptors; Brain Neoplasms
PubMed: 37737541
DOI: 10.1111/1759-7714.15111 -
European Journal of Cancer (Oxford,... Apr 2024The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas...
PURPOSE
The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC.
METHODS
Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m / 125 mg/m (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy.
RESULTS
Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3-5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months.
CONCLUSIONS
In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m / 125 mg/m) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.
Topics: Humans; Gemcitabine; Afatinib; Deoxycytidine; Paclitaxel; Albumins; Pancreatic Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38401449
DOI: 10.1016/j.ejca.2024.113926 -
Aging Jan 2024In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly...
Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.
BACKGROUND
In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC).
METHODS
Treatment-naïve patients with -mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared.
RESULTS
This study enrolled 1,343 treatment-naïve patients with -mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: = 0.003; OS: = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib.
CONCLUSIONS
This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with -mutated advanced NSCLC.
Topics: Aged; Humans; Afatinib; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 38194721
DOI: 10.18632/aging.205395