Das nationale Netzwerk Genomische Medizin (nNGM)

Büttner, R.; Wolf, Jürgen; Kron, Anna; Medizin, Nationales Netzwerk Genomische

doi:10.1007/s00292-019-0605-4

Cited by 31 publications

(15 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nevertheless, 66 patients could be identified in a timeframe of six years just in our network, which represents a notable number of patients for whom no targeted approach exists. Larger-scale screening efforts like our national Network Genomic Medicine (nNGM) consisting of 15 centers will probably lead to larger potential patient numbers [38], as the occurrence of MAP2K1 mutations is not limited to AD: as a novel finding of this analysis, four patients (6.1%) had SqCC histology.…”

Section: Discussionmentioning

confidence: 91%

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

et al. 2020

View full text Add to dashboard Cite

Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. Methods: Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. Results: We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. Conclusion: Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.

show abstract

Section: Discussionmentioning

confidence: 91%

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

et al. 2020

View full text Add to dashboard Cite

show abstract

“…ALK rearrangement will be determined locally by one or more ALK assays that are approved in Germany and/or have been validated within the German Network for Genomic Medicine, e.g. RNA-based NGS, fluorescence in situ hybridization using the ZytoLight SPEC ALK probe (ZytoVision GmbH, Bremerhaven, Germany) and immunohistochemistry using the D5F3 clone (Roche, Mannheim, Germany) [ 18 , 29 – 31 ].…”

Section: Methodsmentioning

confidence: 99%

Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial

et al. 2021

View full text Add to dashboard Cite

Background Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. Methods/design In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. Discussion Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a “chronic disease” will be distinguished from “high-risk” cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. Trial registration Clinicaltrials.gov, NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019–001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36

show abstract

“…For example, the TKI larotrectinib, which was approved by the FDA and EMA based on impressive response rates of 60%-80% in NTRK-altered solid tumors according to phase 2 single-arm data, received a negative reimbursement recommendation in Germany due to the "lack of suitable data for benefit assessment", 29 a negative reimbursement recommendation in Spain due to "uncertainties regarding its therapeutic value", 30 a reimbursement recommendation only in pediatric, but not adult patients in France, 31 and reimbursement for both adult and pediatric patients in Sweden. 32 More recently, the EGFR/MET bispecific antibody amivantamab, which was approved by the FDA and EMA for platinum-pretreated NSCLC with EGFR exon 20 insertions based on single-arm data from the Chrysalis study (NCT02609776), was subsequently withdrawn from the German market by the company due to a negative, "no-added-benefit" reimbursement recommendation, despite contrary RWE from the prospective nation-wide CRISP and NNGM registries, 33,34 to prevent a price similar as that of decades-old chemotherapy. 35 Thus, German patients can currently get amivantamab only via international pharmacies after a laborious and time- regulations and the pan-European health data space, 37,38 in order to ensure conformity with the declared standards and facilitate extraction of RWD suitable for approval and pricing decisions with minimal effort and delays (Figure 2).…”

Section: Harmonizing the Regulatory Frameworkmentioning

confidence: 99%

Real‐world data for precision cancer medicine—A European perspective

Christopoulos

Schlenk

Kazdal

et al. 2023

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Leveraging real‐world data (RWD) for drug access is necessary to overcome a key challenge of modern precision oncology: tackling numerous low‐prevalence oncogenic mutations across cancers. Withholding a potentially active medication in patients with rare mutations for the sake of control chemotherapy or “best” supportive care is neither practicable nor ethically justifiable anymore, particularly as RWD could meanwhile be used instead, according to scientific principles outlined by the US Food and Drug Administration, European Medicines Agency and other stakeholders. However, practical implementation varies, with occasionally opposite recommendations based on the same evidence in different countries. In the face of growing need for precision drugs, more transparency of evaluation, a priori availability of guidance for the academia and industry, as well as a harmonized framework for health technology assessment across the European Union (EU) are imperative. These could in turn trigger infrastructural changes in national and pan‐European registries, cancer management guidelines (e.g., frequency of routine radiologic restaging, inclusion of patient‐reported outcomes), and the health data space, to ensure conformity with declared standards and facilitate extraction of RWD sets (including patient‐level data) suitable for approval and pricing with minimal effort. For an EU‐wide unification of precision cancer medicine, collective negotiation of drug supply contracts and funding solidarity would additionally be required to handle the financial burden. According to experience from pivotal European programs, off‐label use could potentially also be harmonized across EU‐states to accelerate availability of novel drugs, streamline collection of valuable RWD, and mitigate related costs through wider partnerships with pharmaceutical companies.

show abstract

Das nationale Netzwerk Genomische Medizin (nNGM)

Cited by 31 publications

References 9 publications

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial

Real‐world data for precision cancer medicine—A European perspective

Contact Info

Product

Resources

About