Aim of the present network meta-analysis (NMA) is the comparison across glucose-lowering drugs (GLA) concerning their effects on glucose control, body weight, hypoglycemia, gastrointestinal adverse events, and quality of life.
This NMA includes randomized clinical trials comparing different head-to-head comparison trials with EMA-approved GLA in type 2 diabetes, with a duration of ≥52 weeks. All drugs have to be administered at the maximal approved dose. Primary endpoints were HbA1c at 12, 52, and 104+ weeks. Secondary endpoints were body weight, quality of life, hypoglycemia, and gastrointestinal disorders. Indirect comparisons of different GLA were performed by NMA choosing metformin as reference. The standardized difference in means (SDM) and Mantel-Haenzel Odds Ratio [MH-OR] (using random-effect models) with 95% Confidence Intervals were calculated for categorical and continuous variables, respectively. We included 68 trials fulfilling all inclusion criteria. At 12 weeks, when considering indirect comparisons, insulin secretagogues (IS) were associated with a significantly greater reduction in comparison with metformin (SDM, -0.3 [-0.4;-0.2]%); a significantly lower efficacy was observed for pioglitazone. At 52 weeks, IS were no longer associated with a greater reduction of HbA1c; whereas a significant decrease in HbA1c was observed for GLP-1 RA (SDM, -0.2 [-0.1;-0.3]%). At 104+ weeks, only SGLT-2 inhibitors showed a significantly greater HbA1c reduction (SDM, -0.2 [-0.1;-0.3]%), whereas sulfonylureas and insulin showed a significantly lower efficacy (SDM, 0.1 [0.0; 0.2]%), and 0.4 [0.3; 0.5]%, respectively).
The results of this meta-analysis should be considered together with evidence on long-term outcomes for selecting the most appropriate drugs for individual patients.

Efficacy and safety of glucose-lowering agents in patients with type 2 diabetes: A network meta-analysis of randomized, active comparator-controlled trials.

Uncommon epidermal growth factor receptor (EGFR) mutations collectively account for 10% of EGFR mutations, harboring heterogeneous molecular alterations within exons 18-21 with clinically variable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced Non-Small Cell Lung Cancer (NSCLC) patients. In addition, with the introduction of different NGS gene approach an improvement of EGFR mutations detection was reported. Today, no specific studies have prospectively evaluated uncommon sensitizing mutations in detail and no firm standard of care has been established in the first-line setting. The aim of this comprehensive review is to critically consider the clinical role of uncommon EGFR mutations highlighting the results of several in vitro and in vivo studies, which singly evaluated the sensitivity of uncommon mutations to currently European of Medicines Agency (EMA)-approved EGFR TKIs in cell lines, xenograft models and humans, in order to obtain a practical guide for refining the clinical decision-making process.

The significance of epidermal growth factor receptor uncommon mutations in non-small cell lung cancer: A systematic review and critical appraisal.

In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician.

Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe.

Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials.
The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC.
Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration.
The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology.

PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology.

This network meta-analysis (NMA), based on one phase II and nine phase III studies, involving 6,124 patients with metastatic NSCLC, indirectly compares Atezolizumab + Bevacizumab + chemotherapy (ABC), Atezolizumab + chemotherapy (AC), Pembrolizumab + chemotherapy (PC), Pembrolizumab alone, Bevacizumab + chemotherapy (BC) and chemotherapy alone. Each of these is recommended as front-line interventions, according to the US FDA and the European Medicines Agency (EMA) for advanced NSCLC without EGFR mutation or ALK rearrangement. Studies were identified through PubMed, EMBASE, the Cochrane Library, Medline, and abstracts found in oncology articles. Primary endpoints, i.e., progression-free survival (PFS) and overall survival (OS) with corresponding hazard ratios (HR), objective response rates (ORR) and adverse event (AEs) with odds risk (OR) were pooled according to frequentist network meta-analytical techniques. PD-L1 expression thresholds, as well as non-squamous/squamous were used to determine subgroups. Immunotherapy plus chemotherapy appeared superior to Pembrolizumab alone for PD-L1-high (i.e., TPS≥50%) NSCLC patients. BC might also be specifically recommended as an initial first-line treatment for PD-L1-high, non-squamous NSCLC patients, since BC was not inferior to Pembrolizumab alone. PC and ABC might be preferred for NSCLC patients with intermediate PD-L1 (1% ≤PD-L1, TPS<50%) expression. BC can also be tentatively recommended specifically for PD-L1-intermediate, non-squamous NSCLC patients. Combined immunotherapies can all be recommended for PD-L1-negative (i.e., TPS<1%) NSCLC patients, although especially the ABC combination for non-squamous NSCLC patients, which was superior to PC in regards of PFS. However, PC performed comparable to ABC in the whole population and in all subgroup save this one. More predictive biomarkers could be factored into further analyses to help identifying the most effective treatment regimens for specific patient groups.

Identifying optimal first-line interventions for advanced non-small cell lung carcinoma according to PD-L1 expression: a systematic review and network meta-analysis.

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