Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete.
This retrospective multicenter study included patients with any-stage RET positive (RET+) ...NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated.
For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo 37.7–72.1 versus 16.3 mo 12.7–28.8, p < 0.0001).
Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be ...attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of
Oral supplementation with
after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9
CXCR3
CD4
T lymphocytes into mouse tumor beds.
Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2–1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors ...(TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs’ management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU‐funded project Paediatric Rare Tumours Network ‐ European Registry (PARTNER).
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response ...to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
Introduction: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete.Methods: This retrospective multicenter study included patients with any-stage ...RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated.Results: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo 37.7–72.1 versus 16.3 mo 12.7–28.8, p < 0.0001).Conclusions: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.
Background
Adverse drug events (ADEs) occur frequently in oncology and justify continuous assessment and monitoring. There are several methods for detecting them, but the trigger tool method seems ...the most appropriate. Although a generic tool exists, its use for ADEs in oncology has not been convincing. The development of a focused version is therefore necessary.
Objective
To provide an oncology-focused trigger tool that evaluates the prevalence, harm, and preventability in a standardised method for pragmatic use in ADE surveillance.
Setting
Hospitals with cancer care in France.
Method
The tool has been constructed in two steps: (1) constitution of an oncology-centred list of ADEs; 30 pharmacists/practitioners in cancer care from nine hospitals selected a list of ADEs using a method of agreement adapted from the RAND/UCLA Appropriateness Method; and (2) construction of three standardised dimensions for the characterisation of each ADE (including causality, severity, and preventability).
Main outcome measure
The main outcome measure was validation of the tool, including preventability criteria.
Results
The tool is composed of a final list of 15 ADEs. For each ADE, a ‘reviewer form’ has been designed and validated by the panel. It comprises (1) the trigger(s), (2) flowcharts to guide the reviewer, (3) criteria for grading harm, and (4) a standardised assessment of preventability with 6–14 closed sentences for each ADE in terms of therapeutic management and/or prevention of side-effects.
Conclusion
A complete ‘ready-to-use’ tool for ADE monitoring in oncology has been developed that allows the assessment of three standardised dimensions.
Tumor derived biomarkers including circulating tumor DNA (ctDNA) and/or circulating tumors cells (CTCs) may be detected and quantified through liquid biopsy (LB). ctDNA analysis through LB is a ...validated tool for monitoring response to systemic treatment and detecting molecular mechanisms of resistance at the time of progression of advanced stage malignancies. Several applications of ctDNA have been investigated in the diagnostic phase of cancer or in the post-curative treatment surveillance phase (e.g., minimal residual disease assessment after neoadjuvant or adjuvant therapy). Recently, the improvement of ctDNA technology and its implementation have affected early phase trials design, with significant changes in the inclusion and randomization phases. Implementation of LB has resulted in large-scale development of academic programs aimed at exploiting all the potential applications of ctDNA, such as patients extended molecular screening, molecular oriented treatment decision making, monitoring of anti-cancer treatments response. In this rapid evolving field, the challenge is no longer the technique, but the evaluation of the results and the interpretation of their impact on diagnosis, prognosis, or therapeutic decision. Leading research cancer centers may favor education for scientific community, by capturing data on this evolving technology and sharing knowledge.
In this review we summarize the main applications and challenges of ctDNA genotyping in clinical trials, with special focus on ongoing studies. We finally describe the most important next generation academic and industry-sponsored programs addressing early cancer detection and prevention in high-risk populations through ctDNA genotyping.
Circulating tumor DNA (ctDNA) in clinical trials. Display omitted
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