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Journal of Clinical Pharmacology Jul 2019To fully investigate the diarrhea of human epidermal growth factor receptor 2 (HER2)-targeted agents in cancer patients. The relevant studies of the randomized,... (Meta-Analysis)
Meta-Analysis
To fully investigate the diarrhea of human epidermal growth factor receptor 2 (HER2)-targeted agents in cancer patients. The relevant studies of the randomized, controlled trials (RCTs) in cancer patients treated with HER2-targeted agents were retrieved, and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until August 2018. Forty-two RCTs and 21 633 patients were included. The current meta-analysis suggested that the use of HER2-targeted agents significantly increases the risk of developing all-grade diarrhea (RR, 2.78; 95%CI, 2.37-3.25; P < .00001) and high-grade diarrhea (RR, 4.89; 95%CI, 3.09-7.75; P < .00001). The RRs of all-grade diarrhea and high-grade diarrhea varied significantly according to drug type, control group, and treatment regimen. The RR of all-grade diarrhea varied significantly according to tumor type. Afatinib and neratinib tended to associate with the highest risk of all-grade diarrhea and high-grade diarrhea, respectively. Trastuzumab was associated with the lowest risk of diarrhea. Breast cancer patients tended to have a higher risk of all-grade diarrhea than patients with nonbreast cancer when receiving a HER2-targeted agent. The available data suggested that the use of HER2-targeted agents is associated with a significantly increased risk of diarrhea in cancer patients.
Topics: Antineoplastic Agents; Diarrhea; Humans; Neoplasms; Receptor, ErbB-2; Risk Factors
PubMed: 30707455
DOI: 10.1002/jcph.1382 -
JTO Clinical and Research Reports May 2022Randomized controlled trials have investigated different first-line treatments for patients with advanced -mutated NSCLC. Nevertheless, their efficacy, in particular,...
Overall Survival Benefits of First-Line Treatments for Asian Patients With Advanced EGFR-Mutated NSCLC Harboring L858R Mutation: A Systematic Review and Network Meta-Analysis.
INTRODUCTION
Randomized controlled trials have investigated different first-line treatments for patients with advanced -mutated NSCLC. Nevertheless, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with L858R mutation, remains unclear.
METHODS
We performed a systematic review and frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE, Ovid, EMBASE, Cochrane Library, trial registries, and other sources. We included randomized controlled trials comparing two or more treatments in the first-line setting for Asian patients with L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD 42022295897).
RESULTS
There were a total of 18 trials that involved 1852 Asian patients and 12 treatments, including the following: tyrosine kinase inhibitors (TKIs) (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with L858R mutation had no significant OS benefits from all these treatments. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib, and erlotinib plus bevacizumab were found to be consistent in yielding the best progression-free survival benefit ( scores = 93%, 79%, 77%, and 70%). Combination treatments caused more toxicity, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, resulting in the greatest incidence of grade greater than or equal to 3 adverse events.
CONCLUSIONS
In Asian patients harboring L858R mutation, TKIs and combination treatments had no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with this common but less favorable mutation.
PubMed: 35516725
DOI: 10.1016/j.jtocrr.2022.100322 -
PloS One 2016Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the incidence and relative risk (RR) in cancer patients treated with these agents.
MATERIALS AND METHODS
The scientific literature regarding hyponatraemia was extensively reviewed using MEDLINE, PubMed, Embase and Cochrane databases. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% Confidence Intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.
RESULTS
4803 potentially relevant trials were identified: of them, 13 randomized phase III studies were included in this meta-analysis. 6670 patients treated with 8 targeted agents were included: 2574 patients had hepatocellular carcinoma, whilst 4096 had other malignancies. The highest incidences of all-grade hyponatraemia were observed with the combination of brivanib and cetuximab (63.4) and pazopanib (31.7), while the lowest incidence was reported by afatinib (1.7). The highest incidence of high-grade hyponatraemia was reported by cetuximab (34.8), while the lowest incidences were reported by gefitinib (1.0). Summary RR of developing all-grade and high-grade hyponatraemia with targeted agents was 1.36 and 1.52, respectively. The highest RRs of all-grade and high-grade hyponatraemia were associated with brivanib (6.5 and 5.2, respectively). Grouping by drug category, the RR of high-grade hyponatraemia with angiogenesis inhibitors was 2.69 compared to anti-Epidermal Growth Factor Receptors agents (1.12).
CONCLUSION
Treatment with biological therapy in cancer patients is associated with a significant increased risk of hyponatraemia, therefore frequent clinical monitoring should be emphasized when managing targeted agents.
Topics: Clinical Trials, Phase III as Topic; Humans; Hyponatremia; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 27167519
DOI: 10.1371/journal.pone.0152079 -
Journal of Thoracic Oncology : Official... Mar 2024Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations... (Review)
Review
Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations are scattered and limited to mostly retrospective small cohorts because these patients were usually excluded from clinical trials. This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than exon 20 insertions mutations or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes. This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 1836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first- or second-generation TKIs. G719X, S768I, E709X, L747X, and E709-T710delinsD showed RRs ranging from 47.8% to 72.3% to second-generation TKIs, generally higher than for first- or third-generation TKIs. L861Q mutation exhibited 75% (95% confidence interval [CI]: 56.6%-88.5%) RRs to third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% to second- and third-generation TKIs, although fewer data were available for third generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2%-44.2%), 51.9% (95% CI: 44.4%-59.3%), and 67.9% (95% CI: 47.6%-84.1%) to first-, second-, and third-generation TKIs, whereas for P-loop alpha helix compressing mutations classes mutations, RRs were 37.2% (95% CI: 32.4%-42.1%), 59.6% (95% CI: 54.8%-64.3%), and 46.3% (95% CI: 32.6%-60.4%), respectively. This systematic review supports the use of second-generation TKI afatinib for G719X, S768I, E709X, and L747X mutations and for compound uncommon mutations. For other uncommon mutations such as L861Q, third-generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.
PubMed: 38499147
DOI: 10.1016/j.jtho.2024.03.016 -
Chinese Medical Journal Nov 2023The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR -mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR -mutated NSCLC patients with different BM statuses.
METHODS
Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR -mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework.
RESULTS
This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.20, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For patients without BM, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 47.1%. For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively.
CONCLUSION
Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR -mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Bevacizumab; Bayes Theorem; Network Meta-Analysis; Protein Kinase Inhibitors; Pemetrexed; ErbB Receptors; Brain Neoplasms; Mutation
PubMed: 37160733
DOI: 10.1097/CM9.0000000000002468 -
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 -
Neurosurgery Mar 2019What evidence is available regarding emerging and investigational treatment options for metastatic brain tumors?
Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Emerging and Investigational Therapties for the Treatment of Adults With Metastatic Brain Tumors.
QUESTION
What evidence is available regarding emerging and investigational treatment options for metastatic brain tumors?
TARGET POPULATION
Adult patients with brain metastases.
INTERSTITIAL MODALITIES
There is insufficient evidence to make a recommendation regarding the routine use of existing local therapies, such as interstitial chemotherapy, brachytherapy, or other local modalities, aside from their use in approved clinical trials.
IMMUNE MODULATORS
There is insufficient evidence to make a recommendation regarding the use of immune therapy for brain metastases.
MOLECULAR TARGETED AGENTS
Level 1: The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.There is insufficient evidence to make recommendations regarding: the use of epidermal growth factor receptor inhibitors erlotinib and gefitinib in patients with brain metastasis due to nonsmall cell lung cancerthe use of BRAF inhibitors dabrafenib and vemurafenib in the treatment of patients with brain metastases due to metastatic melanomathe use of HER2 agents trastuzumab and lapatinib to treat patients with brain metastases due to metastatic breast cancerthe use of vascular endothelial growth factor agents bevacizumab, sunitinib, and sorafenib in the treatment of patients with solid tumor brain metastases.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_9.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Congresses as Topic; Drugs, Investigational; Female; Humans; Neurosurgeons; Practice Guidelines as Topic; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 30629215
DOI: 10.1093/neuros/nyy547 -
Cancer Treatment Reviews Mar 2014Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged... (Review)
Review
BACKGROUND
Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.
MATERIALS AND METHODS
A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.
RESULTS
This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.
CONCLUSION
Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.
Topics: Ado-Trastuzumab Emtansine; Afatinib; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Female; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Maytansine; Molecular Targeted Therapy; Neoadjuvant Therapy; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolines; Quinolines; Receptor, ErbB-2; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab; Treatment Outcome; Up-Regulation
PubMed: 24080156
DOI: 10.1016/j.ctrv.2013.09.002 -
Critical Reviews in Oncology/hematology May 2015Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a... (Meta-Analysis)
Meta-Analysis Review
Is there evidence for different effects among EGFR-TKIs? Systematic review and meta-analysis of EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy as first-line treatment for patients harboring EGFR mutations.
Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS. The relative probability of overall response was gefitinib versus erlotinib 0.96 (95% CI 0.69-1.34), gefitinib versus afatinib 0.91 (95% CI 0.67-1.23), erlotinib versus afatinib 0.94 (95% CI 0.65-1.35). Indirect comparisons for safety showed the RR for diarrhea gefitinib versus erlotinib 0.80 (95% CI 0.63-1.01), gefitinib versus afatinib 0.29 (95% CI 0.20-0.41), erlotinib versus afatinib 0.36 (95% CI 0.25-0.54); for rash gefitinib versus erlotinib 1.00 (95% CI 0.82-1.22), gefitinib versus afatinib 0.41(95% CI 0.25-0.65), erlotinib versus afatinib 0.41 (95% CI 0.25-0.66); for hypertransaminasemia gefitinib versus erlotinib 2.29 (95% CI 1.63-3.23). Our analysis showed that all treatments had similar efficacy but they differ for toxicities.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Odds Ratio; Proportional Hazards Models; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 25523487
DOI: 10.1016/j.critrevonc.2014.11.005