Targeting RET alterations in non-small cell lung cancer.

Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1-2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. While first-generation RET inhibitors have become part of the standard of care for RET-fusion positive NSCLC, a new challenge has emerged: acquired resistance to RET inhibitors. RET resistance is a complex phenomenon that can manifest as either on-target or off-target resistance. Numerous studies have been conducted to identify the mechanisms behind this resistance. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.

Comparison of neoadjuvant regimens for resectable gastroesophageal junction cancer: a systematic review of randomized clinical trials across three decades.

Background: The optimal perioperative treatment for adenocarcinoma of gastroesophageal junction (GEJ) tumor remains uncertain. The systematic review aims to assess the best neoadjuvant modality, namely chemotherapy (CT) versus chemoradiotherapy (CRT) based on randomized controlled trials (RCTs) for resectable gastric, esophageal and GEJ tumors. Methods: We performed a comprehensive PubMed database and Cochrane Library search to identify relevant RCTs related to neoadjuvant treatment for resectable GEJ adenocarcinoma. We included all published RCTs (phase 2 or 3) that tested specific neoadjuvant therapies (CT or CRT) if the patient population included GEJ tumors. We applied the Version 2 Cochrane risk-of-bias tool (RoB 2) to all the eligible studies. Outcomes examined included R0 resection and pathological response based on intention-to-treat (ITT) analysis, surgical outcomes, notable adverse events, and overall survival (OS). Each randomized group of every study was noted to be neoadjuvant CRT, CT, or surgery alone in order to compare the outcomes among these treatment approaches. Results: We identified 25 RCTs with 7,855 patients published from 1996 to 2019. Seven studies tested preoperative CT versus surgery alone, 7 tested preoperative radiotherapy (RT) or CRT versus surgery alone, 4 tested preoperative RT or CRT versus preoperative CT, and 7 tested other combinations. The R0 resection ranged 47-100% and the 3-year OS ranged 6-66.1% in all the study arms. In an exploratory analysis, CRT strategies showed a superior R0 resection rate [80.2%; 95% confidence interval (CI): 79.8-80.6%] to surgery alone (60.9%; 95% CI: 60.4-61.3%; P<0.01) and to preoperative CT (63.9%; 95% CI: 63.6-64.2%; P<0.01). When comparing 3- and 5-year OS, improvement was noted when comparing CRT to surgery alone (P<0.01), and perioperative CT to surgery alone (P<0.01), but no definite difference was noted between CRT versus CT. Discussion: Preoperative CRT showed improvement in R0 resection rate to surgery alone and preoperative CT. However, there is no significant difference in OS between CRT and CT. Both neoadjuvant strategies remain clinically meaningful options for patients with resectable GEJ tumors. Lack of patient-level data and inconsistent reporting of key outcomes across studies were the main limitations of our study.

A systematic review of head-to-head trials of approved monoclonal antibodies used in cancer: an overview of the clinical trials agenda.

BACKGROUND: Since 1997, several monoclonal antibodies (mAbs) targeting the same receptor or its ligand have been approved for use in oncology. However, no studies have summarized head-to-head trials of these mAbs. METHODS: Systematic search of the biomedical literature and ClinicalTrials.gov for randomized studies comparing mAbs targeting the same receptor or its ligand that have been completed and published, completed and unpublished, or ongoing. We extracted trial characteristics including phase, indication, enrollment or target enrollment, randomization, primary endpoint and sponsor. RESULTS: Twenty-two approved cancer mAbs had at least one other approved mAb targeting the same receptor or its ligand, totaling 41 different oncology indications. These include 5 anti-CD20 mAbs, 5 anti-PD1/PDL1 mAbs, 4 anti-HER2 mAbs, 3 anti-EGFR mAbs, 3 anti-VEGF mAbs and 2 anti-IL6/IL6R mAbs. Seventeen were completed and published and 14 were unpublished or ongoing trials. The completed and published trials enrolled 11,373 patients and tested 13 mAbs (13/22, 59%). Additionally, 13 (76%) contained drugs manufactured by the same company and 13 (76%) reached conclusions felt to be favorable to the sponsor. Of the 14 ongoing/completed unpublished trials, there is a total target enrollment of 3404 patients with 9 mAbs tested. Of these, 86% (12/14) are testing mAbs manufactured by the same company and 71% (10/14) are sponsored by the company that made the drug being tested. CONCLUSIONS: Most trials test drugs manufactured or sponsored by the same company. An overview of clinical trials agenda may lead to more uniform testing, helping clinicians make better evidence-informed prescribing decisions.

A comprehensive review of exceptional responders to anticancer drugs in the biomedical literature.

IMPORTANCE: There is broad interest in patients who have exceptional responses to cancer drugs and only one prior systematic review of published case reports. OBJECTIVE: To systematically summarise case reports of patients who have had a super response to a cancer drug and determine patterns and completeness of documentation. DESIGN, SETTING AND PARTICIPANTS: This is a systematic search of biomedical literature and hand searches of seven prominent oncology journals. All cases were adults with cancer in the metastatic or unresectable setting and who were classified as having a remarkable response to a drug therapy were included. Our study was conducted between January 2017 and April 2017. MAIN OUTCOMES AND MEASURES: We extracted patient and tumour characteristics, characteristics surrounding the exceptional response and pertinent oncologic history. Additionally, we noted authors' financial conflicts of interest, if given. RESULTS: We found 180 cases of exceptional response. The most common malignancy was breast cancer (28/180), and the most common class of drug therapy used was targeted therapies (161/274). The median year of publication was 2015. Depth of response included 33% (61/180) complete response, 55% (100/180) partial response and 7.7% (14/180) stable disease. The median length of response to the drug was 14 months. Fifty-nine percent (107/180) reported a driver mutation, and only 52% (56/107) reported two or more correlative studies. Only 14% (26/180) reported a denominator or total number treated to observe this response. Of cases that reported duration of response to a previous drug given in the unresectable setting, 49% demonstrated a progression-free survival ratio of exceptional response to prior line of 1.3 or greater (Von Hoff ratio). CONCLUSIONS AND RELEVANCE: Our survey found that exceptional responders tended to have solid organ malignancies and most received targeted therapies. Many of our cases of exceptional responders were missing important information about the response and key oncologic history. Standardised criteria should be used to maximise usefulness of these case reports in the future.

Grape seed extracts inhibit platelet aggregation by inhibiting protein tyrosine phosphatase.

Platelets play an important role in various thrombotic diseases, including myocardial infarction. Because red wine consumption is inversely associated with death due to ischemic heart diseases, the effects of grape components on platelet function have been extensively investigated. Grape seed extracts (GSEs) reportedly inhibit platelet aggregation; however, the underlying mechanism has not been elucidated. We discovered that GSEs inhibit platelet aggregation induced by collagen and thrombin-receptor agonist peptide and increase basal levels of tyrosine phosphorylation, which was also observed in the presence of a protein tyrosine phosphatase (PTP) inhibitor. An in vitro phosphatase assay indicated that GSE dose dependently inhibited PTP-1B and Src homology 2 domain-containing phosphatase-1 activity, which positively regulates platelet aggregation. We propose that GSEs inhibit platelet aggregation by inhibiting tyrosine phosphatase activity. Moreover, we showed that GSE ingestion inhibited platelet aggregation in mice without enhancing tail bleeding, implying that GSE supplementation might be beneficial to prevention of thrombotic diseases.