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Frontiers in Oncology 2022Tyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation....
OBJECTIVES
Tyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI-based combination treatment modes show encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on overall survival (OS).
MATERIALS AND METHODS
Randomized controlled trials and meeting abstracts that investigated EGFR-TKIs alone or in combination as front-line care for patients with NSCLC were systematically searched in relevant databases and reviewed. Fixed and random effects network meta-analysis models were used to estimate progression-free survival (PFS), OS, overall response rate, and grade three and higher adverse events (AEs). Surface under the cumulative ranking curves (SUCRAs) were used to rank treatment effects.
RESULTS
Eighteen studies covering six treatments and involving a total of 4389 patients were included in this network meta-analysis. On OS, the top three treatment were first-generation EGFR-TKIs (1G EGFR-TKIs) plus chemotherapy (SUCRA, 88.1%), osimertinib (SUCRA, 65.8%) and second-generation EGFR-TKIs (2GEGFR-TKIs) (SUCRA, 63.3%). On PFS, the top three treatments were osimertinib (SUCRA, 96.0%), 1G EGFR-TKIs plus chemotherapy (SUCRA, 67.1%), and 1G EGFR-TKIs plus antiangiogenesis (SUCRA, 48.2%). Two types of TKI-based combination therapy have significantly higher risk of grade three and higher AEs than TKI alone.
CONCLUSION
1G EGFR-TKIs plus chemotherapy and osimertinib seem to be the two better options as first-line care in advanced NSCLC patients with EGFR-mutation. Osimertinib caused the lowest incidence of AEs. However, TKIs-based combination therapy significantly increased AEs.
PubMed: 35978809
DOI: 10.3389/fonc.2022.616546 -
JCO Precision Oncology Aug 2022Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified... (Meta-Analysis)
Meta-Analysis
PURPOSE
Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.
METHODS
We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival.
RESULTS
A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors.
CONCLUSION
This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.
Topics: Humans; Lung Neoplasms; Melanoma; Mitogen-Activated Protein Kinases; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; United States
PubMed: 35977349
DOI: 10.1200/PO.22.00107 -
Frontiers in Oncology 2022Gastric metastasis from lung cancer (GMLC) is a rare occurrence. The clinicopathological characteristics, outcomes, and prognostic factors remain largely elusive.
BACKGROUND
Gastric metastasis from lung cancer (GMLC) is a rare occurrence. The clinicopathological characteristics, outcomes, and prognostic factors remain largely elusive.
METHODS
We conducted a systematic review on case reports and case series of GMLC by scanning MEDLINE, Embase, and ISI Web of Knowledge. Data involving the clinicopathological features, treatment, and outcomes were extracted and analyzed. Survival analysis was performed using Kaplan-Meier method. The Cox proportional hazards regression model was used to identify potential prognostic factors associated with survival. Furthermore, a case of metastatic gastric adenocarcinoma of pulmonary origin with epidermal growth factor receptor (EGFR) L858R+T790M mutation was also described and included.
RESULTS
Seventy-eight records involving 114 cases (including ours) were finally included. The median age on admission was 65 years with a male predominance of 79.8%. Lung adenocarcinoma (42.1%), located in the right upper lobe (30.3%), was the most frequent primary tumor. Bleeding (36.7%) and abdominal pain (35.8%) were the two most common symptoms. Endoscopically, gastric lesions were typically presented as elevated lesions with or without volcano-like ulceration, or ulcerative lesions, mostly involving the gastric corpus. The median overall survival time and survival time after diagnosis of metastatic cancer were 11 months [95% confidence interval (CI): 7-14] and 4.5 months (95% CI: 3-9), respectively. The survival analyses revealed that surgical interventions (including lung surgery and/or abdominal surgery) and systemic therapy (including chemotherapy, radiotherapy, and/or targeted therapy) seemed to be positive prognostic factors for both overall survival and survival after diagnosis of metastatic cancer.
CONCLUSIONS
Clinicians should be alerted to the occurrence of gastric metastasis in lung cancer patients. Comprehensive evaluation and appropriate treatment for specific patients may improve the survival rate of GMLC patients.
PubMed: 35875072
DOI: 10.3389/fonc.2022.922016 -
Cureus Jun 2022Erdheim Chester disease (ECD) is a type of histiocytosis characterized by a variable clinical presentation. The treatment of ECD is complex and mainly unknown. We aim to... (Review)
Review
Erdheim Chester disease (ECD) is a type of histiocytosis characterized by a variable clinical presentation. The treatment of ECD is complex and mainly unknown. We aim to conduct a literature review of the treatment of ECD and consolidate the knowledge about the most recent and updated treatment for ECD. To conduct the systematic review, we used the preferred reporting items for systematic reviews and meta-analysis (PRISMA) protocol. To analyze the bias, we used the Cochrane collaboration risk-of-bias tool to assess the bias. We included observational studies and clinical trials on humans, which were written in English. Papers not fulfilling the objective of our study were excluded. Overall, the drug showed efficacy in the clinical trials, showing prolonged improvement and high rates of response rate. Overall, the drug was not well tolerated, and patients had a long list of side effects. Nevertheless, the drug seems to be a good option for second-line treatment for patients with ECD and BRAFV600 mutation.
PubMed: 35844342
DOI: 10.7759/cureus.25935 -
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 -
Frontiers in Oncology 2022Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial...
Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis.
BACKGROUND
Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial activity in both treatment-naïve and previously treated BM patients. We aimed to investigate if there was any difference in response of BRAF inhibitors in these two cohorts.
MATERIALS AND METHODS
Electronic database search included PubMed, Medline, and Cochrane library until March 2021 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included intracranial response rate as the primary outcome and survival and safety outcomes as the secondary outcomes. Review Manager version 5.4 was used for data analysis.
RESULTS
Three studies comprising 410 BRAF-mutated melanoma patients with BMs were included according to eligibility criteria. The comparative cohort included patients with treatment-naïve BMs (TN cohort; = 255) and those who had progressive disease after receiving local brain treatment for BMs (PT cohort; = 155). Meta-analysis revealed that BRAF inhibitors (vemurafenib and dabrafenib) and BRAF/MEK inhibitor combination (dabrafenib and trametinib) induced significantly higher intracranial disease control (OR 0.58 [95% CI: 0.34, 0.97], = 0.04) and a trend toward improved progression-free survival (PFS) (HR 1.22 [95% CI: 0.98, 1.52], = 0.08) in the PT cohort as compared to the TN cohort. Overall survival was not significantly different between the cohorts (HR 1.16 [95% CI: 0.89, 1.51], = 0.28). Subgroup analysis revealed that PFS was significantly improved (HR 1.67 [95% CI: 1.06, 2.62], = 0.03), and a trend toward improved OS (HR 1.62 [95% CI: 0.95, 2.75], = 0.08) was achieved in patients receiving BRAF/MEK inhibitor combination and patients with BRAFv600K mutation receiving dabrafenib alone. No increase in overall adverse events (AEs), grade 3/4 AEs, and severe adverse events (SAEs) was observed between the cohorts.
CONCLUSIONS
BRAF inhibitors (plus MEK inhibitor) may achieve better intracranial disease stability in BRAF-mutant melanoma patients who have received previous local treatment for BMs.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/), identifier CRD42020185984.
PubMed: 35814449
DOI: 10.3389/fonc.2022.704890 -
ESMO Open Aug 2022Pathogenic variants (PVs) in BRCA1/2 genes account for ∼6% of breast and 20% of ovarian cancers. Most breast tumors developed by BRCA1 carriers are triple negative....
BACKGROUND
Pathogenic variants (PVs) in BRCA1/2 genes account for ∼6% of breast and 20% of ovarian cancers. Most breast tumors developed by BRCA1 carriers are triple negative. BRCA2 tumors have similar rates of estrogen receptor positivity as sporadic controls but are less likely to be human epidermal growth factor receptor 2 (HER2)-positive. Prevalence of HER2 positivity among breast cancers (BCs) in BRCA1/2 mutation carriers is poorly and variably described, ranging from 0% to 10% and 0% to 13% in BRCA1 and BRCA2 carriers, respectively.
PATIENTS AND METHODS
We assessed the prevalence of HER2 positivity among a single institutional cohort of 398 BCs developed in carriers of BRCA1/2 PVs (240 BRCA1, 158 BRCA2). Subsequently, a systematic review of the literature and pooled analysis was carried out.
RESULTS
In our series we found a 7% HER2 positivity rate among all first BRCA1/2 BCs overall. In BRCA1 carriers, 5.4% of BCs were HER2-positive compared with 9.5% in BRCA2-mutated patients. Among bilateral BCs, HER2-positive cases were 15.2% in the BRCA1 group and 23.1% in the BRCA2 group. Notably, six BRCA1 and eight BRCA2 carriers showed discordant HER2 status between BC and bilateral BC (23.7%, 14/59). The systematic review included 21 083 BRCA1/2 patients from 73 eligible studies. The pooled rate of BRCAmut/HER2-positive BCs is 9.1% (95% confidence interval 7.3% to 11.2%). BRCA1 and BRCA2 when reported as separate data ranged from 0% to 33.3% (mean 8.3%) and from 0% to 86% (mean 10.3%), respectively.
CONCLUSIONS
As compared with sporadic cases, BCs occurring in BRCA1 and/or BRCA2 PVs carriers are less frequently HER2-positive. Prevalence of HER2 positivity in our series was consistent with pooled analysis and did not exceed 10%. Although not common, co-existence of BRCA mutations and HER2 overexpression and/or gene amplification should be acknowledged. More research is needed to better characterize this subgroup of patients who should not be excluded a priori from clinical trials of targeted therapy for BRCA1/2-driven cancers.
Topics: Breast Neoplasms; Female; Genes, BRCA2; Humans; Receptor, ErbB-2
PubMed: 35810556
DOI: 10.1016/j.esmoop.2022.100531 -
Frontiers in Oncology 2022Epidermal growth factor receptor (EGFR) T790M-negative/unknown advanced non-small cell lung cancer (NSCLC) patients lack subsequent approved targeted therapies. This...
Efficacy of Osimertinib in EGFR-Mutated Advanced Non-small-Cell Lung Cancer With Different T790M Status Following Resistance to Prior EGFR-TKIs: A Systematic Review and Meta-analysis.
PURPOSE
Epidermal growth factor receptor (EGFR) T790M-negative/unknown advanced non-small cell lung cancer (NSCLC) patients lack subsequent approved targeted therapies. This meta-analysis aimed to assess the efficacy of osimertinib in advanced NSCLC patients with different T790M status after resistance to prior first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and to predict the subgroups that may benefit beside T790M-positive disease.
METHODS
PubMed, Embase, Web of Science, and Cochrane Library databases were searched for relevant trials. Meeting abstracts were also reviewed to identify appropriate studies. Studies evaluating the efficacy and/or survival outcomes of osimertinib in patients with different T790M status (positive, negative, or unknown) after resistance to prior first- or second-generation EGFR-TKIs were enrolled, and data were pooled to assess hazard ratios (HRs) or relative risk ratios (RRs) in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).
RESULTS
A total of 1,313 EGFR-mutated NSCLC patients from 10 retrospective and one prospective studies treated with osimertinib after resistance to first- or second-generation EGFR-TKIs were included. In overall groups, T790M-positive patients showed an improved OS (HR=0.574, p=0.015), PFS (HR = 0.476, p = 0.017), and ORR (RR = 2.025, p = 0.000) compared with T790M-negative patients. In the brain metastases subgroup, no significant difference in OS was observed between T790M-positive and T790M-negative patients (HR = 0.75, p = 0.449) or between T790M-positive and T790M-unknown patients (HR = 0.90, p = 0.673). In the plasma genotyping subgroup, PFS was similar between T790M-positive and T790M-negative patients (HR = 1.033, p = 0.959).
CONCLUSION
Patients with progressive brain metastases on first- or second-generation EGFR-TKIs can benefit from subsequent osimertinib therapy regardless of T790M status. Patients with plasma T790M-negative status and lack of tissue genotyping should be allowed to receive osimertinib treatment.
PubMed: 35785185
DOI: 10.3389/fonc.2022.863666 -
Annals of Translational Medicine May 2022Non-small cell lung cancer (NSCLC) is the most common subtype of all lung cancers, and KRAS is the most common mutation in this population. Unfortunately, this subgroup...
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common subtype of all lung cancers, and KRAS is the most common mutation in this population. Unfortunately, this subgroup remains "undruggable" with the lack of an approved targeted therapy. Selumetinib has been investigated as a secondary therapy in several trials and compared to various drug regimens. Therefore, we conducted this systematic review and network meta-analysis to determine the comparative effectiveness of this drug as compared to others in patients with late-stage and malignant NSCLC.
METHODS
Up to July 1, 2020, 9 databases (PubMed, Scopus, Web of Science, mRCT, ICTRP, clinicaltrials.gov, VHL, SIGLE, and Google Scholar) were searched for studies following the PICOS framework: randomized trials reporting the efficacy (rate of disease progression/lack of response) of selumetinib compared to other therapies in patients with late-stage/metastatic NSCLC. The quality of retrieved studies were assessed with the revised Cochrane risk-of-bias tool. Frequentist network meta-analysis was conducted to estimate the efficacy of selumetinib as compared to other therapies and/or placebo.
RESULTS
Out of the 163 articles yielded from the primary search, 9 studies (1,195 patients) were finally included in our systematic review. The majority of clinical cases had a performance status (PS) of 0-2, and the mean age was 62 years. The overall efficacy of selumetinib was 71.77% (95% CI: 63.24-81.45%), with selumetinib administered alone having better efficacy compared to combined therapy (65.20% 74.08%). In the network analysis, selumetinib had higher efficacy compared to chemo- or immune therapy, but not significantly so. The overall SAE rate of selumetinib was 42.96% (95% CI: 34.74-53.13%), with selumetinib having a significantly better safety profile compared to combined therapy (10.49% 47.38%). In the network analysis, the placebo had the best safety profile followed by selumetinib and chemo- and immune therapy. Five studies had high risk of bias, 2 had some concerns, and 2 had low risk of bias.
DISCUSSION
The efficacy of selumetinib is not superior compared to combined therapy for treating NSCLC but does have a better safety profile. Current evidence is still limited, and more robust trials are still required.
PubMed: 35722363
DOI: 10.21037/atm-22-1849 -
MedRxiv : the Preprint Server For... Jun 2023During pandemics, early outpatient treatments reduce the health system burden. Randomized controlled trials (RCTs) in COVID-19 outpatients have tested therapeutic...
BACKGROUND
During pandemics, early outpatient treatments reduce the health system burden. Randomized controlled trials (RCTs) in COVID-19 outpatients have tested therapeutic agents, but no RCT or systematic review has been conducted comparing the efficacy of the main outpatient treatment classes to each other. We aimed in this systematic review of outpatient RCTs in COVID-19 to compare hospitalisation rate reductions with four classes of treatment: convalescent plasma, monoclonal antibodies, small molecule antivirals and repurposed drugs.
METHODS
We conducted a systematic review and meta-analysis of all COVID-19 outpatient RCTs that included the endpoint of progression to hospitalisation. We assembled, from multiple published and preprint databases, participant characteristics, hospitalisations, resolution of symptoms and mortality from January 2020 to May 21, 2023. The risk of bias from COVID-NMA was incorporated into the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We measured heterogeneity with I . Meta-analysis by a random or fixed effect model dependent on significant heterogeneity (I >50%) was performed. The protocol was registered in PROSPERO, CRD42022369181.
FINDINGS
The search identified 281 studies of which 54 RCTs for 30 diverse interventions were included in the final analysis. These trials, performed largely in unvaccinated cohorts during pre-Omicron waves, focused on populations with at least one COVID-19 hospitalisation risk factor. Grouping by class, monoclonal antibodies (OR=0.31 [95% CI=0.24-0.40]) had highest efficacy, followed by COVID-19 convalescent plasma (CCP) (OR=0.69 [95% CI=0.53 to 0.90]) and small molecule antivirals (OR=0.78 [95% CI=0.48-1.33]) for hospital reduction. Repurposed drugs (OR=0.82 [95% CI-0.72-0.93]) had lower efficacy.
INTERPRETATION
Inasmuch as omicron sublineages (XBB and BQ.1.1) are now resistant to monoclonal antibodies, oral antivirals are the preferred treatment in outpatients where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.
FUNDING
US Department of Defense and National Institute of Health.
RESEARCH IN CONTEXT
We systematically searched the published and preprint data bases for outpatient randomized clinical trials of treatment of COVID-19 disease with hospitalisation as an endpoint. Previous systematic reviews and meta-analyses have confined the reviews to specific classes such as convalescent plasma, monoclonal antibodies, small molecule antivirals or repurposed drugs. Few comparisons have been made between these therapeutic classes. The trials took place both in the pre-vaccination and the vaccination era, spanning periods with dominance of different COVID variants. We sought to compare efficacy between the four classes of treatments listed above when used in outpatient COVID-19 patients as shown in randomized, placebo-controlled trials.
ADDED VALUE OF THIS STUDY
This systematic review and meta-analysis brings together trials that assessed hospitalisation rates in diverse COVID-19 outpatient populations varying in age and comorbidities, permitting us to assess the efficacy of interventions both within and across therapeutic classes. While heterogeneity exists within and between these intervention classes, the meta-analysis can be placed in context of trial diverse populations over variant time periods of the pandemic. At present most of the world population has either had COVID-19 or been vaccinated with a high seropositivity rate, indicating that future placebo-controlled trials will be limited because of the sample sizes required to document hospitalisation outcomes.
IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE
Numerous diverse therapeutic tools need to be ready for a resilient response to changing SARS-CoV-2 variants in both immunocompetent and immunocompromised COVID-19 outpatient populations. To date few head-to-head randomized controlled trials (RCTs) has compared treatment options for COVID-19 outpatients, making comparisons and treatment choices difficult. This systematic review compares outcomes among RCTs of outpatient therapy for COVID-19, taking into account time between onset of symptoms and treatment administration. We found that small-chemical antivirals, convalescent plasma and monoclonal antibodies had comparable efficacy between classes and amongst interventions within the four classes. Monoclonals have lost efficacy with viral mutation, and chemical antivirals have contraindications and adverse events, while intravenous interventions like convalescent plasma or remdesivir remain resilient options for the immunocompromised, and, in the case of CCP, in resource constrained settings with limited availability of oral drugs.
PubMed: 35665014
DOI: 10.1101/2022.05.24.22275478