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International Journal of Cancer Jun 2017Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung... (Comparative Study)
Comparative Study Meta-Analysis Review
Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung cancer (NSCLC) with proven efficacy. We undertook a systematic review and meta-analysis to synthesize existing studies with direct comparisons of EGFR TKIs in NSCLC in terms of both efficacy and safety. Eight randomized trials and 82 cohort studies with a total of 17,621 patients were included for analysis. Gefitinib and erlotinib demonstrated comparable effects on progression-free survival (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.95 to 1.04), overall survival (HR, 0.99; 95% CI, 0.93 to 1.06), overall response rate (risk ratio [RR], 1.05; 95% CI, 1.00 to 1.11), and disease control rate (RR, 0.98; 95% CI, 0.96 to 1.01), which did not vary considerably with EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status. Gefitinib was associated with more grade 3/4 liver dysfunction, but tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 adverse events (RR, 0.78; 95% CI 0.65 to 0.94), and a number of specific adverse events such as rash and diarrhea. No solid evidence was found that afatinib had greater efficacy than gefitinib or erlotinib in first-line treatment of EGFR-mutant NSCLC. However, afatinib was more effective than erlotinib as second-line treatment of patients with advanced squamous cell carcinoma. The grade 3/4 adverse events rate of afatinib was comparable to that of erlotinib but higher than that of gefitinib.
Topics: Afatinib; Carcinoma, Non-Small-Cell Lung; Diarrhea; Disease-Free Survival; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Gefitinib; Humans; Lung Neoplasms; Mutation; Outcome Assessment, Health Care; Proportional Hazards Models; Protein Kinase Inhibitors; Quinazolines; Randomized Controlled Trials as Topic
PubMed: 28295308
DOI: 10.1002/ijc.30691 -
BMJ (Clinical Research Ed.) Oct 2019To compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). (Meta-Analysis)
Meta-Analysis
Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis.
OBJECTIVE
To compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Published and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher.
RESULTS
18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation.
CONCLUSIONS
These results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42018111954.
Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Mutation; Network Meta-Analysis
PubMed: 31591158
DOI: 10.1136/bmj.l5460 -
Current Oncology (Toronto, Ont.) Jan 2022Compound epidermal growth factor receptor () mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon mutations. We... (Review)
Review
Compound epidermal growth factor receptor () mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon mutations. We conducted a systematic review to investigate the available data on this patients' subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4-26% of total mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40-80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20-70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound mutations, taking into account different sensitivity profile of accompanying mutations for selecting the most adequate EGFR TKI for individual patients.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 35049698
DOI: 10.3390/curroncol29010024 -
Cancers Feb 2021Several randomized controlled trials (RCTs) evaluated the afatinib efficacy in patients with advanced non-small cell lung cancer (NSCLC) and recurrent/metastatic head... (Review)
Review
Several randomized controlled trials (RCTs) evaluated the afatinib efficacy in patients with advanced non-small cell lung cancer (NSCLC) and recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). This review systemically outlined and meta-analyzed the afatinib efficacy in NSCLC and R/M HNSCC in terms of overall survival (OS) and progression-free survival (PFS) endpoints. Records were retrieved from PubMed, Web of Science, and ScienceDirect from 2011 to 2020. Eight afatinib RCTs were included and assessed for the risk of bias. In meta-analysis, overall pooled effect size (ES) of OS in afatinib group (AG) significantly improved in all RCTs and NSCLC-RCTs [hazard ratios (HRs): 0.89 (95% CI: 0.81-0.98, = 0.02); I = 0%, = 0.71/ 0.86 (95% CI: 0.76-0.97; = 0.02); I = 0%, = 0.50, respectively]. ES of PFS in AG significantly improved in all RCTs, NSCLC-RCTs, and HNSCC-RCTs [HRs: 0.75 (95% CI: 0.68-0.83; < 0.00001); I = 26%, = 0.24; 0.75 (95% CI: 0.66-0.84; < 0.00001); I = 47%, = 0.15/0.76 (95% CI: 0.65-88; = 0.0004); I = 34%, = 0.0004, respectively]. From a clinical viewpoint of severity, interstitial lung disease, dyspnea, pneumonia, acute renal failure, and renal injury were rarely incident adverse events in the afatinib group. In conclusion, first- and second-line afatinib monotherapy improved the survival of patients with NSCLC, while second-line afatinib monotherapy could be promising for R/M HNSCC. The prospective protocol is in PROSPERO (ID = CRD42020204547).
PubMed: 33567737
DOI: 10.3390/cancers13040688 -
Cancers Sep 2022Several new drugs and combination strategies can be used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma in the second-line... (Review)
Review
Comparison of Second-Line Treatments for Patients with Platinum-Resistant Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Bayesian Network Meta-Analysis.
Several new drugs and combination strategies can be used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma in the second-line treatment. Questions regarding the relative efficacy and safety of any two of the multiple second-line treatment strategies have emerged. This study aims to compare second-line treatments for patients with platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify relevant articles. Direct and indirect evidence in terms of the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events grade ≥ 3 (grade ≥ 3 trAE) were analyzed in this Bayesian network meta-analysis. A total of twenty-three trials involving 5039 patients were included. These studies compared 20 different treatments, including the standard of care (SOC: docetaxel, methotrexate, or cetuximab), PD-1 inhibitors (nivolumab or pembrolizumab), durvalumab, tremelimumab, durvalumab + tremelimumab, palbociclib + SOC, tivantinib + SOC, sorafenib + SOC, EMD1201081 + SOC, vandetanib + SOC, PX-866 + SOC, 5-fluorouracil + SOC, cixutumumab + SOC, gefitinib + SOC, cabazitaxel, nolatrexed, duligotuzumab, zalutumumab, gefitinib, and afatinib. Among the currently available treatment options, compared to the standard of care (SOC: docetaxel, methotrexate, or cetuximab), the PD inhibitor significantly improved OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS. In conclusion, compared to the SOC, the PD-1 inhibitor significantly improved the OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS.
PubMed: 36139631
DOI: 10.3390/cancers14184472 -
Frontiers in Pharmacology 2021As one of the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, afatinib brings survival benefits to patients with common and rare... (Review)
Review
As one of the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, afatinib brings survival benefits to patients with common and rare EGFR mutations. This study aimed to compare the effectiveness and safety of 30 and 40 mg of afatinib in patients with non-small cell lung cancer (NSCLC) using qualitative and quantitative analysis methods so as to provide reference for clinical medication. The PubMed, Embase, ClinicalTrials.gov, Cochrane Library, China National Knowledge Infrastructure, and WanFang databases were thoroughly searched from inception to February 26, 2021. Two researchers independently screened the literature, extracted data, and evaluated the quality. RevMan and Stata 15.0 were used for meta-analysis. Twelve cohort studies including 1290 patients for final analysis were selected; of which, 1129 patients were analyzed to measure the effectiveness outcomes and 470 patients were analyzed for safety outcomes. In patients with non-brain metastasis, the progression-free survival of the first- or second-line treatment with reduced-dose afatinib was equivalent to the conventional dose. In terms of safety, the reduced dose could significantly lower the incidence of severe diarrhea and severe rash, but not the total incidence of diarrhea, rash, and all levels of paronychia. The incidence of common serious adverse reactions was significantly lower with 30 mg of afatinib than with 40 mg of afatinib in patients with NSCLC. The effectiveness appeared to be similar to that in patients with non-brain metastasis. This study provides a reference for clinical dose reduction of afatinib. [PROSPERO], identifier [CRD42021238043].
PubMed: 34912228
DOI: 10.3389/fphar.2021.781084 -
Frontiers in Oncology 2022Lung adenocarcinoma is a common disease with a high mortality rate. Epidermal growth factor receptor () mutations are found in adenocarcinomas, and oral EGFR-tyrosine...
BACKGROUND
Lung adenocarcinoma is a common disease with a high mortality rate. Epidermal growth factor receptor () mutations are found in adenocarcinomas, and oral EGFR-tyrosine kinase inhibitors (EGFR-TKIs) show good responses. EGFR-TKI therapy eventually results in resistance, with the most common being T790M. T790M is also a biomarker for predicting resistance to first- and second-generation EGFR-TKIs and is sensitive to osimertinib. The prognosis was better for patients with acquired T790M who were treated with osimertinib than for those treated with chemotherapy. Therefore, T790M mutation is important for deciding further treatment and prognosis. Previous studies based on small sample sizes have reported very different T790 mutation rates. We conducted a meta-analysis to evaluate the T790M mutation rate after EGFR-TKI treatment.
METHODS
We systematic reviewed the electronic databases to evaluate the T790M mutation rate after treatment with first-generation (gefitinib, erlotinib, and icotinib) and second-generation (afatinib and dacomitinib) EGFR-TKIs. Random-effects network meta-analysis and single-arm meta-analysis were conducted to estimate the T790M mutation rate of the target EGFR-TKIs.
RESULTS
A total of 518 studies were identified, of which 29 were included. Compared with afatinib, a higher odds ratio (OR) of the T790M mutation rate was observed after erlotinib [OR = 1.48; 95% confidence interval (CI):1.09-2.00] and gefitinib (OR = 1.45; 95% CI: 1.11-1.90) treatments. An even OR of the T790M mutation rate was noted after icotinib treatment (OR = 0.91, 95% CI: 0.46-1.79) compared with that after afatinib. The T790M mutation rate was significantly lower with afatinib (33%) than that with gefitinib (49%) and erlotinib treatments (47%) ( < 0.001). The acquired T790M mutation rate in all participants was slightly lower in Asians (43%) than that in Caucasians (47%).
CONCLUSIONS
Erlotinib and gefitinib had a higher OR for the T790M mutation than afatinib. The T790M mutation rate was significantly lower in afatinib than in gefitinib and erlotinib. T790M is of great significance because osimertinib shows a good prognosis in patients with T790M mutation.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier CRD42021257824.
PubMed: 35837103
DOI: 10.3389/fonc.2022.869390 -
Cancers Jul 2022HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the... (Review)
Review
Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody-Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis.
HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician's choice of treatment (HR 0.17; 95% CrI 0.03-0.82) or afatinib (HR 0.14; 95% CrI 0.02-1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS.
PubMed: 35884431
DOI: 10.3390/cancers14143372 -
Cancers Jul 2022(1) Background: Randomized controlled trials (RCTs) have explored various primary treatments for individuals diagnosed as having later-stage epidermal growth factor... (Review)
Review
Overall Survival Benefits of First-Line Treatments for Asian Patients with Advanced Epidermal Growth Factor Receptor-Mutated NSCLC Harboring Exon 19 Deletion: A Systematic Review and Network Meta-Analysis.
(1) Background: Randomized controlled trials (RCTs) have explored various primary treatments for individuals diagnosed as having later-stage epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer. Nevertheless, the extent to which such treatments are efficacious, particularly with regard to overall survival (OS) rates of patients from Asia with exon 19 deletion (19del), has yet to be clarified. (2) Methods: A systematic review and frequentist network meta-analysis were conducted by obtaining pertinent studies from PubMed/MEDLINE Ovid, Embase, Cochrane Library, and trial registries, as well as various other sources. RCTs in which two or multiple treatments in the primary setting for patients from Asia with EGFR 19del were compared were included. This research has been recorded in the Prospective Register of Systematic Reviews (CRD 42022320833). (3) Results: A total of 2715 patients from Asia participated in 18 trials in which 12 different treatments were administered, which included: EGFR 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). Such treatments were not significantly beneficial in terms of OS for patients from Asia who had 19del. It was demonstrated that erlotinib plus bevacizumab, ramucirumab plus erlotinib, and osimertinib consistently yielded the greatest benefits regarding progression-free survival benefit (P-scores = 94%, 84%, and 80%, respectively). Combination treatments resulted in increased toxicity, particularly gefitinib plus apatinib and erlotinib plus bevacizumab, causing the highest prevalence of grade ≥ 3 adverse events. Icotinib and osimertinib had the fewest grade ≥ 3 adverse events. Specific treatments were associated with a wide range of toxicity levels. (4) Conclusions: In patients from Asia with 19del, both EGFR-TKIs and treatments in which therapies were combined exhibited no OS benefits in comparison with standard chemotherapy treatments. Additional research is required to study TKIs' resistance mechanisms and possible combined approaches for individuals harboring this common mutation.
PubMed: 35884423
DOI: 10.3390/cancers14143362 -
ESMO Open Jun 2022Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2 tyrosine kinase inhibitors (TKIs) are promising agents for the treatment of BM. In this study, we assess the clinical outcomes of patients with HER2-positive MBC and BM treated with TKI-containing regimens compared with those treated with non-TKI-containing regimens.
MATERIALS AND METHODS
PubMed, Embase, Cochrane Library, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) were searched up to June 2021. The primary endpoint was progression-free survival (PFS) in patients with BM. Secondary endpoints included PFS in patients without BM and overall survival (OS). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models.
RESULTS
This systematic review and meta-analysis included data from 2437 patients (490 with and 1947 without BM at baseline) enrolled in five trials assessing tucatinib-, lapatinib-, pyrotinib-, or afatinib-based combinations. A nonstatistically significant PFS benefit favoring TKI-containing regimens was observed in both patients with BM [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.41-1.12; P = 0.13] and without BM (HR 0.55, 95% CI 0.24-1.26; P = 0.16). Sensitivity analysis, excluding each study singly, demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM after the exclusion of afatinib from the analysis (HR 0.56, 95% CI 0.35-0.90; P = 0.016). No statistically significant differences in OS were observed between the comparison groups.
CONCLUSIONS
A trend in PFS favoring TKI-containing regimens was observed in patients with BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib, or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM.
Topics: Afatinib; Brain Neoplasms; Breast Neoplasms; Female; Humans; Lapatinib; Protein Kinase Inhibitors
PubMed: 35653982
DOI: 10.1016/j.esmoop.2022.100501