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Targeted Oncology Jun 2024Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer....
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making.
OBJECTIVE
This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs.
METHODS
We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted.
RESULTS
Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease.
CONCLUSIONS
Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.
PubMed: 38824269
DOI: 10.1007/s11523-024-01073-w -
Cancer Treatment Reviews Jun 2021Innovative strategies to fully exploit the antitumor activity of multitargeted tyrosine kinase inhibitors (TKIs) are urgently needed. Higher concentrations of TKIs at...
BACKGROUND
Innovative strategies to fully exploit the antitumor activity of multitargeted tyrosine kinase inhibitors (TKIs) are urgently needed. Higher concentrations of TKIs at their target site, i.e. intratumorally, may lead to broader kinase inhibition, which might be essential for the optimal suppression of tumor growth and induction of apoptosis. To reach these higher intratumoral concentrations, without encountering dose limiting toxicity, alternative TKI dosing strategies employing higher daily and high intermittent doses have been studied. In this systematic review, we evaluated the current clinical evidence to support (intermittent) high TKI dosing regimens.
METHODS
A systematic review was conducted in the following databases: PubMed®, EMBASE® and Cochrane Library©, to evaluate efficacy of alternatively scheduled high-dosed regimen (a higher dose in a regular daily schedule than registered or a higher dose in an alternative intermittent schedule) of TKIs in (haemato-)oncology. Data were extracted independently by two authors according to predefined criteria. Extracted data were tabulated to summarize key findings.
RESULTS
Out of twenty studies that met the inclusion criteria, thirteen investigated higher daily dose schedules of either afatinib, axitinib, erlotinib, gefitinib, imatinib, sorafenib, and sunitinib. Five of these studies included pharmacokinetic analyses, reporting marginal higher maximum drug concentrations (C) in plasma (1.3-4-fold higher) compared to the standard dose schedules. Seven clinical trials investigated intermittent high-dose schedules requiring treatment breaks, with the following TKIs: afatinib, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib. Six of these included pharmacokinetic results, all reporting higher (2-21-fold) C in plasma compared to the standard daily dose schedule, with manageable toxicity. No data on tumor concentrations were presented. Data on the efficacy outcomes were limited due to small sample size, study designs, phase 1 population and heterogeneous tumor types.
CONCLUSIONS
Early phase clinical studies show that high-dose intermittent TKI-treatment schedules can lead to an increased C compared to standard (low-dose) daily administration with manageable toxicity. These higher concentrations are assumed to reflect higher intratumoral concentrations. Further investigation of the potential improvement in clinical benefit of a high-dose intermittent strategy with multitargeting TKIs is warranted.
Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Neoplasms; Prognosis; Protein Kinase Inhibitors
PubMed: 33823432
DOI: 10.1016/j.ctrv.2021.102171 -
European Journal of Oncology Nursing :... Feb 2021To investigate the effectiveness of different interventions for the prevention and treatment of EGFRI treatment-induced rash (EGFRIr) that appeared in the last decade,...
The extent to which the last decade has yielded additional treatment options for EGFR-associated rash besides classic treatment with antibiotics and corticosteroids - A systematic review.
PURPOSE
To investigate the effectiveness of different interventions for the prevention and treatment of EGFRI treatment-induced rash (EGFRIr) that appeared in the last decade, excluding antibiotics and steroids products alone.
METHOD
A systematic review was performed in 2019 and was updated in 2020. The search strategy was limited to studies published within the last 10 years on the Medline database accessed via Pubmed and the Cochrane database. The search was performed using keywords combined with AND, OR.
RESULTS
The search yielded thirteen studies. The studies were divided into two categories, based on the intervention method used: four studies used creams containing vitamin K1 or vitamin K3 (henceforth classified as "Category A″) and nine studies ("Category B″) focused on different intervention methods such as laser treatment, Polydatin (PD) cream treatment, treatment with sunscreen, Adapalene gel treatment, topical aloe vera treatment, topical hydration treatment, the impact of a pre-emptive skin treatment and, finally, epidermal growth factor (EGF) ointment treatment. From "Category A″, the results vary as two studies found no benefit from cream use, while two studies indicated a possible improvement on skin reactions from cream use. In "Category B″, a benefit due to laser treatment was indicated, Polydatin-containing moisturizer showed a reduction in the incidence of rash grade ≥ II in patients treated with afatinib, while treatment with sunscreen demonstrated no benefit for the prevention of EGFRIr. Additionally, Adapalene gel use is not recommended as prophylaxis for EGFRIr, topical aloe vera may be used in the management for EGFRIr due to cetuximab, topical hydration resolved the EFGRIr, the pre-emptive skin treatment routine was well tolerated and the epidermal growth factor ointment improved all the symptoms due to EGFRI.
CONCLUSIONS
The results from the studies vary, although this study focuses on reviewing treatment interventions that can be utilized, apart from antibiotics and steroids, in order to alleviate the problems of the patients suffering from EGFRIr. More specifically, the authors of this review cannot draw a conclusion from "Category A″, as the efficacy of vitamin K for the management of EGFRIr is controversial. From "Category B″, some of the suggested treatments show encouraging results, while others may prove ineffective and rather harmful for the patients.
Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Bacterial Agents; Drug Eruptions; ErbB Receptors; Exanthema; Humans; Protein Kinase Inhibitors
PubMed: 33493993
DOI: 10.1016/j.ejon.2021.101896 -
Journal of Cancer 2021Different second-line treatments of patients with trastuzumab-resistant human epidermal growth factor receptor 2 (HER2) positive breast cancer were examined in...
Efficacy of second-line treatments for patients with advanced human epidermal growth factor receptor 2 positive breast cancer after trastuzumab-based treatment: a systematic review and bayesian network analysis.
Different second-line treatments of patients with trastuzumab-resistant human epidermal growth factor receptor 2 (HER2) positive breast cancer were examined in randomized controlled trials (RCTs). A network meta-analysis is helpful to evaluate the comparative survival benefits of different options. We performed a bayesian network meta-analysis using R-4.0.0 software and fixed consistency model to compare the progression free survival (PFS) and overall survival (OS) benefits of different second-line regimens. 13 RCTs (19 publications, 4313 patients) remained for qualitative synthesis and 12 RCTs (17 publications, 4022 patients) were deemed eligible for network meta-analysis. For PFS, we divided network analysis into two parts owing to insufficient connections among treatments. The first part involved 8 treatments in 9 studies and we referred it as PFS (#1). Amid the following 8 interventions: pyrotinib + capecitabine, T-DM1 + atezolizumab, pertuzumab + trastuzumab + capecitabine, T-DM1, trastuzumab + capecitabine, lapatinib + capecitabine, neratinib, and capecitabine, we found consistent benefits between the first three interventions; moreover, pyrotinib + capecitabine was most likely to be associated with the best benefits; capecitabine monotherapy was associated with the worst PFS. The second part included 3 treatments in 2 studies and we referred it as PFS (#2): everolimus + trastuzumab + vinorelbine had better PFS benefits versus trastuzumab + vinorelbine and afatinib + vinorelbine. For OS, we analyzed 7 treatments in 7 studies, and observed T-DM1 + atezolizumab, pertuzumab + trastuzumab + capecitabine, and T-DM1 had similar effectiveness, and the first had the highest probability to yield the longest OS; capecitabine or neratinib alone yielded the worst OS benefits. Our work comprehensively summarized and analyzed current available RCT-based evidence of the second-line treatments for trastuzumab-treated, HER2-positive, advanced breast cancer. These results provide clinicians and oncologists meaningful references for clinical drug administration and the development of novel effective therapies.
PubMed: 33613756
DOI: 10.7150/jca.51845 -
Annals of Palliative Medicine Jul 2020To compare the survival outcomes of first-line treatment regimens for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To compare the survival outcomes of first-line treatment regimens for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with stable brain metastases.
METHODS
We conducted a systematic review of available data from randomized controlled trials (RCTs) of first-line treatment regimens of NSCLC patients with stable brain metastases. Progression free survival (PFS) and overall survival (OS) were extracted and analysed from the RCT subgroups. A network meta-analysis was constructed using the Bayesian statistical model to synthesize the survival outcomes of all the treatments.
RESULTS
The analysis included 6 eligible RCT subgroups with 417 patients and 7 treatment regimens osimertinib, afatinib, first-generation EGFR-TKI (gefitinib or erlotinib), erlotinib + bevacizumab, gefitinib + pemetrexed + carboplatin, gemcitabine + cisplatin, and pemetrexed + cisplatin. Of these seven treatment regimens, gefitinib + pemetrexed + carboplatin had the highest potential for favorable PFS and OS, followed by osimertinib, in the treatment of advanced EGFR-mutant NSCLC patients with stable brain metastases. None of the results met the predetermined statistical significance of P<0.05.
CONCLUSIONS
The regimens of "Gefitinib + pemetrexed + carboplatin" and "Osimertinib" were associated with the most favorable PFS and OS compared to the other therapies in advanced EGFR-mutant NSCLC patients with stable brain metastases, although the difference between these regimens and the others was not statistically significantly different.
Topics: Bayes Theorem; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Survival Analysis
PubMed: 32692221
DOI: 10.21037/apm-20-1136