Publications by authors named "Jürgen Wolf"

150 Publications

High sensitivity of PD-L1 analysis from pleural effusion in nonsmall cell lung cancer.

ERJ Open Res 2021 Jan 22;7(1). Epub 2021 Mar 22.

Institute of Pneumology, University of Cologne, Solingen, Germany.

Programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) immune checkpoint inhibitors have been approved for monotherapy of metastatic nonsmall cell lung cancer (mNSCLC) depending on tumour cells' PD-L1 expression. Pleural effusion is common in mNSCLC. The significance of immunocytochemistry PD-L1 analysis from pleural effusion samples is unclear. The aim of the study was to analyse the sensitivity regarding immunocytochemistry PD-L1 analysis of pleural effusion in NSCLC as compared to immunohistochemistry of pleural biopsies. Fifty consecutive subjects (17 female, median age 72.5 years, seven never-smokers) were enrolled in this prospective controlled two-centre study. Inclusion criteria were pleural effusion, suspected or known lung cancer, indication for pleural puncture and thoracoscopy, and written informed consent. Immunocytochemistry and immunohistochemistry PD-L1 analyses were performed with the Dako-PDL1-IHC-22C3pharmDx assay. Analysis for sensitivity, specificity, and positive and negative predictive value was performed for PD-L1 detection from pleural effusion. 50 subjects underwent pleural puncture and thoracoscopy. Pathological diagnoses were lung cancer (48), lymphoma (1) and mesothelioma (1). Sensitivity, specificity, positive predictive value and negative predictive value of PD-L1-testing with expression ≥50% defined as positive were 100% (95% CI 46-100%), 63% (36-84%), 45% (18-75%) and 100% (66-100%), and with expression ≥1% defined as positive 86% (56-97%), 43% (12-80%), 75% (47-92%) and 60% (17-93%). PD-L1 analysis in tumour-positive pleural effusion samples shows a very high sensitivity and negative predictive value, especially regarding PD-L1 expression levels ≥50% (European Medicines Agency approval). Negative results are reliable and help in the decision against a first-line checkpoint inhibitor monotherapy. However, a 1% cut-off level (United States Food and Drug Administration approval) leads to a markedly lower negative predictive value, making other invasive procedures necessary (NCT02855281).
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http://dx.doi.org/10.1183/23120541.00787-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983225PMC
January 2021

The evolving landscape of biomarker testing for non-small cell lung cancer in Europe.

Lung Cancer 2021 04 22;154:161-175. Epub 2021 Feb 22.

University of Cologne, Cologne Institute of Pathology, Cologne, Germany. Electronic address:

The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small-molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment. Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single-driver mutations have been implemented. Improvements in DNA- and RNA-based next-generation sequencing technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing. Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second- or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.026DOI Listing
April 2021

Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy.

J Thorac Oncol 2021 Apr 9;16(4):572-582. Epub 2020 Dec 9.

Network Genomic Medicine, Cologne, Germany; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital of Cologne, Cologne, Germany. Electronic address:

Introduction: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp).

Methods: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS).

Results: METamp tumors (n = 278) had a high frequency of co-occurring mutations (>80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN < 4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN < 4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN < 10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p < 0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147).

Conclusions: METex14, METamp GCN ≥ 10, and METamp GCN < 10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.
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http://dx.doi.org/10.1016/j.jtho.2020.11.017DOI Listing
April 2021

Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated positive non-small-cell lung cancer.

Future Oncol 2021 Mar 5;17(7):763-773. Epub 2020 Nov 5.

Oncology Center, Hospital Sírio Libanês, Sao Paulo, Brazil.

Selpercatinib, a novel, highly selective and potent, inhibitor of , demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. NCT04194944 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0935DOI Listing
March 2021

Prevalence and potential biological role of TERT amplifications in ALK translocated adenocarcinoma of the lung.

Histopathology 2021 Mar 19;78(4):578-585. Epub 2020 Nov 19.

Institute of Pathology, University Hospital Cologne, Cologne, Germany.

Aims: The advent of specific ALK-targeting drugs has radically changed the outcome of patients with ALK translocated non-small-cell lung cancer (NSCLC). However, emerging resistance to treatment with ALK inhibitors in these patients remains a major concern. In previous studies, we analysed two ALK+ patient cohorts (TP53 wild-type/TP53 mutated) in terms of copy number alterations. All patients belonging to the TP53 wild-type group had mainly genetically stable genomes, with one exception showing chromosomal instability and amplifications of several gene loci, including TERT. Here, we aimed to determine the prevalence of TERT amplifications in these ALK+ lung cancer patients by analysing an independent cohort of 109 ALK translocated cases. We further analysed the copy numbers of numerous cancer-relevant genes and other genetic aberrations.

Methods And Results: The prevalence of TERT amplifications was determined by means of FISH analyses. Copy numbers of 87 cancer-relevant genes were determined by NanoString nCounter technology, FoundationOne and lung-specific NGS panels in some of these TERT-amplified samples, and clinical data on patients with TERT-amplified tumours were collected. Our data revealed that five (4.6%) of all 109 analysed ALK+ patients harboured amplification of TERT and that these patients had genetically unstable genomes.

Conclusions: Our preliminary study shows that ALK+ adenocarcinomas should be evaluated in the context of their genomic background in order to more clearly understand and predict patients' individual course of disease.
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http://dx.doi.org/10.1111/his.14256DOI Listing
March 2021

Treatment Monitoring of Immunotherapy and Targeted Therapy Using F-FET PET in Patients with Melanoma and Lung Cancer Brain Metastases: Initial Experiences.

J Nucl Med 2021 Apr 4;62(4):464-470. Epub 2020 Sep 4.

Center of Integrated Oncology, Universities of Aachen, Bonn, Cologne, and Duesseldorf, Germany.

We investigated the value of -(2-F-fluoroethyl)-l-tyrosine (F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastasis (BM) since contrast-enhanced MRI often remains inconclusive. We retrospectively identified 40 patients with 107 BMs secondary to melanoma ( = 29 with 75 BMs) or non-small cell lung cancer ( = 11 with 32 BMs) treated with ICI or TT who had F-FET PET ( = 60 scans) for treatment monitoring from 2015 to 2019. Most patients ( = 37; 92.5%) had radiotherapy during the course of the disease. In 27 patients, F-FET PET was used to differentiate treatment-related changes from BM relapse after ICI or TT. In 13 patients, F-FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 mo). In all lesions, static and dynamic F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios [TBR], time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathologic findings as a reference. A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% ( = 0.003). Metabolic responders to ICI or TT on F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; = 0.004). Furthermore, at follow-up, time to peak in metabolic responders increased significantly ( = 0.019). F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.
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http://dx.doi.org/10.2967/jnumed.120.248278DOI Listing
April 2021

Capmatinib in Exon 14-Mutated or -Amplified Non-Small-Cell Lung Cancer.

N Engl J Med 2020 09;383(10):944-957

From the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne and University of Cologne, Cologne (J.W.), Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.), the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (T.R.O.), and Hämato-Onkologie Hamburg, Hamburg (E.L.) - all in Germany; the National Hospital Organization Kyushu Cancer Center, Fukuoka (T.S.), Aichi Cancer Center, Nagoya (T.H.), the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.), the Department of Respiratory Medicine, Okayama University Hospital, Okayama (K.O.), and the National Kyushu Cancer Center, Fukuoka (R.T.) - all in Japan; the National Cancer Center, Gyeonggi-do (J.-Y.H.), and the Department of Internal Medicine, Seoul National University Hospital, Seoul (T.-M.K.) - both in South Korea; the Hospital Clinic of Barcelona (N.R.), Translational Genomic and Targeted Therapeutics in Solid Tumors (IDIBAPS) (N.R.), and Vall d'Hebron University Hospital-Vall d'Hebron Institute of Oncology (E.F.), Barcelona; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); the University of Groningen and University Medical Center Groningen, Groningen (H.J.M.G.), Erasmus MC Cancer Institute, Rotterdam (M.J.), and the Netherlands Cancer Institute, Amsterdam (E.F.S.) - all in the Netherlands; the National Cancer Centre Singapore, Singapore (D.S.W.T.); St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (S.V.O.); University Hospital of Lyon-Sud, Lyon (P.-J.S.), and Novartis Pharma, Rueil-Malmaison (S.L.M.) - both in France; the Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium (J.V.); the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); Novartis Pharmaceuticals, East Hanover, NJ (A.R., M.G.); Novartis Pharma, Basel, Switzerland (M.W.-L., M.A.); and Novartis Institutes for BioMedical Research, Cambridge (B.S., O.A.B., X.C.), and Massachusetts General Hospital, Boston (R.S.H.) - both in Massachusetts.

Background: Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.

Methods: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and status ( exon 14 skipping mutation or amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.

Results: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.

Conclusions: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a exon 14 skipping mutation, particularly in those not treated previously. The efficacy in -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
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http://dx.doi.org/10.1056/NEJMoa2002787DOI Listing
September 2020

Efficacy of Selpercatinib in Fusion-Positive Non-Small-Cell Lung Cancer.

N Engl J Med 2020 08;383(9):813-824

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D., E.R.) and New York University Langone Medical Center (V.V.), New York, and Roswell Park Comprehensive Cancer Center, Buffalo (G.K.D.) - all in New York; Dana-Farber Cancer Institute (G.R.O.) and Massachusetts General Hospital (J.G.), Boston; National Cancer Centre Singapore, Singapore (D.S.W.T.); the Chinese University of Hong Kong, Hong Kong, China (H.H.F.L.); Sarah Cannon Research Institute, Nashville (M.J.); University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (C.E.M.), University of California, San Diego, Moores Cancer Center, La Jolla (L.B.), and City of Hope Comprehensive Cancer Center, Duarte (K.L.R.) - all in California; University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); Institut Gustave Roussy, Villejuif (B.B.), Hospital La Timone, Marseille (F.B.), and Centre Léon Bérard, Lyon (P.A.C.) - all in France; Severance Hospital, Yonsei University Health System (B.C.C.), and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), Seoul, and Seoul National University Bundang Hospital, Seongnam (Y.J.K.) - all in South Korea; Soroka University Medical Center, Beer-Sheva, Israel (N.P.); University of North Carolina-Chapel Hill, Chapel Hill (J. Weiss); National Cancer Center Hospital (Y.O.) and Cancer Institute Hospital of the Japanese Foundation for Cancer Research (M. Nishio), Tokyo, National Hospital Organization Kyushu Cancer Center, Fukuoka (T. Seto), Tottori University Hospital, Tottori (T. Sakamoto), Hyogo Cancer Center, Akashi (M.S.), Okayama University Hospital, Okayama (K.O.), and National Cancer Center Hospital East, Chiba (K.G.) - all in Japan; University of Chicago, Chicago (J.P.); the Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.), and Cleveland Clinic, Cleveland (N.A.P.); Istituto Nazionale Tumori-National Cancer Institute, Università degli Studi di Milano, Milan (F.D.B.); Vall d'Hebron Institute of Oncology, Hospital Universitario Vall d'Hebron, Barcelona (E.G.); Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany (J. Wolf); Peter MacCallum Cancer Institute, Melbourne, VIC, Australia (B.S.); Sarah Cannon Research Institute at HealthONE, Denver (G.F.); Loxo Oncology, Stamford, CT (K.E., M. Nguyen, B.N., E.Y.Z., L.Y., X.H., E.O., S.M.R.); and the University of Texas M.D. Anderson Cancer Center, Houston (V.S.).

Background: fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with advanced fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 105 consecutively enrolled patients with fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.

Conclusions: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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http://dx.doi.org/10.1056/NEJMoa2005653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506467PMC
August 2020

Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.

Cancer Med 2020 07 21;9(14):4991-5007. Epub 2020 May 21.

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group, University of Cologne, Cologne, Germany.

Background: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR.

Methods: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination.

Results: Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively.

Conclusions: Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.
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http://dx.doi.org/10.1002/cam4.3131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367645PMC
July 2020

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors.

BMC Cancer 2020 May 12;20(1):408. Epub 2020 May 12.

Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, D-50937, Cologne, Germany.

Background: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI and later the 2nd -generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI.

Methods: Rebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification.

Results: One hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib- vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M.

Conclusions: The EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.
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http://dx.doi.org/10.1186/s12885-020-06920-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216404PMC
May 2020

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

Lung Cancer 2020 06 24;144:40-48. Epub 2020 Apr 24.

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lungcan.2020.04.020DOI Listing
June 2020

Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):261-270. Epub 2019 Dec 11.

School of Medicine, University of Colorado, Aurora, CO, USA. Electronic address:

Background: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.

Methods: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).

Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred.

Interpretation: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30690-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811790PMC
February 2020

Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study.

Clin Cancer Res 2019 12 10;25(23):6958-6966. Epub 2019 Sep 10.

Ohio State University, Columbus, Ohio.

Purpose: Although extensive-stage small-cell lung cancer (SCLC) is highly responsive to first-line therapy, virtually all patients develop resistance with short survival. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting delta-like 3 protein (DLL3). This open-label, single-arm, phase II study (TRINITY) assessed safety and efficacy of Rova-T in patients with DLL3-expressing SCLC in the third-line and beyond (3L+) setting.

Patients And Methods: Patients with DLL3-expressing SCLC (determined by mouse antibody immunohistochemistry [IHC] assay), and ≥2 prior regimens, received 0.3 mg/kg Rova-T once every 6 weeks for two cycles. During study, a rabbit antibody IHC assay was developed and used for the final analysis, with DLL3-positive and DLL3-high defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. The primary endpoints were objective response rate (ORR) and overall survival (OS).

Results: Among 339 patients enrolled, 261 (77%) had two prior lines of therapy and 78 (23%) had ≥3. DLL3-high and DLL3-positive tumors by rabbit IHC were seen in 238 (70%) and 287 (85%) patients, respectively. The remaining 52 (15%) were DLL3-negative only by rabbit IHC or had missing results. ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. The most common adverse events (AE) were fatigue, photosensitivity reaction, and pleural effusion. Grade 3-5 AEs were seen in 213 (63%) patients.

Conclusions: Rova-T is the first targeted agent in SCLC to use DLL3, a novel biomarker. However, results demonstrate modest clinical activity in 3L+ SCLC, with associated toxicities.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105795PMC
December 2019

Immune checkpoint inhibitor treatment in patients with oncogene- addicted non-small cell lung cancer (NSCLC): summary of a multidisciplinary round-table discussion.

ESMO Open 2019 17;4(3):e000498. Epub 2019 Jun 17.

Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

The introduction of targeted treatments and more recently immune checkpoint inhibitors (ICI) to the treatment of metastatic non-small cell lung cancer (NSCLC) has dramatically changed the prognosis of selected patients. For patients with oncogene-addicted metastatic NSCLC harbouring an epidermal growth factor receptor () or v-Raf murine sarcoma viral oncogene homologue B1 () mutation or an anaplastic lymphoma kinase () or ROS proto-oncogene 1, receptor tyrosine kinase () gene alteration (translocation, fusion, amplification) mutation-specific tyrosine kinase inhibitors (TKI) are already first-line standard treatment, while targeted treatment for other driver mutations affecting human epidermal growth factor receptor ( 2, tropomyosin receptor kinases () 1-3 and others are currently under investigation. The role of ICI in these patient subgroups is currently under debate. This article summarises a round-table discussion organised by ESMO Open in Vienna in July 2018. It reviews current clinical data on ICI treatment in patients with metastatic oncogene-addicted NSCLC and discusses molecular diagnostic assessment, potential biomarkers and radiological methods for response evaluation of ICI treatment. The round-table panel concluded ICI should only be considered in patients with oncogene-addicted NSCLC after exhaustion of effective targeted therapies and in some cases possibly after all other therapies including chemotherapies. More clinical trials on combination therapies and biomarkers for ICI therapy based on the specific differing characteristics of oncogene-addicted NSCLC need to be conducted.
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http://dx.doi.org/10.1136/esmoopen-2019-000498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586213PMC
June 2019

Acquired KRAS mutation and loss of low-level MET amplification after durable response to crizotinib in a patient with lung adenocarcinoma.

Lung Cancer 2019 07 6;133:20-22. Epub 2019 May 6.

Department I of Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Germany. Electronic address:

Objectives: Resistance to tyrosine kinase inhibitor (TKI) therapy occurs inevitably in lung cancer patients with targetable genetic alterations. MET amplification has found to be an oncogenic driver in lung cancer with several reports showing response to MET TKI especially in cases with high-level amplification.

Materials And Methods: We report the case of a patient with lung adenocarcinoma harbouring low-level MET amplification and strong MET expression who was treated with crizotinib.

Results: The patient developed a durable response to crizotinib. A KRAS mutation and loss of MET amplification was found in a new lesion at time of progression as a potential mechanism of acquired resistance.

Conclusion: MET amplification is a continuous biomarker with responses to MET TKI observed even in patients with low-level amplification. KRAS mutations may act as a resistance mechanism to MET inhibition in MET dependent lung cancer.
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http://dx.doi.org/10.1016/j.lungcan.2019.05.006DOI Listing
July 2019

Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial.

J Thorac Oncol 2019 07 9;14(7):1266-1276. Epub 2019 Apr 9.

Lung Cancer Group Cologne, Department I for Internal Medicine and Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany. Electronic address:

Introduction: ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).

Patients And Methods: The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.

Results: Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7-20.0 versus 24.1 months, 95% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%).

Conclusions: Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.
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http://dx.doi.org/10.1016/j.jtho.2019.03.020DOI Listing
July 2019

Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

JCO Precis Oncol 2019 27;3. Epub 2019 Mar 27.

University Hospital of Cologne, Cologne, Germany.

Purpose: Third-generation epidermal growth factor receptor () tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes.

Methods: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs.

Results: Co-occurring genetic aberrations were found in 74.4% of p.T790-positive samples (n = 124). Mutations in were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor () amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 8.2 months; 95% CI, 1.69 to 14.77 months; ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, amplification, mutations).

Conclusion: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.
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http://dx.doi.org/10.1200/PO.18.00210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446436PMC
March 2019

K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways.

J Thorac Oncol 2019 04 31;14(4):606-616. Epub 2018 Dec 31.

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany. Electronic address:

Introduction: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes.

Methods: Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients.

Results: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds.

Conclusion: KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
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http://dx.doi.org/10.1016/j.jtho.2018.12.013DOI Listing
April 2019

Monitoring Treatment Response to Erlotinib in EGFR-mutated Non-small-cell Lung Cancer Brain Metastases Using Serial O-(2-[F]fluoroethyl)-L-tyrosine PET.

Clin Lung Cancer 2019 03 5;20(2):e148-e151. Epub 2018 Nov 5.

Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln, Bonn, Germany; Network Genomic Medicine (NGM) Lung Cancer, Cologne, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2018.10.011DOI Listing
March 2019

Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies.

Mod Pathol 2019 05 20;32(5):627-638. Epub 2018 Nov 20.

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Although non-small-cell lung cancer is a leading cause of cancer-related deaths, the molecular characterization and classification of its genetic alterations has drastically changed treatment options and overall survival within the last few decades. In particular, tyrosine kinase inhibitors targeting specific molecular alterations, among other MET, have greatly improved the prognosis of non-small-cell lung cancer patients. Here, we compare the genomic background of a subset of non-small-cell lung cancer cases harboring either a MET high-level amplification (n = 24) or a MET exon 14 skipping mutation (n = 26), using next-generatison sequencing, fluorescence in situ hybridization, immunohistochemistry, and Nanostring nCounter technology. We demonstrate that the MET-amplified cohort shows a higher genetic instability, compared with the mutant cohort (p < 0.001). Furthermore, MET mutations occur at high allele frequency and in the presence of co-occurring TP53 mutations (n = 7), as well as MDM2 (n = 7), CDK4 (n = 6), and HMGA2 (n = 5) co-amplifications. No other potential driver mutation has been detected. Conversely, in the MET-amplified group, we identify co-occurring pathogenic NRAS and KRAS mutations (n = 5) and a significantly higher number of TP53 mutations, compared with the MET-mutant cohort (p = 0.048). Of note, MET amplifications occur more frequently as subclonal events. Interestingly, despite the significantly (p = 0.00103) older age at diagnosis of stage IIIb/IV of MET-mutant patients (median 77 years), compared with MET high-level amplified patients (median 69 years), MET-mutant patients with advanced-stage tumors showed a significantly better prognosis at 12 months (p = 0.04). In conclusion, the two groups of MET genetic alterations differ, both clinically and genetically: our data strongly suggest that MET exon 14 skipping mutations represent an early driver mutation. In opposition, MET amplifications occur usually in the background of other strong genetic events and therefore MET amplifications should be interpreted in the context of each tumor's genetic background, rather than as an isolated driver event, especially when considering MET-specific treatment options.
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http://dx.doi.org/10.1038/s41379-018-0182-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760650PMC
May 2019

Overcoming EGFR-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors.

Nat Commun 2018 11 7;9(1):4655. Epub 2018 Nov 7.

Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR-negative but EGFR-positive subclones and osimertinib resistance. We demonstrate that EGFR limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFR mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFR-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFR-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFR-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
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http://dx.doi.org/10.1038/s41467-018-07078-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220297PMC
November 2018

Author Correction: LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells.

Sci Rep 2018 Nov 1;8(1):16452. Epub 2018 Nov 1.

Institute of Pathology, University Hospital of Cologne, 50931, Cologne, Germany.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-31451-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210192PMC
November 2018

BRAF Inhibition in -Mutant Gliomas: Results From the VE-BASKET Study.

J Clin Oncol 2018 12 23;36(35):3477-3484. Epub 2018 Oct 23.

Thomas Kaley, Lisa M. DeAngelis, Jose Baselga, and David M. Hyman, Memorial Sloan Kettering Cancer Center; Thomas Kaley, Lisa M. DeAngelis, Jose Baselga, and David M. Hyman, Weill Cornell Medical College, New York; Igor Puzanov, Roswell Park Cancer Institute, Buffalo, NY; Mehdi Touat and Antoine Hollebecque, Institut Gustave Roussy, Villejuif; Franck Bielle, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris; Florence Joly, Centre François Baclesse, Caen; Jean-Yves Blay, Centre Léon Bérard, Lyon, France; Vivek Subbiah, MD Anderson Cancer Center, Houston, TX; Jordi Rodon, Vall d'Hebron University Hospital, Barcelona, Spain; A. Craig Lockhart, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL; Vicki Keedy, Vanderbilt University Medical Center, Nashville, TN; Ralf-Dieter Hofheinz, Universitätsmedizin Mannheim, Mannheim; Jurgen Wolf, Universitätsklinikum Köln, Cologne, Germany; Ian Chau, The Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Noopur S. Raje, Massachusetts General Hospital, Boston, MA; Martina Makrutzki, F Hoffmann-La Roche, Basel, Switzerland; Todd Riehl, Genentech, South San Francisco, CA; and Bethany Pitcher, F Hoffmann-La Roche, Mississauga, Ontario, Canada.

Purpose: mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma. We sought to determine the activity of vemurafenib, a selective inhibitor of , in patients with gliomas that harbor this mutation.

Patients And Methods: The VE-BASKET study was an open-label, nonrandomized, multicohort study for -mutant nonmelanoma cancers. Patients with -mutant glioma received vemurafenib 960 mg twice per day continuously until disease progression, withdrawal, or intolerable adverse effects. Key end points included confirmed objective response rate by RECIST version 1.1, progression-free survival, overall survival, and safety.

Results: Twenty-four patients (median age, 32 years; 18 female and six male patients) with glioma, including malignant diffuse glioma (n = 11; six glioblastoma and five anaplastic astrocytoma), PXA (n = 7), anaplastic ganglioglioma (n = 3), pilocytic astrocytoma (n = 2), and high-grade glioma, not otherwise specified (n = 1), were treated. Confirmed objective response rate was 25% (95% CI, 10% to 47%) and median progression-free survival was 5.5 months (95% CI, 3.7 to 9.6 months). In malignant diffuse glioma, best response included one partial response and five patients with stable disease, two of whom had disease stabilization that lasted more than 1 year. In PXA, best response included one complete response, two partial responses, and three patients with stable disease. Additional partial responses were observed in patients with pilocytic astrocytoma and anaplastic ganglioglioma (one each). The safety profile of vemurafenib was generally consistent with that of previously published studies.

Conclusion: Vemurafenib demonstrated evidence of durable antitumor activity in some patients with -mutant gliomas, although efficacy seemed to vary qualitatively by histologic subtype. Additional study is needed to determine the optimal use of vemurafenib in patients with primary brain tumors and to identify the mechanisms driving differential responses across histologic subsets.
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http://dx.doi.org/10.1200/JCO.2018.78.9990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286161PMC
December 2018

Vemurafenib in Patients With Relapsed Refractory Multiple Myeloma Harboring Mutations: A Cohort of the Histology-Independent VE-BASKET Study.

JCO Precis Oncol 2018 31;2. Epub 2018 Aug 31.

and Massachusetts General Hospital, Boston, MA; and Royal Marsden Hospital, Sutton, Surrey, United Kingdom; and Memorial Sloan Kettering Cancer Center, New York; Roswell Park Cancer Institute, Buffalo, NY; and Institut Gustave Roussy, Villejuif; Centre Leon-Berard, Lyon, France; and , Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; University Hospital Köln, Köln, Germany; and F. Hoffmann-La Roche Ltd, Basel, Switzerland; and F. Hoffmann-La Roche Ltd, Mississauga, Ontario, Canada.

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http://dx.doi.org/10.1200/PO.18.00070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446434PMC
August 2018

Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers.

J Thorac Oncol 2018 10 11;13(10):1595-1601. Epub 2018 Jul 11.

Department of Medicine, Cantonal Hospital Lucerne, Luzern, Switzerland.

Introduction: In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized.

Methods: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined.

Results: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months).

Conclusions: Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.
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http://dx.doi.org/10.1016/j.jtho.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434708PMC
October 2018

Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations.

J Pathol 2018 09 31;246(1):67-76. Epub 2018 Jul 31.

University Hospital Cologne, Institute of Pathology, Cologne, Germany.

The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC-overexpressing ALK+ TP53-mutated cells had a proliferative advantage compared to wild-type cells. ChIP-Seq data revealed MYC-binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53-mutated cells resulted in an upregulation of EML4-ALK, indicating a potential MYC-dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumours than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumours that harbour chromosomal instability, leading to the co-occurrence of pathogenic aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120547PMC
September 2018

Novel approaches against epidermal growth factor receptor tyrosine kinase inhibitor resistance.

Oncotarget 2018 Mar 8;9(20):15418-15434. Epub 2018 Mar 8.

Molecular Pathological Diagnostics, Institute of Pathology, University Hospital Cologne, Cologne, Germany.

Background: The identification and characterization of molecular biomarkers has helped to revolutionize non-small-cell lung cancer (NSCLC) management, as it transitions from target-focused to patient-based treatment, centered on the evolving genomic profile of the individual. Determination of epidermal growth factor receptor () mutation status represents a critical step in the diagnostic process. The recent emergence of acquired resistance to "third-generation" EGFR tyrosine kinase inhibitors (TKIs) via multiple mechanisms serves to illustrate the important influence of tumor heterogeneity on prognostic outcomes in patients with NSCLC.

Design: This literature review examines the emergence of TKI resistance and the course of disease progression and, consequently, the clinical decision-making process in NSCLC.

Results: Molecular markers of acquired resistance, of which T790M and or amplifications are the most common, help to guide ongoing treatment past the point of progression. Although tissue biopsy techniques remain the gold standard, the emergence of liquid biopsies and advances in analytical techniques may eventually allow "real-time" monitoring of tumor evolution and, in this way, help to optimize targeted treatment approaches.

Conclusions: The influence of inter- and intra-tumor heterogeneity on resistance mechanisms should be considered when treating patients using resistance-specific therapies. New tools are necessary to analyze changes in heterogeneity and clonal composition during drug treatment. The refinement and standardization of diagnostic procedures and increased accessibility to technology will ultimately help in personalizing the management of NSCLC.
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http://dx.doi.org/10.18632/oncotarget.24624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880615PMC
March 2018

Clinical and Pathological Characteristics of - and -Mutated Non-Small Cell Lung Carcinoma (NSCLC).

Clin Cancer Res 2018 07 3;24(13):3087-3096. Epub 2018 Apr 3.

Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.

and mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with or mutations were assessed. mutations occurred with a frequency of 11.3% ( = 157) and mutations with a frequency of 3.5% ( = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. mutations were found mainly in adenocarcinoma (AD; 72%), while mutations were more common in squamous cell carcinoma (LSCC; 59%). mutations were spread over the whole protein, whereas mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating mutations or amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with mutation had a response on systemic treatment in first-, second-, or third-line setting. Of -mutated patients, none responded to second- or third-line therapy.- and -mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3416DOI Listing
July 2018

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

Nat Commun 2018 03 13;9(1):1048. Epub 2018 Mar 13.

Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1/DLL3/NOTCH, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1/DLL3/NOTCH, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.
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http://dx.doi.org/10.1038/s41467-018-03099-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849599PMC
March 2018