80 results on '"Hochmair MJ"'
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2. First-Line Therapy Using Brigatinib vs. Crizotinib in Patients With Advanced Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Results From a Phase 3 Trial
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Hochmair, MJ, additional, Camidge, DR, additional, Kim, HR, additional, Ahn, MJ, additional, Yang, JCH, additional, Youn Han, J, additional, Lee, KH, additional, Delmonte, A, additional, Garcia Campelo, MR, additional, Kim, DW, additional, Griesinger, F, additional, Felip, E, additional, Califano, R, additional, Spira, A, additional, Gettinger, S, additional, Tiseo, M, additional, Ni, Q, additional, Zhang, P, additional, and Popat, S, additional
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- 2020
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3. Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK–Inhibitor-Naive ALK+ Non–Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study
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Myung J, Ahn, Hye R, Kim, James C H, Yang, Ji-Yu, Han, Jacky Yu-Chung, Li, Maximilian J, Hochmair, Gee-Chen, Chang, Angelo, Delmonte, Ki H, Lee, Rosario G, Campelo, Cesare, Gridelli, Alexander I, Spira, Raffaele, Califano, Frank, Griesinger, Sharmistha, Ghosh, Enriqueta, Felip, Dong-Wan, Kim, Yuyin, Liu, Pingkuan, Zhang, Sanjay, Popat, D Ross, Camidge, Institut Català de la Salut, [Ahn MJ] Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. [Kim HR] Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. [Yang JCH] Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. [Han JY] Center for Lung Cancer, National Cancer Center, Goyang, South Korea. [Li JY] Department of Clinical Oncology, Hong Kong United Oncology Centre, Kowloon, Hong Kong. [Hochmair MJ] Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria. [Felip E] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,Medicaments antineoplàstics - Ús terapèutic ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES] ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Crizotinib ,Asian People ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Asiàtics ,Humans ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS] ,Pulmons - Càncer - Tractament ,Protein Kinase Inhibitors - Abstract
Anaplastic lymphoma kinase; First line; Tyrosine kinase inhibitor Cinasa del linfoma anaplásico; Primera línea; Inhibidor de la tirosina quinasa Quinasa del limfoma anaplàsic; Primera línia; Inhibidor de la tirosina quinasa Background Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non–small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial. Patients and Methods This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor–naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases. Results Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients. Conclusion Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients. This study was supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The sponsor designed and conducted the study and collected the data together with the authors. The sponsor managed and analyzed the data. Data were interpreted by the authors and the sponsor. The sponsor together with the authors prepared, reviewed, and approved the manuscript and made the decision to submit the manuscript for publication.
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- 2022
4. Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial
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D. Ross Camidge, Myung-Ju Ahn, Maximilian Hochmair, Ji Youn Han, Enriqueta Felip, Marcello Tiseo, Dong Wan Kim, Sanjay Popat, Raffaele Califano, Huifeng Niu, Pingkuan Zhang, Alexander I. Spira, Ki Hyeong Lee, Florin Vranceanu, Hye Ryun Kim, Yuyin Liu, James Chih-Hsin Yang, Angelo Delmonte, Frank Griesinger, Scott N. Gettinger, Maria Rosario Garcia Campelo, Huamao M. Lin, Institut Català de la Salut, [Camidge DR] Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado. [Kim HR] Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. [Ahn MJ] Division of Hematology-Oncology, Samsung Medical Center, Seoul, South Korea. [Yang JCH] Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan. [Han JY] Department of Precision Medicine, National Cancer Center, Gyeonggi, South Korea. [Hochmair MJ] Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna, Austria. [Felip E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Phases of clinical research ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Organophosphorus Compounds ,Crizotinib ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Lung cancer ,Protein Kinase Inhibitors ,business.industry ,Hazard ratio ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES] ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] ,medicine.disease ,ALK inhibitor ,Pyrimidines ,Tolerability ,Avaluació de resultats (Assistència sanitària) ,business ,Pulmons - Càncer - Tractament ,medicine.drug - Abstract
ALK tyrosine kinase inhibitor; Brigatinib; Non–small cell lung cancer Inhibidor de la tirosina quinasa ALK; Brigatinib; Cáncer de pulmón de células no pequeñas Inhibidor de la tirosina cinasa ALK; Brigatinib; Càncer de pulmó de cèl·lules no petites Introduction In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Methods Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.
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- 2021
5. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor–Naive ALK-Positive Non–Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial
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Huamao M. Lin, Myung-Ju Ahn, Pingkuan Zhang, Angelo Delmonte, Marcello Tiseo, D. Ross Camidge, Frank Griesinger, Scott N. Gettinger, Dong Wan Kim, Maria Rosario Garcia Campelo, Maximilian Hochmair, Enriqueta Felip, Ki Hyeong Lee, Alexander I. Spira, Q. Ni, Neeraj Gupta, Michael J. Hanley, James Chih-Hsin Yang, Hye Ryun Kim, Sanjay Popat, Ji Youn Han, Raffaele Califano, Institut Català de la Salut, [Camidge DR] University of Colorado Cancer Center, Aurora, CO. [Kim HR] Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. [Ahn MJ] Samsung Medical Center, Seoul, South Korea. [Yang JCH] National Taiwan University Hospital, Taipei, Taiwan. [Han JY] National Cancer Center, Goyang, South Korea. [Hochmair MJ] Department of Respiratory and Critical Care Medicine, Krankenhaus Nord–Klinik Floridsdorf, Vienna, Austria. [Felip E] Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Lung Neoplasms ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,ALECTINIB ,0302 clinical medicine ,QUALITY-OF-LIFE ,Carcinoma, Non-Small-Cell Lung ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,OUTCOMES ,QLQ-C30 ,ORIGINAL REPORTS ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES] ,CHEMOTHERAPY ,Middle Aged ,Diagnosis::Prognosis::Treatment Outcome::Progression-Free Survival [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Progression-Free Survival ,Survival Rate ,SAFETY ,030220 oncology & carcinogenesis ,Female ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Brigatinib ,diagnóstico::pronóstico::resultado del tratamiento::supervivencia libre de progresión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,medicine.drug_class ,EGFR ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Antineoplastic Agents ,Young Adult ,03 medical and health sciences ,Organophosphorus Compounds ,Crizotinib ,Internal medicine ,medicine ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Progression-free survival ,Thoracic Oncology ,Lung cancer ,Survival rate ,Aged ,Medicaments antineoplàstics - Ús terapèutic - Eficàcia ,Science & Technology ,business.industry ,Receptor Protein-Tyrosine Kinases ,1103 Clinical Sciences ,KINASE INHIBITOR ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] ,EFFICACY ,medicine.disease ,Interim analysis ,ALK inhibitor ,EML4-ALK FUSION GENE ,Pyrimidines ,030104 developmental biology ,Quality of Life ,business ,Pulmons - Càncer - Tractament - Abstract
Càncer de pulmó; Brigatinib; Estudi ALTA-1L Cáncer de pulmón; Brigatinib; Estudio ALTA-1L Lung cancer; Brigatinib; ALTA-1L study PURPOSE Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor–naive ALK-positive non–small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events). METHODS Patients with ALK inhibitor–naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected. RESULTS Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration–time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69). CONCLUSION Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC. Supported by ARIAD Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, Parsippany, NJ, an OPEN Health company, and funded by Millennium Pharmaceuticals. Supported by National Health Service funding to the Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre (S.P.).
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- 2020
6. Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy.
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Saalfeld FC, Möller J, Christopoulos P, Wenzel C, Rasokat A, Wang XA, Vathiotis I, König D, Illini O, Grohé C, Wiesweg M, Wesseler C, Schubart C, Pelusi N, Rohde G, Overbeck TR, Kirfel J, Alt J, Kauffmann-Guerrero D, Griesinger F, Kulhavy J, Allgäuer M, Klimova A, Schütz M, Aust DE, Hochmair MJ, Rothschild SI, Syrigos KN, Veluswamy R, Michels S, Stenzinger A, Jöhrens K, and Wermke M
- Abstract
Introduction: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target., Methods: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry., Results: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive., Conclusions: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT., Presented Elsewhere: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Allgäuer, M received speaker fees from Boehringer Ingelheim. Alt, J received speaker fees and/or honoraria for advisory boards by Astra Zeneca, Pfizer, Daichii Sankyo, Roche, Amgen, MSD, Novartis, Janssen, Boehringer Ingelheim, Merck, BMS. Aust, DEA received honoraria from Roche, Astra Zeneca, MSD, Pfizer, Novartis. Christopoulos. P received research funding from Roche, Amgen, Boehringer Ingelheim, Takeda, Merck, AstraZeneca, and Novartis, honoraria from Roche, Takeda, Gilead, AstraZeneca, Merck, Thermo Fisher, Janssen, Pfizer, and Novartis, travel support from AstraZeneca, Pfizer, Janssen, Merck, Gilead, Daiichi Sankyo, Takeda, Novartis, Eli Lilly and compensation for advisory roles for Pfizer, Chugai, Boehringer Ingelheim, Takeda, Janssen, Novartis, astraZeneca, MSD, Roche. Griesinger, F received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen, Sanofi, Daiichi-Sankyo, Beigene. Grohé, C received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Hochmair, M received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Illini, O received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Menarini, Merck Sharp & Dohme, Pfizer, and Roche and received research grants from Amgen and AstraZeneca outside of the submitted study. Jöhrens, K received compensation for advisory roles for BMS, GSK, Merck Sharp & Dohme, honoraria from AstraZeneca, Agilent, Boehringer Ingelheim, and DSO, and serves as medical advisor for QuIP. Kauffmann-Guerrero received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Pfizer, Roche, Takeda. Kirfel, J received speaker fees and/or honoraria for advisory boards, from AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer and Roche. König, D received a personal grant from Geistlich-Stucki-Stiftung, consulting fees from AstraZeneca, Merck, MSD, Novartis, PharmaMar, honoraria for presentations from Amgen, BMS, Mirati, Sanofi, Swiss Oncology in Motion, support for attending meetings from Amgen, Roche, Sanofi, honoraria for advisory boards from AstraZeneca, BMS, Merck, MSD, PharmaMar, Roche. Michels, S received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. Overbeck, T received speaker fees and/or honoraria for advisory boards by AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Roche, Takeda, Tesaro/GSK, Lilly, Roche, travel reimbursement by AstraZeneca, Boehringer-Ingelheim, Janssen-Cilag, Lilly, and Roche. Rohde, G received personal fees from Astra Zeneca, Atriva, Boehringer Ingelheim, GSK, Insmed, MSD, Sanofi, Novartis and Pfizer for consultancy during advisory board meetings and personal fees from Astra Zeneca, Berlin Chemie, BMS, Boehringer Ingelheim, Chiesi, Essex Pharma, Grifols, GSK, Insmed, MSD, Roche, Sanofi, Solvay, Takeda, Novartis, Pfizer and Vertex for lectures. Rothschild, S received honoraria (institutional) from, Roche, AstraZeneca, BMS, Boheringer Ingelheim, MSD Oncology, Novartis, Amgen, Lilly, Eisai, Merck serono, Pfizer, Takeda, Bayer, Janssen Oncology, Otsuka, PharmaMar, and Sanofi, compensation for advisory roles for AstraZeneca, Boerhinger Ingelheim, BMS, Pfizer, Eisai, Eli Lilly, Merck Serono, MSD Oncology, Novartis, Roche Pharma AG, Takeda, Amgen, Otsuka, PharmaMar, serves for the speakers bureau of Roche Pharma AG, Sanodi/Aventis, Amgen, AstraZeneca, Takeda, received research funding from Abbvie, BMS, AstraZeneca, Boerhinger Ingelheim, Merck Serono, Roche Pharma AG, and travel support, accomodation, expenses from Sanofi, Roche Pharma AG, BMS, MSD Oncology, AstraZeneca, Takeda, Boehringer Ingelheim, Amgen. He serves at the Federal Drug Comission of the Federal Office of Public Health and the Swiss Group for Clinical Cancer Research (SAKK). Saalfeld, F received research funding from Roche, consultancy fees from Boehringer Ingelheim, honoraria for lectures from AstraZeneca, Janssen, Takeda, Pfizer, Novartis, Thieme, and GWT-TUD, travel support from Janssen and Eli Lilly, and compensation for advisory meetings with BMS, Pfizer, AstraZeneca, Janssen, MSD, and Roche. Stenzinger, A received research grants from Bayer, BMS, Chugai, Incyte, and MSD, and compensation for advisory boards/speaker’s bureau: Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Sanofi, Seagen, Servier, Takeda, Thermo Fisher. Syrigos, K received honoraria for advisory boards from Merck Sharp & Dohme, AstraZeneca, BMS Amgen. Thomas, M received research funding (institution) from AstraZeneca, BMS, Merck, Roche, Takeda, speaker fees and/or honoraria for advisory boards by Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Takeda. Veluswamy, R served on advisory boards for Bristol-Myers Squibb, Astrazeneca, Merck, Boehringer Ingelheim, Merus, Novocure, Regeneron, BerGenBio, and Serna Bio, on unbranded speaker’s bureau of Astrazeneca and EMD Serono, received consulting honorarium from Beigene, received research funding from Bristol-Myers Squibb, Onconova, Astrazeneca, Boehringer Ingelheim, Lung Cancer Research Foundation, Stand Up 2 Cancer. Wenzel, C received speaker fees from Astra Zeneca. Wermke, M received honorary from Lilly, Boehringer-Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer, BMS and has/had paid consulting or advisory positions for BMS, Novartis, Lilly, Boehringer-Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, ImCheck, AstraZeneca, Tacalyx, Regeneron, Daiichi, Zymeworks, PharmaMar. He receive research funding (instution) from Roche and travel support from Pfizer, BMS, AstraZeneca, Amgen, Gemoab, Sanofi-Aventis, Merck Serono, Immatics, Janssen, Iovance, Daiichi-Sankyo. Wesseler, C received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, MSD, Novartis, Takeda, AstraZeneca, Chugai, BMS. Wiesweg, M received honoraria and Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda, and travel costs from Amgen, Janssen, Daiichi Sankyo, and research funding from Bristol-Myers Squibb, Takeda. Klimova, A, Kulhvay, J, Möller, J, Pelusi, N, Rasokat, A, Schubart, C, Schütz, M, Wang, A, and Vathiotis, J have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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7. Adenosquamous Carcinoma of the Lung: Survival, Radiologic Findings, PD-L1, and Driver Mutations.
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Illini O, Fabikan H, Fischer E, Lang-Stöberl AS, Krenbek D, Jarius C, Azarnia-Medan S, Gasser S, Hochmair MJ, Weinlinger C, Valipour A, and Watzka S
- Abstract
Background: Adenosquamous carcinoma of the lung (ASC) is a rare non-small-cell lung cancer (NSCLC) subtype combining components of squamous cell carcinoma (SCC) and adenocarcinoma (AC). Data on ASC, particularly in Caucasian populations, are limited. Methods: We reviewed clinicopathological and radiological characteristics of ASC patients diagnosed between 1996 and 2023. Patients were classified into AC-predominant ASC (AC-ASC) and SCC-predominant ASC (SCC-ASC) groups for analysis. Results: Among the 66 patients included, the median overall survival was 41.7 (95% CI, 25.0-54.4), while it was 48.1 (95% CI, 27.3-88.0) in patients treated with curative surgery (n = 44) and 15.3 (95% CI, 6.5-42.6) months for palliative patients (n = 22). The five-year survival rates were 39% and 26%, respectively. Recurrence occurred in 43% of stage I patients and was associated with worse survival (HR 3.303 (95% CI, 1.10-9.89) p = 0.033). AC-ASCs (n = 17) more frequently showed air-bronchogram ( p = 0.002) and pleural effusions ( p = 0.054) compared to SCC-ASCs (n = 26). SCC-ASCs exhibited more vascular invasion ( p = 0.006) and PD-L1 values between 1 and 49% (TPS) ( p = 0.032). The subtype did not influence survival. EGFR and ALK alterations were found in 17% and 2% of patients, respectively. Conclusions: Despite early-stage disease, ASC patients had a high recurrence rate, associated with worse survival. Clinicopathologic differences between AC-ASCs and SCC-ASCs did not influence survival.
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- 2024
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8. Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.
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Hochmair MJ, Vermaelen K, Mountzios G, Carcereny E, Dooms C, Lee SH, Morocz E, Kato T, Ciuleanu TE, Dy GK, Parente B, O'Byrne KJ, Chu QS, Castro Junior G, Girard N, Snyder W, Tran Q, Kormany W, Houk B, Mehta B, and Curioni-Fontecedro A
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Aged, 80 and over, Drug Administration Schedule, Pyridines adverse effects, Pyridines administration & dosage, Pyridines pharmacokinetics, Pyridines therapeutic use, Progression-Free Survival, Piperazines, Pyrimidines, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Proto-Oncogene Proteins p21(ras) genetics, Mutation
- Abstract
Background: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg., Methods: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing., Results: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC
0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %)., Conclusions: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications., Clinical Trial Registration: NCT03600883., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. J. Hochmair: Financial Interests, Personal, Other, Consulting or Advisory role: Takeda, Roche, Lilly, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Lilly, MSD Oncology, Novartis, Roche, Amgen. K. Vermaelen: Financial Interests, Personal, Research Grant: Bristol Myers Squibb (BMS); Financial Interests, Personal, Other, Honoraria: BMS; Financial Interests, Personal, Other, Support for Attending Meetings: AstraZeneca, BMS, Merck; Financial Interests, Personal, Other, Patents Planned/Issued/Pending: Ghent University; Financial Interests, Personal, Other, Data Safety Monitoring Board or Advisory Board: Amgen, AstraZeneca, BMS, Merck. G. Mountzios: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, BMS GmbH & Co. KG, Boehringer Ingelheim, MSD, Novartis, Roche, Takeda; Financial Interests, Personal, Other, Consulting or Advisory Board: Amgen, AstraZeneca/Greece, BMS GmbH & Co. KG, MSD, Novartis, Roche, Takeda; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MSD; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, BMS GmbH & Co. KG, Ipsen, MSD, Novartis, Roche. E. Carcereny: No conflicts to disclose. C. Dooms: No conflicts to disclose. S.-H. Lee: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca/MedImmune, Lilly, Merck, Roche; Financial Interests, Personal, Other, Consulting or Advisory Role: AstraZeneca, BMS/Ono, IMBdx, Janssen, Lilly, Merck, Pfizer, Roche, Takeda; Financial Interests, Personal, Research Grant: AstraZeneca, Lunit, Merck; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Novartis. E. Morocz: No conflicts to disclose. T. Kato: Financial Interests, Personal, Advisory Board, Speaker, Consultancy: AstraZeneca, Eli Lilly, Merck Biopharma, MSD; Financial Interests, Personal, Advisory Board, Speaker: Pfizer, Amgen, Janssen; Financial Interests, Personal, Other, Consultancy: Daiichi Sankyo, Takeda, Taiho; Financial Interests, Personal, Other, Consultancy, Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Ono, Novartis, BMS, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: BeiGene, GSK; Financial Interests, Personal, Advisory Board, Steering Committee: Roche; Financial Interests, Personal, Full or Part-Time Employment, Family Member: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Chugai, MSD, Pfizer, Eli Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck Biopharma, Haihe Biopharma, Blueprint Medicines, Turning Point, BeiGene, Gilead, GSK, Janssen, Bayer, Takeda, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Local PI: AstraZeneca. T.-E. Ciuleanu: Financial Interests, Personal, Other, Consulting or Advisory Role: Astellas Pharma, Janssen, BMS, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck Sharp & Dohme (MSD), Sanofi, Novartis, Servier, A&D Pharma; Financial Interests, Personal, Other, Travel Support: Pfizer, Sanofi, Boehringer Ingelheim, Merck, Servier, Ipsen, Amgen, A&D Pharma, AstraZeneca, Genentech, BMS, MSD Oncology, Eli Lilly, Janssen, Novartis, Astellas Pharma. G. K. Dy: Financial Interests, Personal, Other, Consulting or Advisory Role: AstraZeneca, Mirati Therapeutics, Lilly, Amgen, Regeneron, Eli Lilly; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Mirati Therapeutics, Lilly, Sanofi, BioAtla, Regeneron, Iovance Biotherapeutics, Revolution Medicines. B. Parente: No conflicts to disclose. K. J. O’Byrne: Financial Interests, Personal, Stocks/Shares: Carpe Vitae Pharmaceuticals, DGC Diagnostics, Replica Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Ipsen, Janssen-Cilag, Merck Group, MSD, Novartis, Pfizer, Roche, Seagen, Takeda, TriStar, Yuhan; Financial Interests, Personal, Other, Consulting or advisory Role: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Ipsen, Janssen-Cilag, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Seagen, Yuhan; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: three active patents. Q. S. Chu: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AnHeart Therapeutics, Astellas, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Jazz Pharmaceutical, Johnson and Johnson, Merck, Novartis, Pfizer, Roche, Takeda. G. De Castro Jr.: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Pfizer, MSD, BMS, Novartis, Roche, Amgen, Janssen, Merck Serono, Daiichi Sankyo, Sanofi, Lilly; Financial Interests, Personal, Other, Consulting or Advisory Role: Boehringer Ingelheim, Pfizer, Bayer, Roche, MSD, BMS, AstraZeneca, Yuhan, Merck Serono, Janssen, Libbs, Sanofi, Novartis, Daiichi Sankyo, Lilly; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bayer, Novartis, Roche, Merck Serono, BMS, MSD, Boehringer Ingelheim, Pfizer, Janssen, Amgen, Lilly, Daiichi Sankyo; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MSD, Novartis, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Merck Serono, Daiichi Sankyo. N. Girard: Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, MSD, Novartis, Pfizer, Sivan, Trizell; Financial Interests, Personal, Other, Consulting or Advisory Role: BMS, AstraZeneca, AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, MSD, Mirati, Novartis, Pfizer, Roche, Sanofi, Sivan; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Invited Speaker, Participation in Data Safety Monitoring Board: Roche; Financial Interests, Personal, Other, Leadership Role: International Thymic Malignancy Interest Group; Financial Interests, Personal, Full or Part-Time Employment, Employment of a Family Member: AstraZeneca. W. Snyder, Q. Tran, W. Kormany, B. Houk, B. Mehta: Financial Interests, Personal, Full or Part-Time Employment: Amgen Inc.; Financial Interests, Personal, Stocks/Shares: Amgen Inc. A. Curioni-Fontecedro: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis, Amgen, Roche, Takeda, Janssen; Non-Financial Interests, Personal, Leadership Role: Swiss Academy for Clinical Cancer Research (SAKK); Non-Financial Interests, Personal, Principal Investigator of Clinical Trials: Roche; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials: Takeda, MSD, BMS., (Copyright © 2024. Published by Elsevier Ltd.)- Published
- 2024
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9. Overcoming resistance in small-cell lung cancer.
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Hamilton G, Hochmair MJ, and Stickler S
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- Humans, Neoplasm Recurrence, Local, Neoplastic Cells, Circulating pathology, Spheroids, Cellular, Animals, Prognosis, Small Cell Lung Carcinoma pathology, Small Cell Lung Carcinoma drug therapy, Drug Resistance, Neoplasm, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Antineoplastic Agents therapeutic use, Neoplastic Stem Cells pathology, Neoplastic Stem Cells drug effects
- Abstract
Introduction: Small-cell lung cancer (SCLC) accounts for 15% of lung cancers and has a dismal prognosis due to early dissemination and acquired chemoresistance. The initial good response to chemotherapy is followed by refractory relapses within 1-2 years. Mechanisms leading to chemoresistance are not clear and progress is poor., Areas Covered: This article reviews the current evidence of the resistance of SCLCs at the cellular level including alteration of key proteins and the possible presence of cancer stem cells (CSCs). Without compelling evidence for cellular mechanisms and clinical failures of novel approaches, the study of SCLC has advanced to the role of 3D tumor cell aggregates in chemoresistance., Expert Opinion: The scarcity of viable tumor specimen from relapsed SCLC patients has hampered the investigations of acquired chemoresistance but a panel of nine SCLC circulating tumor cell (CTC) cell lines have revealed characteristics of SCLC in the advanced refractory states. The chemoresistance of relapsed SCLC seems to be linked to the spontaneous formation of large spheroids, termed tumorospheres, which contain resistant quiescent and hypoxic cells shielded by a physical barrier. So far, drugs to tackle large tumor spheroids are in preclinical and early clinical development.
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- 2024
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10. Recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer.
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Malapelle U, Leighl N, Addeo A, Hershkovitz D, Hochmair MJ, Khorshid O, Länger F, de Marinis F, Peled N, Sheffield BS, Smit EF, Viteri S, Wolf J, Venturini F, O'Hara RM Jr, and Rolfo C
- Subjects
- Humans, Circulating Tumor DNA genetics, Circulating Tumor DNA blood, Carcinoma, Non-Small-Cell Lung genetics, High-Throughput Nucleotide Sequencing methods, High-Throughput Nucleotide Sequencing standards, Lung Neoplasms genetics
- Abstract
Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports., (© 2024. The Author(s).)
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- 2024
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11. Prognostic significance of circulating tumor cells and tumor related transcripts in small cell lung cancer: A step further to clinical implementation.
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Welsch E, Holzer B, Schuster E, Fabikan H, Weinlinger C, Hauptmann-Repitz E, Illini O, Hochmair MJ, Fischer MB, Weiss E, Zeillinger R, and Obermayr E
- Subjects
- Humans, Prognosis, Biomarkers, Tumor genetics, Membrane Proteins, Intracellular Signaling Peptides and Proteins, Small Cell Lung Carcinoma drug therapy, Lung Neoplasms pathology, Neoplastic Cells, Circulating pathology
- Abstract
Small-cell lung cancer (SCLC) is a fatal disease with limited treatment options. Circulating tumor cells (CTCs) in liquid biopsy samples may serve as predictive and prognostic biomarkers; but the analysis of CTCs is still challenging. By using microfluidic or density gradient CTC enrichment in combination with immunofluorescent (IF) staining or qPCR of CTC-related transcripts, we achieved a 60.8% to 88.0% positivity in SCLC blood samples. Epithelial and neuroendocrine transcripts including the druggable target DLL3 were associated with shorter overall survival (OS), indicating the clinical value of these markers in terms of differential diagnosis and treatment decisions. High CTC counts and the presence of CTC duplets detected by IF staining were prognostic for OS, and thus may serve as indicators of disease progression or therapy failure. In patient samples with high CTC load detected by IF staining, a concordance of the transcripts positivity in circulating free plasma RNA and CTCs was observed. Our data emphasize the role of CTCs and CTC-related transcripts and underline the clinical value of liquid biopsy analysis in SCLC., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2024
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12. Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.
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Illini O, Saalfeld FC, Christopoulos P, Duruisseaux M, Vikström A, Peled N, Demedts I, Dudnik E, Eisert A, Hashemi SMS, Janzic U, Kian W, Mohorcic K, Mohammed S, Silvoniemi M, Rothschild SI, Schulz C, Wesseler C, Addeo A, Armster K, Itchins M, Ivanović M, Kauffmann-Guerrero D, Koivunen J, Kuon J, Pavlakis N, Piet B, Sebastian M, Velthaus-Rusik JL, Wannesson L, Wiesweg M, Wurm R, Albers-Leischner C, Aust DE, Janning M, Fabikan H, Herold S, Klimova A, Loges S, Sharapova Y, Schütz M, Weinlinger C, Valipour A, Overbeck TR, Griesinger F, Jakopovic M, Hochmair MJ, and Wermke M
- Subjects
- Male, Humans, Female, Aged, ErbB Receptors genetics, Exons, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Aniline Compounds, Indoles, Pyrimidines
- Abstract
EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
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- 2024
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13. Prognostic factors of recurrence and disease-free survival in radically resected pulmonary carcinoids: a real-world analysis.
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Spils M, Klikovits T, Krenbek D, Hochmair MJ, Jankovic I, Schulte L, Krajc T, Benej M, Getman V, Navarrete JR, Akan A, Mueller MR, Aigner C, and Watzka SB
- Abstract
Background: Pulmonary carcinoids (PCs) are rare neuroendocrine lung tumors which may recur, thus worsening their otherwise favorable overall prognosis. Aiming to identify patients at risk for recurrence, we examined parameters affecting disease-free survival (DFS)., Methods: A retrospective single-center analysis of 82 consecutive patients undergoing curative intent resection for primary PC tumors between 2010 and 2019 was carried out. Kaplan-Meier method was utilized for survival analysis. Independent prognostic factors were determined using multivariable Cox and logistic regression., Results: During the observation period 82 patients, 48 females (58.5%) and 34 males (41.5%) were operated, representing 84 cases of PCs, 56 typical (TCs) (66.7%) and 28 atypical (ACs) (33.3%) carcinoids. Five-year overall survival was 87.5% and 84.7%, 5-year DFS 97.5% and 74.9% (P=0.012) for TCs and ACs, respectively. Recurrences occurred in one patient (1.8%) with TCs and five patients (17.9%) with ACs (P=0.014). Using multivariable Cox regression, tumor size (cm) remained as an independent prognostic factor for reduced DFS (P=0.018). In logistic regression, nodal involvement (P=0.043) and tumor size (cm) (P=0.023) were independently associated with higher risk of recurrence. Age, sex, smoking, location, and Ki-67 index were not independently associated with recurrence or DFS., Conclusions: Recurrence in PCs after complete resection is relatively rare. However, DFS is reduced in ACs compared to TCs. Tumor size (cm) and nodal involvement appear as the most important prognostic factors associated with recurrence in PCs, independent of histologic type., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1681/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)
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- 2024
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14. Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries.
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de Jager VD, Timens W, Bayle A, Botling J, Brcic L, Büttner R, Fernandes MGO, Havel L, Hochmair MJ, Hofman P, Janssens A, Johansson M, van Kempen L, Kern I, Lopez-Rios F, Lüchtenborg M, Machado JC, Mohorcic K, Paz-Ares L, Popat S, Ryška A, Taniere P, Wolf J, Schuuring E, and van der Wekken AJ
- Abstract
In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control., Competing Interests: WT has received consulting fees from Merck Sharp and Dohme, Bristol-Myers Squibb, and Altana (fees to institution), is board member of Dutch Society of Pathology and member of Council for Research and Innovation of the Federation of Medical Specialists (FMS); AB has received consulting fees from Sanofi (OncoCollective advisory board), payments or honoraria from Roche (oral presentation), support for attending ASCO 2023 from Pfizer; JB has received research grants from Amgen and Bristol-Myers Squibb, lecture honoraria from AstraZeneca, Merck Sharp and Dohme, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, GSK, Eli Lilly, Amgen, and Sanofi, and support for attending meetings and/or travel from Amgen; LB has received grants or contract from Takeda, Roche, AstraZeneca, and Bristol-Myers Squibb, payments or honoraria from Invitae, Eli Lilly, AstraZeneca, Roche, Merck Sharp and Dohme, Merck, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, and Janssen, has participated in data safety monitoring boards or advisory boards for Invitae, Eli Lilly, AstraZeneca, Roche, Merck Sharp and Dohme, Merck, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, and Janssen, is Int. Secretary of the Austrian Society of Pathology, PPS Membership and Awards Committee, and is Member of the Mesothelioma Committee of IASLC; RB has received payments or honoraria for lectures and advisory boards for Abbvie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Illumina, Janssen, Lilly, Merck-Serono, Merck Sharp and Dohme, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc., has received payments for expert testimony from Merck Sharp and Dohme, is co-founder and co-owner of Gnothis Inc. (SE), Timer Therapeutics Inc. (GE); GF has received fees for advisory boards participation, meetings, or as invited speaker, from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Janssen, Merck Sharp and Dohme, Pfizer, Roche Farmacêutica Química Lda, and Takeda; MH has received payments or honoraria from Merck Sharp and Dohme, Roche, Lilly, AstraZeneca, and Takeda; PH has received consulting fees from AstraZeneca, Roche, Abbvie, Qiagen, and Pfizer, has received payments or honoraria from Thermofisher Scientist, Novartis, Janssen, AstraZeneca, and Biocartis, has received support for attending meetings and/or travel from Thermofisher Scientist, Novartis, Janssen, AstraZeneca, and Biocartis, has participated on a Data Safety Monitoring Board or Advisory Board for Thermofisher Scientist, Novartis, Janssen, AstraZeneca, Biocartis, Bristol-Myers Squibb, Sanofi, Roche, and Abbvie; LvK has received institutional grants or contract from Amgen, AstraZeneca, Bayer, Janssen-Cilag, Merck, Roche, and Servier, has received institutional payments or honoraria from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, and Roche, has received institutional support for attending meeting and/or travel from Roche, has participated on a Data Safety Monitoring Board or Advisory Board from Janssen-Cilag, Merck, and Roche, has a leadership or fiduciary role in the Commission Personalized Medicine—Belgium (unpaid), has stock or stock options in Cyclomics (institutional/personal); JCM has received payments or honoraria from Lilly Portugal, Novartis Portugal, Roche Portugal, Fresco Produções, Janssen-Cilag Portugal, Pierre Fabre Portugal, and Servier Portugal; has participated on a Data Safety Monitoring Board or Advisory Board of Roche Portugal; KM has received payments or honoraria from Takeda, Janssen, Pfizer, Merck Sharp and Dohme, Bristol-Myers Squibb, Roche, Amgen, Novartis, and Eli Lilly, has participated on a Data Safety Monitoring Board or Advisory Board of BMS, Takeda, AstraZeneca, Amgen, Roche, Boehringer Ingelheim, and Janssen; SP has received consulting fees (personal fees) from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, Merck Sharp and Dohme, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx, has received payments or honoraria (personal fees) from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda, has received payments for expert testimony (personal fees) from Roche, and Merck Serono, has received reimbursement of travel expenses from Janssen, and Roche, has participated on a Data Safety Monitoring Board or Advisory Board as per consulting fees, has a leadership role or fiduciary role (all unpaid) in the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board; AR has received consulting fees for participation on advisory boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Amgen, Merck Sharp and Dohme, Gilead, and Sanofi, has received honoraria for lectures and presentations from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Amgen, Merck Sharp and Dohme, Gilead, Roche, Merck-Serono, has received support for attendings meetings and travel from Sanofi, Gilead, Roche, and Bristol-Myers Squibb; JW has received payments or honoraria, has received support for attendings meetings and travel, and has participated in a Data Safety Monitoring Board or Advisory Board, from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda, and Turning Point; ES has received unrestricted grants (all paid to UMCG institution) from Abbott, Biocartis, AstraZeneca, Invitae/Archer, Bayer, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics, MSD/MERCK, and Boehringer Ingelheim, has received consulting fees (all paid to UMCG institution) from MSD/Merck, AstraZeneca, Roche, Novartis, Bayer, BMS, Lilly, Amgen, Illumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson & Johnson), Astellas Pharma, GSK, Sinnovisionlab, and Sysmex, has received payments or honoraria (all paid to UMCG institution) from Bio-Rad, Seracare, Roche, Biocartis, Lilly, Agena Bioscience, and Illumina, has received support for attending meetings and/or travel from BioRad, Biocartis, Ageno Sciences, and Illumina, is a board member for the Dutch Society of Pathology (unpaid), European Society of Pathology (unpaid), European Liquid Biopsy Society (unpaid), is a secretary/member of the advisory committee for assessment of molecular diagnostics (cieBOD) (honoraria paid to UMCG institution), is committee member of national guideline advisory (honoraria paid to UMCG institution); AvdW, has received grants or contracts from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, and Takeda, has received consulting fees from AstraZeneca, Janssen, Lilly, Roche, and Takeda, has received payments or honoraria from AstraZeneca, BMS, Lilly, Pfizer, and Roche, has a leadership or fiduciary role in the oncology section NVALT, guideline committee NSCLC and CUP, dure geneesmiddelen committee NVALT and FMS. All other authors declare no competing interests., (© 2024 The Authors.)
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- 2024
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15. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.
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Besse B, Pons-Tostivint E, Park K, Hartl S, Forde PM, Hochmair MJ, Awad MM, Thomas M, Goss G, Wheatley-Price P, Shepherd FA, Florescu M, Cheema P, Chu QSC, Kim SW, Morgensztern D, Johnson ML, Cousin S, Kim DW, Moskovitz MT, Vicente D, Aronson B, Hobson R, Ambrose HJ, Khosla S, Reddy A, Russell DL, Keddar MR, Conway JP, Barrett JC, Dean E, Kumar R, Dressman M, Jewsbury PJ, Iyer S, Barry ST, Cosaert J, and Heymach JV
- Subjects
- Humans, Platinum therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antibodies, Monoclonal, Biomarkers, B7-H1 Antigen, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Antineoplastic Agents therapeutic use, Indoles, Morpholines, Pyrimidines, Sulfonamides
- Abstract
For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617., (© 2024. The Author(s).)
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- 2024
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16. Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden.
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Paz-Ares L, Garassino MC, Chen Y, Reinmuth N, Hotta K, Poltoratskiy A, Trukhin D, Hochmair MJ, Özgüroğlu M, Ji JH, Statsenko G, Conev N, Bondarenko I, Havel L, Losonczy G, Xie M, Lai Z, Godin-Heymann N, Mann H, Jiang H, Shrestha Y, and Goldman JW
- Subjects
- Humans, B7-H1 Antigen genetics, Etoposide, Platinum, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized
- Abstract
Purpose: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB)., Experimental Design: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model., Results: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672)., Conclusions: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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17. Expression of cytokines in pleural effusions and corresponding cell lines of small cell lung cancer.
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Rath B, Stickler S, Hochmair MJ, and Hamilton G
- Abstract
Background: Small cell lung cancer (SCLC) is a neuroendocrine aggressive tumor with a dismal prognosis due to the lack of curative therapeutic modalities. Approximately 11% of these patients show a malignant pleural effusion (MPE) that increase in frequency with progression of the disease. In MPE, fluid accumulates due to leaky vessels and mesothelial surfaces as well as impaired removal of fluid due to impaired drainage., Methods: For this investigation, three SCLC MPE samples and supernatants of the corresponding isolated cell lines were analyzed for the content of 105 cytokines, chemokines, and growth factors. Overexpressed pathways including these cytokines were identified using Reactome analysis tools., Results: A large range of cytokines, including vascular endothelial growth factor A ( VEGFA ), were found to be expressed in the MPEs and conditioned media of the corresponding cell line. These mediators are involved in pathways such as interleukin ( IL ) signaling, growth factor stimulation, modulation of cell adhesion molecules and proliferative cell signaling. Cytokine expression by the corresponding SCLC cell lines revealed the specific contributions of the tumor cells and included high expression of VEGFA , tumor-promoting factors and mediators exerting immunosuppressive and protumor effects. MPEs used here showed marked stimulation of the proliferation of four permanent SCLC cell lines., Conclusions: MPEs comprise a large number of cytokines with mixed activities on tumor cells and the invading SCLC cells release a number of protumor mediators and induce an immunosuppressive pleural environment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-569/coif). G.H. serves as an unpaid editorial board member of Translational Lung Cancer Researchfrom September 2023 to August 2025. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)
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- 2024
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18. Unmet needs in EGFR exon 20 insertion mutations in Central and Eastern Europe: reimbursement, diagnostic procedures, and treatment availability.
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Hochmair MJ, Unk M, Spasic J, Cerić T, Konsoulova A, Dediu M, Bogos K, Hegmane A, Oselin K, Stojiljkovic M, Roblek T, and Jakopovic M
- Abstract
Lung cancer remains the leading cause of cancer-related deaths in Europe, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. NSCLC is a heterogeneous disease encompassing various oncogenic alterations. Among them, EGFR exon 20 insertion mutations, constituting 0.3-2.2% of NSCLC cases, rank as the third most common EGFR alteration after exon 19 deletions and the L858R point mutation in exon 21, also known as "typical" EGFR alterations. Recent advancements in understanding the molecular pathogenesis of NSCLC have led to significant breakthroughs in targeted therapies, revolutionizing treatment options for patients with specific genetic alterations.This article presents the outcomes of a Virtual Meeting conducted on the online platform (provided Within3©) from September 19 to October 30, 2022. The meeting focused on addressing the challenges in the diagnosis and treatment of NSCLC patients with EGFR exon 20 insertion mutations. The participants consisted of healthcare professionals from ten Central and Eastern European countries who shared their experiences and opinions on various aspects, including epidemiology, treatment options, and diagnostic approaches employed in their respective healthcare institutions. The discussions were facilitated through open-ended and multiple-choice questions.The primary objective of this article is to provide an overview of the identified challenges associated with the diagnosis and treatment of this heterogeneous disease, based on the assessments of the meeting participants. Among the major emerging challenges discussed, the reimbursement issues concerning next-generation sequencing (NGS), a recommended method in NSCLC molecular diagnosis, and the availability of approved targeted treatments to enhance patient outcomes were of paramount importance. Furthermore, fostering community awareness of lung cancer and promoting harmonized lung cancer care were identified as areas deserving greater attention. Notably, the rapidly evolving treatment landscape, particularly with NGS for NSCLC patients with genomic alterations like EGFR, ALK, RET, MET, NTRK, and ROS1, necessitates prioritizing the development of new drugs, even for the relatively smaller subgroup with exon 20 insertion mutations., (© 2023. The Author(s).)
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- 2024
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19. Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide.
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Liu SV, Mok TSK, Nabet BY, Mansfield AS, De Boer R, Losonczy G, Sugawara S, Dziadziuszko R, Krzakowski M, Smolin A, Hochmair MJ, Garassino MC, Gay CM, Heymach JV, Byers LA, Lam S, Cardona A, Morris S, Adler L, Shames DS, and Reck M
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- Humans, Carboplatin, Etoposide, Survivors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Objectives: In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival., Materials and Methods: Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS., Results: More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm., Conclusion: These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen., Clinicaltrial: gov Identifier: NCT02763579., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.V.L. declares grants or contracts from Alkermes, Bayer, Blueprint, Bristol Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics; consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/Merck Sharpe & Dohme, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; and participation on a Data Safety Monitoring or Advisory Board for Candel Therapeutics. T.S.K.M. declares consulting and advisory personal fees from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., geneDecode (uncompensated), Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., IQVIA, Incyte Corporation, Janssen, Lilly, Loxo-Oncology, Lunit USA, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., Novartis, OrigiMed, Pfizer, Inc., Puma Biotechnology Inc., Roche, Sanofi-Aventis R&D, Takeda, Yuhan Corporation, SFJ Pharmaceuticals, Curio Science, Inivata, Berry Oncology, Qiming Development (HK) Ltd., Gilead Sciences, Inc., Vertex Pharmaceuticals, and Covidien LP; lecture personal fees from ACEA Pharmaceuticals, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Fishawack Facilitate Ltd., geneDecode, (uncompensated), InMed Medical Communication, Janssen, Lilly, Lunit USA, Inc., MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharpe & Dohme, Novartis, OrigiMed, PeerVoice, Physicians’ Education Resource, P. Permanyer SL, Pfizer, Inc., PrIME Oncology, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd., Shanghai BeBirds Translation & Consulting Co. Ltd., Liangyihui Network Technology Co. Ltd., and Taiho; grants from AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Inc., Roche, Takeda, Clovis Oncology, SFJ Pharmaceuticals, XCovery, and G1 Therapeutics Inc.; personal fees for supporting an advisory board for Inivata, Berry Therapeutics Inc., and G1 Therapeutics Inc.; shareholding for Aurora, Sanomics Ltd., Hutchison ChiMed; and a role on the Board of Directors for Lunit USA, Inc., AstraZeneca PLC, Hutchison ChiMed, Sanomics Ltd., Aurora. B.Y.N declares employment by Genentech and stockholding in Roche. A.S.M declares grants or contracts from NIH/NCI, Verily, Novartis, Department of Defense, and Mark Foundation; payment or honoraria to institution for lecture, presentations, speakers bureaus, manuscript writing or education events from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech; support for attending meetings and/or travel from Shanghai Roche Pharmaceuticals; patents planned, issues, or pending for patents submitted unrelated to this work; and other financial or non-financial interests from non-remunerated director of the Mesothelioma Applied Research Foundation. R. De Boer declares payment of honoraria from Novartis, AstraZeneca, and Gilead; and support for attending meetings and/or travel from Amgen, Novartis, and Roche. S.S. declares payment or honoraria for lectures, presentation, speakers bureaus, manuscript writing, or educations events from Chugai Pharma, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Merck Sharpe & Dohme, Nippon Boehringer-Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, and Company, Novartis, Kyowa Kirin, Yakult Honsha, and Towa Pharmaceutical. R. Dziadziuszko declares consulting fees from Roche, Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Foundation Medicine, Novartis, and Karyopharm; and payment or honoraria from Roche, Novartis, AstraZeneca, and Pfizer. A.S. declares payment or honoraria from AstraZeneca, Bristol Myers Squibb, Roche, Merck Sharpe & Dohme, Novartis, and Pfizer; support for attending meetings and/or travel from Bristol Myers Squibb, Roche, Boehringer-Ingelheim, and AstraZeneca; and participation on data safety monitoring or advisory boards for Bristol Myers Squibb, Roche, Takeda, AstraZeneca, BIOCAD, and Boehringer-Ingelheim. M.J.H declares payment or honoraria from Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche; and participation on data safety monitoring or advisory boards for Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche. M.C.G. declares grants from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, GSK, Sanofi; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Janssen, Lilly, Yuhan, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, Libbs, and Sanofi; payment of honoraria from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, Merck Serono, Janssen, and Amgen; support for attending meetings and/or travel from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, and Merck Serono; participation on data safety monitoring or advisory boards for TEVA, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Yuhan, Janssen, Merck Serono, Novartis, Amgen; and payment of honoraria for promotional activities from Boehringer-Ingelheim, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, TEVA, Amgen, and Janssen. C.M.G. declares research grants/funding to self from AstraZeneca; advisory/consultancy to AstraZeneca, Kisoji Biotechnology, Jazz Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau/expert testimony for AstraZeneca and BeiGene. J.V.H declares advisory/consultancy for Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, and Mirati Therapeutics; research support to AstraZeneca, GlaxoSmithKline, and Spectrum; and royalties/licensing fees from Spectrum. L.A.B. declares an advisory role/consultancy for AstraZeneca, AbbVie, Bristol Myers Squibb, and Merck; and research funding from AstraZeneca and AbbVie. S.L. declares employment by Genentech and stockholding in Roche. A.C. declares employment by Roche and stockholding in Roche. S.M. declares employment by Roche and stockholding in Roche. L.A. declares employment by Roche and stockholding in Roche. D.S.S. declares employment by Genentech and stockholding in Roche. M.R. declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; payment of honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; support for attending meetings and/or travel from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; and participation on data safety monitoring or advisory boards for DSMB Sanofi. G.L. and M.K. declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)
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- 2023
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20. Assessing the Performance of a Novel Stool-Based Microbiome Test That Predicts Response to First Line Immune Checkpoint Inhibitors in Multiple Cancer Types.
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Robinson I, Hochmair MJ, Schmidinger M, Absenger G, Pichler M, Nguyen VA, Richtig E, Rainer BM, Ay L, Jansen C, Pacífico C, Knabl A, Sladek B, Gasche N, and Valipour A
- Abstract
The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne
® , a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri , and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter . When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients ( n = 38), BiomeOne® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne® , the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice.- Published
- 2023
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21. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study.
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Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, and Rodríguez-Abreu D
- Subjects
- Humans, Pemetrexed therapeutic use, Platinum therapeutic use, ErbB Receptors, Receptor Protein-Tyrosine Kinases therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.
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- 2023
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22. Neoadjuvant immune-checkpoint inhibitors in lung cancer - a primer for radiologists.
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Kifjak D, Hochmair MJ, Krenbek D, Milos RI, Heidinger BH, Prayer F, Röhrich S, Watzenboeck ML, Oberndorfer F, Klikovits T, Aigner C, Sinn K, Hoda MA, Hoetzenecker K, Haug AR, Prosch H, and Beer L
- Subjects
- Humans, Immune Checkpoint Inhibitors, Neoadjuvant Therapy methods, Immunotherapy methods, Radiologists, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms diagnostic imaging, Lung Neoplasms drug therapy, Lung Neoplasms pathology
- Abstract
The introduction of neoadjuvant immune checkpoint inhibitors plus platinum-based chemotherapy has changed treatment regimens of patient's early-stage lung cancer. This treatment combination induces high rates of complete pathologic response and improves clinical endpoints. Imaging plays a fundamental role in assessment of treatment response, monitoring of (immune-related) adverse events and enables both the surgeon and pathologist optimal treatment and diagnostic workup of the resected tumor samples. Knowledge of the strengths and weaknesses of diagnostic imaging in this setting are essential for radiologists to provide valuable input in multidisciplinary team decisions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [Helmut Prosch reports financial support was provided by Christian Doppler Laboratories. Lucian Beer reports a relationship with Bayer, Novartis, MSD, Roche that includes: speaking and lecture fees and travel reimbursement]., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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23. Lymph Node Log-Odds Ratio Accurately Defines Prognosis in Resectable Non-Small Cell Lung Cancer.
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Benej M, Klikovits T, Krajc T, Bohanes T, Schulte L, Hochmair MJ, Watzka S, Mosleh B, Hoetzenecker K, Aigner C, Hoda MA, and Mueller MR
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Objectives: The ratio of positive and resected lymph nodes (LN ratio) has been shown to be prognostic in non-small cell lung cancer (NSCLC). Contrary to the LN ratio, calculating the LN log-odds ratio (LN-LOR) additionally considers the total number of resected lymph nodes. We aim to evaluate LN-LOR between positive and resected lymph nodes as a prognostic factor in operable NSCLC., Methods: Patients with NSCLC who underwent curative intent lobectomy treated at two high-volume centers were retrospectively studied. LN-LOR was dichotomized according to impact on OS and further combined with N descriptors and correlated with clinical variables and survival., Results: 944 patients were included. Cut-off analysis revealed that an LN-LOR of -0.34 significantly discriminated patients according to OS ( p < 0.001, chi-squared test 41.26). When combined with N1 and N2 descriptors, LN-LOR low risk (median OS not reached and 83 months) and LN-LOR high-risk patients (median OS 50 and 59 months) had similar survival irrespective of the anatomical location of the positive lymph nodes. Multivariable Cox regression analysis revealed that age (HR 1.02, 95% CI 1.001-1.032), sex (male, HR 1.65, 95% CI 1.25-2.19), histological subtype (HR 2.11, 95% CI 1.35-3.29), pathological stage (HR 1.23, 95% CI 1.01-1.45) and LN-LOR risk groups (low risk, HR 0.48, 95% CI 0.32-0.72) were independent prognostic factors for OS., Conclusions: This retrospective two-center analysis shows that LN-LOR is significantly associated with OS in resectable NSCLC and might better reflect the biological behavior of the disease, regardless of anatomical lymph node locations. This finding may additionally support the value of extensive LN dissection.
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- 2023
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24. Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK-Inhibitor-Naive ALK+ Non-Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study.
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Ahn MJ, Kim HR, Yang JCH, Han JY, Li JY, Hochmair MJ, Chang GC, Delmonte A, Lee KH, Campelo RG, Gridelli C, Spira AI, Califano R, Griesinger F, Ghosh S, Felip E, Kim DW, Liu Y, Zhang P, Popat S, and Camidge DR
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- Humans, Crizotinib adverse effects, Protein Kinase Inhibitors therapeutic use, Asian People, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung ethnology, Lung Neoplasms drug therapy, Lung Neoplasms ethnology, Lung Neoplasms pathology
- Abstract
Background: Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non-small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial., Patients and Methods: This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor-naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases., Results: Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients., Conclusion: Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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25. Effect of short-term storage of blood samples on gene expression in lung cancer patients.
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Obermayr E, Koppensteiner N, Heinzl N, Schuster E, Holzer B, Fabikan H, Weinlinger C, Illini O, Hochmair MJ, and Zeillinger R
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- Humans, Biomarkers, Tumor, Prognosis, Gene Expression, Neoplastic Cells, Circulating pathology, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Objectives: The stability of gene transcripts associated with the presence of circulating tumor cells (CTCs) has been predominantly studied in cultured cancer cell lines added to blood samples under artificial conditions. In the present study the effect of storage on CTC-related transcripts was assessed in blood samples taken from patients with non-small lung cancer (n=58)., Methods: The blood samples were split in two equal parts to compare the gene expression with and without storage for 24 h at ambient temperature without preservative added. After enrichment using the microfluidic Parsortix
® technology, the expression levels of selected genes were assessed using quantitative PCR following a gene-specific pre-amplification. The prognostic relevance of each gene in fresh and stored blood samples was evaluated using the R-package Survminer., Results: Some genes were either not affected ( TWIST 1, CDH5 , CK19 ) or upregulated upon storage ( NANOG , MET , UCHL1 ) but still associated with poor prognosis. In contrast, ERBB3 , PTHLH , EpCAM , and TERT were no longer associated with the overall survival of the patients., Conclusions: The study demonstrates the surprising stability of CTC-related transcripts, which makes overnight shipping of native blood samples possible. Careful verification is required when using model systems - such as normal blood spiked with tumor cells - or other CTC-related markers, as individual transcripts may respond differently to storage., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)- Published
- 2022
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26. Sequential Afatinib and Osimertinib in Asian Patients with EGFR Mutation-Positive Non-Small Cell Lung Cancer and Acquired T790M: Combined Analysis of Two Global Non-Interventional Studies.
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Miura S, Jung HA, Lee SY, Lee SH, Lee MK, Lee YC, Hochmair MJ, Yang CT, Märten A, Yang JC, and Popat S
- Abstract
Objective: Two recent non-interventional trials, GioTag and UpSwinG, demonstrated encouraging time-to-treatment failure (TTF) and overall survival (OS) in patients with epidermal growth factor receptor ( EGFR) mutation-positive non-small cell lung cancer (NSCLC) (Del19 or L858R) who received sequential afatinib/osimertinib, especially in Asians. Here, we have undertaken a combined analysis of Asian patients from both studies., Materials and Methods: Existing medical/electronic records were identified for consecutive EGFR-tyrosine kinase inhibitor (TKI)-naïve patients who received first-line afatinib/second-line osimertinib in "real-world" practice (all T790M-positive). Patients with active brain metastases were excluded. The primary objective was TTF. OS was a key secondary objective., Results: One hundred and sixty-eight patients were analyzed. Most patients were recruited from South Korea or Japan (52/21%). At the start of afatinib, median age (range) was 61.5 years (35-88), 58% were female, Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0/1/≥2) was 29/62/9%, 17% had brain metastases, and EGFR mutation status (Del19/L858R) was 65/35%. At the start of osimertinib, ECOG PS (0/1/≥2) was 22/61/17% and 14% had brain metastases. Median TTF and OS were 30.0 months (95% CI: 24.5-32.5) and 45.2 months (95% CI: 41.7-71.1), respectively. Median OS was 63.5 months in patients with a Del19 mutation. Median OS in patients with brain metastases or ECOG PS ≥2 was 26.4 and 33.1 months, respectively., Conclusion: Sequential afatinib/osimertinib showed encouraging activity in Asian patients with EGFR mutation-positive NSCLC and T790M-mediated acquired resistance, especially those with Del19-positive disease. Activity was observed across "real-world" patients including those with poor ECOG PS and/or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib., Competing Interests: SM reports receiving honoraria from Chugai Pharma, AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Bristol Myers Squibb, Taiho Pharma, and Pfizer. HAJ, SYL, SHL, MKL, and YCL declare no potential conflict of interest. MJH reports receiving consulting fees from Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, Roche, and honoraria from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche. C-TY declares no potential conflict of interest. AM declares employment with Boehringer Ingelheim. JC-HY reports receiving personal and/or institutional fees from Amgen; personal and institutional fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals; institutional fees from Bayer, Daiichi Sankyo, Eli Lilly, Merck KGaA (Darmstadt, Germany), Merck Sharp & Dohme, Johnson & Johnson; personal fees from Bristol Myers Squibb, Ono Pharmaceuticals, Pfizer; grants from AstraZeneca. SP reports receiving grant support, honoraria, consulting fees, and travel support from Boehringer Ingelheim; consulting fees and travel support from Bristol Myers Squibb; honoraria and consulting fees from Roche, Takeda, AstraZeneca; honoraria from Chugai Pharma; consulting fees from Novartis, Guardant Health, AbbVie, Pfizer; consulting fees and travel support from Merck Sharp & Dohme., (© 2022 Miura et al.)
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27. Long-Term Efficacy and Safety of Brigatinib in Crizotinib-Refractory ALK + NSCLC: Final Results of the Phase 1/2 and Randomized Phase 2 (ALTA) Trials.
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Gettinger SN, Huber RM, Kim DW, Bazhenova L, Hansen KH, Tiseo M, Langer CJ, Paz-Ares Rodríguez LG, West HL, Reckamp KL, Weiss GJ, Smit EF, Hochmair MJ, Kim SW, Ahn MJ, Kim ES, Groen HJM, Pye J, Liu Y, Zhang P, Vranceanu F, and Camidge DR
- Abstract
Introduction: We report brigatinib long-term efficacy and safety from phase 1/2 and phase 2 (ALTA) trials in ALK -rearrangement positive ( ALK +) NSCLC., Methods: The phase 1/2 study evaluated brigatinib 30 to 300 mg/d in patients with advanced malignancies. ALTA randomized patients with crizotinib-refractory ALK+ NSCLC to brigatinib 90 mg once daily (arm A) or 180 mg once daily (7-d lead-in at 90 mg; arm B)., Results: In the phase 1/2 study, 79 of 137 brigatinib-treated patients had ALK+ NSCLC; 71 were crizotinib pretreated. ALTA randomized 222 patients (n = 112 in arm A; n = 110 in arm B). Median follow-up at phase 1/2 study end (≈5.6 y after last patient enrolled) was 27.7 months; at ALTA study end (≈4.4 y after last patient enrolled), 19.6 months (A) and 28.3 months (B). Among patients with ALK + NSCLC in the phase 1/2 study, median investigator-assessed progression-free survival (PFS) was 14.5 months (95% confidence interval [CI]: 10.8-21.2); median overall survival was 47.6 months (28.6-not reached). In ALTA, median investigator-assessed PFS was 9.2 months (7.4-11.1) in arm A and 15.6 months (11.1-18.5) in arm B; median independent review committee (IRC)-assessed PFS was 9.9 (7.4-12.8) and 16.7 (11.6-21.4) months, respectively; median overall survival was 25.9 (18.2-45.8) and 40.6 (32.5-not reached) months, respectively. Median intracranial PFS for patients with any brain metastases was 12.8 (9.2-18.4) months in arm A and 18.4 (12.6-23.9) months in arm B. No new safety signals were identified versus previous analyses., Conclusions: Brigatinib exhibited sustained long-term activity and PFS with manageable safety in patients with crizotinib-refractory ALK+ NSCLC., (© 2022 The Authors.)
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- 2022
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28. Effectiveness of Outpatient Pulmonary Rehabilitation in Patients with Surgically Resected Lung Cancer: A Retrospective Real-World Analysis.
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Illini O, Valipour A, Gattinger D, Petrovic M, Fabikan H, Hochmair MJ, and Zwick RH
- Abstract
Patients with lung cancer frequently suffer from physical deconditioning, low exercise capacity, and reduced quality of life. There is little evidence on the effects of a structured outpatient pulmonary rehabilitation program (OPR) on exercise capacity and symptom load in these patients. We performed a retrospective, single-center analysis of surgically resected lung cancer patients, who underwent a multiprofessional 6-week OPR. The primary endpoint was a change in the six-minute walk test distance (6 MWT). Secondary endpoints included changes in maximal workload and constant work-rate test results during cycle-ergometry, upper and lower extremity strength, and inspiratory muscle strength. The COPD Assessment Test (CAT) was used to assess symptom burden. Fifty-seven patients were included. Of those, fifty-two (91.2%) completed the full 6 weeks of OPR. The mean age was 56.4 (SD 9.2) years, and 58% were female. At completion of OPR, there was a statistically significant mean of a 50 m (95% CI, 29.6−70.7; p < 0.001) increase in 6 MWT. Significant improvements were also seen in all other exercise and strength tests (p < 0.001), accompanied by a significant reduction in the CAT score (mean difference −3.1, p = 0.001). No adverse effects were reported. OPR for surgically resected lung cancer patients was safe and effective and showed high adherence in the current study.
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- 2022
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29. Characteristics and Treatment Outcomes in Advanced-Stage Non-Small Cell Lung Cancer Patients with a KRAS G12C Mutation: A Real-World Study.
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Illini O, Fabikan H, Hochmair MJ, Weinlinger C, Krenbek D, Brcic L, Setinek U, Terbuch A, Absenger G, Konjić S, and Valipour A
- Abstract
About 15% of patients with non-small cell lung cancer (NSCLC) harbor the Kirsten rat sarcoma homolog G12C mutation ( KRAS
G12C ). Selective KRASG12C inhibitors offer new treatment opportunities, but little is known about the prevalence, characteristics, and outcomes of standard-of-care treatment (SOC) in this population. We retrospectively assessed the clinicopathological features of patients with KRASG12C -mutated advanced NSCLC and responses to SOC at two high-volume centers in Austria. Out of 2495 NSCLC patients tested, we identified 174 patients with advanced-stage disease carrying a KRASG12C mutation. Most patients were ≥65 years old (55%), heavy smokers (55%), and presented with comorbidities. The most frequent co-alteration was TP53 (18%). PD-L1 expression was high (TPS ≥ 50%) in 31%, very high (TPS ≥ 90%) in 11%, and negative in 31% of patients. A total of 138 patients (79%) received oncologic systemic treatment. The most common first-line therapy (1 L) was anti-PD-1/PD-L1 plus platinum-based chemotherapy. Median overall survival measured from 1 L treatment was 15.3 months (95% CI, 8.6-21.9), 9.4 (95% CI, 5.3-13.5) from 2 L treatment, and 8.4 (95% CI, 1.7-15.1) from 3 L treatment. The time-to-next-treatment was 8.4 (95% CI, 5.2-11.6) from 1 L and 6.1 (95% CI, 2.7-9.7) months from 2 L to 3 L. These poor outcomes underscore the need for the implementation of new treatment options and for specific molecular testing.- Published
- 2022
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30. Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program.
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Illini O, Fabikan H, Swalduz A, Vikström A, Krenbek D, Schumacher M, Dudnik E, Studnicka M, Öhman R, Wurm R, Wannesson L, Peled N, Kian W, Bar J, Daher S, Addeo A, Rotem O, Pall G, Zer A, Saad A, Cufer T, Sorotsky HG, Hashemi SMS, Mohorcic K, Stoff R, Rovitsky Y, Keren-Rosenberg S, Winder T, Weinlinger C, Valipour A, and Hochmair MJ
- Abstract
Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal-epithelial transition ( MET ) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials., Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021., Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48-91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47-69), whereas it was 68% (95% CI, 50-82) in treatment-naïve and 50% (95% CI, 35-65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7-14.3), whereas it was 10.6 months (95% CI, 5.5-15.7) in first-line and 9.1 months (95% CI, 3.1-15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2-23.1). In patients with measurable brain metastases ( n = 11), the intracranial ORR was 46% (95% CI, 17-77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%)., Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting., Competing Interests: Conflict of interest statement: Oliver Illini: Received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Menarini, Merck Sharp & Dohme, Pfizer, and Roche. Hannah Fabikan: Speaker fee from Roche. Aurélie Swalduz: Honoraria for Advisory Boards: Roche, Bristol-Myers Squibb, Takeda, Lilly, Pfizer, Amgen, Janssen. Symposiums: Roche, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer, Takeda. Anders Vikström: Speaker fees, consultations and honoraria for advisory boards from Amgen, Astra Zeneca, BMS, Boehringer-Ingelheim, ELI-Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Research grants from Boehringer-Ingelheim. Dagmar Krenbek: Received speaker fees and/or honoraria for advisory boards from Amgen, Eli Lilly, Merck Sharp & Dohme, Pfizer, Janssen, Merck, Novartis. Michael Schumacher: Received speaker fees and/or honoraria for advisory boards and/or travel grants from Boehringer Ingelheim, Eli Lilly, Menarini, Merck Sharp & Dohme, Pfizer, Roche, BMS, Novartis, Takeda, Amgen. Elizabeth Dudnik: Personal fees from Roche, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Astra Zeneca, personal fees from Pfizer, personal fees from MSD, personal fees from BMS, personal fees from Novartis, personal fees from Takeda, personal fees from Sanofi, personal fees from Janssen – all outside the submitted work. Michael Studnicka: Nothing to declare. Ronny Öhman: Speaker fee and advisory board for; Eli Lilly, AstraZeneca, Roche, MSD, Takeda, BMS, Novartis, and Janssen. Robert Wurm: Received speaker fees and/or honoraria for advisory boards from Amgen, Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Pfizer, Roche, Sanofi, and Takeda. Luciano Wannesson: Received speaker fees and/or honoraria for advisory boards from Novartis, Eli Lilly, Takeda, Merck Sharp and Dohme, Bristol Myers Squibb, and Roche. Received a research grant from Roche. Nir Peled: NP reports receiving grants and personal fees from: Advisor & Honorarium from & Research with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Foundation Medicine, Gaurdant360, Merk, MSD, Novartis, NovellusDx, Pfizer, Roche, and Takeda. Waleed Kian: Nothing to declare. Jair Bar: Research funding (for the institute): MSD, Abbvie, Novartis, AstraZeneca, Roche, and Takeda. Consultant fees: MSD, Takeda, AstraZeneca, Novartis, Abbvie, Merck, Causalis, Roche, BMS, and Pfizer. Sameh Daher: Received speaker fees from Boehringer Ingelheim, Merck Sharp & Dohme, Rhenium, Bristol Myers Squibb, AstraZeneca, Novartis, Takeda, and Roche. Alfredo Addeo: Consulting or Advisory Role: BMS, AstraZeneca, Boehringer-Ingelheim, Roche, MSD, Pfizer, Eli Lilly, and Astellas. Speaker Bureau: Eli Lilly and Astrazeneca. Ofer Rotem: Received speaker fees and/or honoraria for advisory boards from Astrazeneca, Boehringer Ingelheim, BMS, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Takeda, and Teva. Georg Pall: Speaker fees and/or honoraria for advisory boards: Novartis, Merck, Astra Zeneca, and Pfizer. Alona Zer: Received speaker fees and/or honoraria for advisory boards from Takeda, Astra Zeneca, Menarini, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Akram Saad: Nothing to declare. Tanja Cufer: Received speaker fees and/or honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. Hadas Gantz Sorotsky: Lectures/Speakers Bureau/Personal fees/Travel, Accommodations, Expenses Expert Testimony – Roche-Genentech, MSD, BMS, AstraZeneca, Takeda, Astellas, Pfizer, and Medison. Sayed M.S. Hashemi: Advisory Board/Speaker fee: Abbvie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, GSK, Loxo, MSD, Novartis, Roche, Takeda, and Xcovery. Katja Mohorcic: Received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, Takeda, BMS Astra Zeneca, Amgen, and Jansen. Ronen Stoff: Received speaker fees from: BMS, MSD, Roche, Medison, Dexcel, and Novartis. Yulia Rovitsky: Nothing to declare. Shoshana Keren-Rosenberg: Nothing to declare. Thomas Winder: Received speakers fees and/or honoraria for advisory boards from MSD, Roche, Merck, Bayer, Servier, Eli Lilly, and Pfizer. Christoph Weinlinger: Nothing to declare. Arschang Valipour: Personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Merck, Novartis, and Roche for lectures and/or advisory boards outside of the submitted study. Maximilian J. Hochmair: Honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche., (© The Author(s), 2022.)
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31. Complete Remission to Afatinib in a Patient Harboring a Novel Epidermal Growth Factor Mutation in De Novo Small-Cell Lung Cancer: A Case Report: Clinical Lung Cancer.
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Hochmair MJ, Illini O, Prosch H, Krenbek D, and Valipour A
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- Afatinib therapeutic use, Epidermal Growth Factor genetics, Humans, Mutation genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma genetics
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- 2022
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32. Multimodal Treatment of Malignant Pleural Mesothelioma: Real-World Experience with 112 Patients.
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Holzknecht A, Illini O, Hochmair MJ, Krenbek D, Setinek U, Huemer F, Bitterlich E, Kaindl C, Getman V, Akan A, Weber M, Leobacher G, Valipour A, Mueller MR, and Watzka SB
- Abstract
Malignant pleural mesothelioma (MPM) is a rare pleural cancer associated with asbestos exposure. According to current evidence, the combination of chemotherapy, surgery and radiotherapy improves patients’ survival. However, the optimal sequence and weighting of the respective treatment modalities is unclear. In anticipation of the upcoming results of the MARS-2 trial, we sought to determine the relative impact of the respective treatment modalities on complications and overall survival in our own consecutive institutional series of 112 patients. Fifty-seven patients (51%) underwent multimodality therapy with curative intent, while 55 patients (49%) were treated with palliative intent. The median overall survival (OS) of the entire cohort was 16.9 months (95% CI: 13.4−20.4) after diagnosis; 5-year survival was 29% for patients who underwent lung-preserving surgery. In univariate analysis, surgical treatment (p < 0.001), multimodality therapy (p < 0.001), epithelioid subtype (p < 0.001), early tumor stage (p = 0.02) and the absence of arterial hypertension (p = 0.034) were found to be prognostic factors for OS. In multivariate analysis, epithelioid subtype was associated with a survival benefit, whereas the occurrence of complications was associated with worse OS. Multimodality therapy including surgery significantly prolonged the OS of MPM patients compared with multimodal therapy without surgery.
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- 2022
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33. Impact of Brain Metastases on Treatment Patterns and Outcomes With First-Line Durvalumab Plus Platinum-Etoposide in Extensive-Stage SCLC (CASPIAN): A Brief Report.
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Chen Y, Paz-Ares L, Reinmuth N, Garassino MC, Statsenko G, Hochmair MJ, Özgüroğlu M, Verderame F, Havel L, Losonczy G, Conev NV, Hotta K, Ji JH, Spencer S, Dalvi T, Jiang H, and Goldman JW
- Abstract
Introduction: In the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone ( p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases., Methods: Patients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of durvalumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophylactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020., Results: At baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radiotherapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44-1.41) or without (0.76, 0.62-0.92) brain metastases, with similar PFS results (0.73, 0.42-1.29 and 0.80, 0.66-0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophylactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%)., Conclusions: The OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use., (© 2022 The Authors.)
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34. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN.
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Paz-Ares L, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Musso E, Havel L, Bondarenko I, Losonczy G, Conev N, Mann H, Dalvi TB, Jiang H, and Goldman JW
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- Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Etoposide therapeutic use, Humans, Platinum therapeutic use, Lung Neoplasms drug therapy, Small Cell Lung Carcinoma drug therapy
- Abstract
Background: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years., Patients and Methods: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP., Results: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off., Conclusions: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC., Competing Interests: Disclosure LPA reports receiving grants from AstraZeneca, Bristol-Myers Squibb, MSD, and Pfizer; consulting fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Ipsen, Lilly, Merck, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Servier; and honoraria from AstraZeneca, Janssen, Merck, Mirati, and Sanofi, and reports a leadership role with Genomica and Altum Sequencing, all outside the submitted work. YC reports receiving honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Guardant Health, Jazz Pharmaceutical, Merck, Pfizer, and Takeda; and a research contract and support for meeting attendance/travel from Ipsen, all outside the submitted work. NR reports receiving honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Hoffmann-La Roche, Lilly, Merck, MSD, Pfizer, and Takeda; and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Hoffmann-La Roche, Merck, MSD, Pfizer, and Takeda, all outside the submitted work. KH reports receiving grants and personal fees from AstraZeneca during the conduct of the study; grants from Bristol-Myers Squibb, Chugai, Lilly, and MSD outside the submitted work; and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, MSD, Nippon Kayaku, Ono, Pfizer, Taiho, and Takeda outside the submitted work. MJH reports receiving speakers’ honoraria from AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, Roche, and Takeda outside the submitted work. MCG reports receiving grants from AstraZeneca and Merck, and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Takeda, all outside the submitted work. EM reports receiving grants from AstraZeneca during the conduct of the study and grants from Roche outside the submitted work. HM and TD report full-time employment and stock ownership with AstraZeneca. HJ reports full-time employment and stock ownership with AstraZeneca, and a patent pending for the CASPIAN study trial design. JWG reports receiving research grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, and Merck; consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, and Genentech; and support for travel from AstraZeneca all outside the submitted work. All other authors have declared no conflicts of interest. Data sharing Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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35. Nintedanib plus Docetaxel after Immune Checkpoint Inhibitor Failure in Patients with Advanced Non-Small-Cell Lung Cancer: A Case Series.
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Hochmair MJ, Kolb R, Wurm R, Zach H, and Bittner N
- Abstract
Advances in the treatment of non-small-cell lung cancers (NSCLCs) lacking an actionable driver mutation have included the approval of immunotherapies, such as monotherapy or in combination with chemotherapy. However, limited evidence exists to guide clinical decision-making after progression with immunotherapy. The vascular endothelial growth factor (VEGF) signaling pathway promotes tumor angiogenesis and the development of an immunosuppressive tumor microenvironment (TME). Anti-VEGF treatment is postulated to favor an immunosupportive TME through an "angio-immunogenic switch." Nintedanib, an anti-VEGF receptor treatment, is approved in the EU and other countries, in combination with docetaxel for the treatment of locally advanced, metastatic, or locally recurrent adenocarcinoma NSCLC after failure of first-line chemotherapy. We present a case series from 5 patients treated with nintedanib plus docetaxel, after chemotherapy and immunotherapy, during routine clinical practice in Austria and Hungary. Four patients were treated with nintedanib plus docetaxel as a second- or third-line treatment after chemotherapy and immunotherapy, and a fifth patient received immunotherapy before and after nintedanib plus docetaxel. Although these patients would typically have a poor prognosis, each achieved a partial response with nintedanib plus docetaxel, with response duration from 8 months to over 30 months. Adverse events were manageable. The fifth patient case shows that nintedanib does not preclude later-line immunotherapy or chemotherapy, supporting the angio-immunogenic switch hypothesis. Overall, the case studies indicate that nintedanib plus docetaxel is an effective and well tolerated treatment, after sequential or combined chemo-immunotherapy for advanced NSCLC, and is compatible with a rechallenge with immunotherapy., Competing Interests: M.J.H. received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. R.K. received speaker fees/honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Roche. N.B. received consultancy fees/honoraria from Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Roche, and Takeda. H.Z. is an employee of Boehringer Ingelheim. R.W. has no conflicts of interest., (Copyright © 2022 by S. Karger AG, Basel.)
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- 2022
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36. Influence of temporal muscle thickness on the outcome of radiosurgically treated patients with brain metastases from non-small cell lung cancer.
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Cho A, Hennenberg J, Untersteiner H, Hirschmann D, Gatterbauer B, Zöchbauer-Müller S, Hochmair MJ, Preusser M, Rössler K, Dorfer C, Frischer JM, and Furtner J
- Abstract
Objective: The purpose of this study was to assess the impact of temporal muscle thickness (TMT), a surrogate marker for sarcopenia, in radiosurgically treated patients with brain metastases (BMs) from non-small cell lung cancer (NSCLC)., Methods: For 566 patients with BMs from NSCLC in the period between June 2012 and December 2019, TMT values were retrospectively measured on the planning brain magnetic resonance imaging (MRI) studies that had been obtained before their first Gamma Knife radiosurgery treatment (GKRS1). Predefined sex-specific TMT cutoff values were used to stratify the study cohort into patients at risk for sarcopenia and patients with normal muscle status. Cox regression models adjusted for other prognostic parameters were used to evaluate sarcopenia as an independent prognostic factor., Results: In sarcopenia patients with a TMT below the sex-specific cutoff values, the risk of death was significantly increased (HR 1.908, 95% CI 1.550-2.349, p < 0.001). In addition, sarcopenia was revealed as an independent prognostic factor even after adjusting for age groups, sex, number of BMs, presence of extracranial metastases, NSCLC subtypes, Karnofsky Performance Status groups, recursive partitioning analysis classes, and concomitant immunotherapy or targeted therapy (HR 1.680, 95% CI 1.347-2.095, p < 0.001). However, patients at risk for sarcopenia showed no significant differences in the estimated mean time until local BM progression after GKRS1, compared to patients with normal muscle status (p = 0.639)., Conclusions: TMT obtained from planning MRI studies is an independent prognostic marker in radiosurgically treated patients with BMs from NSCLC and may aid patient stratification in future clinical trials.
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- 2022
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37. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial.
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Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, Garcia Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira AI, Gettinger SN, Tiseo M, Lin HM, Liu Y, Vranceanu F, Niu H, Zhang P, and Popat S
- Subjects
- Anaplastic Lymphoma Kinase genetics, Crizotinib therapeutic use, Humans, Organophosphorus Compounds, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Introduction: In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor-naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results., Methods: Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee-assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy., Results: A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35-0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53-1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21-0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed., Conclusions: In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2021
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38. Sequential afatinib and osimertinib in patients with EGFR mutation-positive NSCLC and acquired T790M: A global non-interventional study (UpSwinG).
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Popat S, Jung HA, Lee SY, Hochmair MJ, Lee SH, Escriu C, Lee MK, Migliorino MR, Lee YC, Girard N, Daoud H, Märten A, and Miura S
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- Acrylamides, Afatinib therapeutic use, Aniline Compounds, ErbB Receptors genetics, Female, Humans, Middle Aged, Mutation, Protein Kinase Inhibitors therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance., Methods: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR)., Results: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups., Conclusion: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2021
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39. Rare case of chemotherapy-refractory metastatic vaginal squamous cell carcinoma with complete response to concurrent pembrolizumab and radiotherapy- case report and literature review.
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Ansari J, Eltigani Mohmmed Y, Ghazal-Aswad S, Ansari H, Akhter SMJ, Hassoun Hadid O, Rizwan S, Almazrouei R, Dawoud E, Azribi F, Elhasin H, Kumar P, Al Sumaida AR, Al-Qawasmeh K, Glaholm J, Hochmair MJ, Hussain S, and Balaraj K
- Abstract
Primary vaginal cancer is a rare malignancy with a lack of international guidelines and supporting clinical trial evidence to guide decision making. Historical results have shown poor outcomes with chemotherapy for stage IVB vaginal squamous cell carcinoma (SCC). The evolving role of checkpoint inhibitors in rare gynaecological cancers prompted us to investigate the role of pembrolizumab in this setting. The efficacy of pembrolizumab in vaginal SCC has never been investigated in any clinical trial. There is established data to support the use of concurrent chemoradiotherapy in gynaecological cancers, however, the data for concurrent use of immunotherapy and radiotherapy is still lacking but is the subject of several clinical trials. We herein present the first reported case of chemotherapy refractory vaginal SCC with complete response to pembrolizumab and concurrent pelvic radiotherapy. We also present wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) as a rare but new immune related adverse event., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)
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- 2021
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40. Plain language summary of the final results from the GioTag study.
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Hochmair MJ
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- Aniline Compounds, ErbB Receptors genetics, Humans, Language, Mutation, Protein Kinase Inhibitors, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
The GioTag study assessed how drugs called afatinib and osimertinib affected people with non-small cell lung cancer (NSCLC) who had mutations in the epidermal growth factor receptor ( EGFR ) gene. Resistance mutations in our genes can lead to resistance to specific treatments, meaning that drugs no longer work. Patients in the current study all initially received afatinib treatment before they developed a certain resistance mutation in the EGFR gene, called T790M. Patients then started osimertinib treatment. The study aimed to identify for how long patients received treatment and for how long patients survived after their first dose of afatinib. Overall, 204 patients were included. Median overall time on treatment (afatinib and osimertinib) was 27.7 months. Median overall survival was 37.6 months. This study showed that afatinib followed by osimertinib treatment was effective in patients with NSCLC with EGFR mutations developing T790M resistance mutations on initial afatinib treatment. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF.
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- 2021
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41. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.
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Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, and Garassino MC
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- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Pemetrexed therapeutic use, Platinum therapeutic use, Randomized Controlled Trials as Topic, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab., Patients and Methods: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m
2 ) and investigators' choice of cisplatin (75 mg/m2 ) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS., Results: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off., Conclusions: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC., Competing Interests: Disclosure DR-A: Honoraria for lectures and consulting from BMS, MSD, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Roche, Novartis, and Pfizer. Study funding to institution from MSD. SFP: Study funding to institution from Bristol-Myers Squibb, Genentech, Incyte, Merck Sharp & Dohme, Pfizer, Novartis, Seattle Genetics, Actuate, and Vyriad. Consulting support to the institution from Bristol-Myers Squibb. MJH: Study funding to institution from MSD. SG: Received personal fees from Merck, AstraZeneca, Genentech/Roche, Takeda/Ariad, Boehringer Ingelheim, Novocure, Bristol-Myers Squibb, AbbVie, Xcovery, Janssen, Pfizer, and Jazz Pharmaceuticals. Study funding to institution from MSD. Research funding from Merck. EE: Study funding to institution from MSD. EF: Received personal fees as an advisor, consultant, and/or speaker from AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime, BerGenBio, and Samsung; and is an independent member of the Board for Grífols. Study funding to institution from MSD. GS: Study funding to institution from MSD. FdA: Study funding to institution from MSD. MD: Received personal fees as an advisor and/or lecturer from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Pfizer, and Roche. Study funding to institution from MSD. SYC: Study funding to institution from MSD. HGB: Study funding to institution from MSD. NP: Received grants, personal fees, and/or honoraria as an advisor from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, NovellusDx, Foundation Medicine, and Guardant360. Study funding to institution from MSD. MR: Received personal fees/honoraria for consultancy and lectures from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck, MSD, Eli Lilly, Pfizer, AbbVie, Roche, and Novartis. Study funding to institution from MSD. RH: Received personal fees for advisory boards from MSD, AstraZeneca, BMS, Eli Lilly, Merck, Novartis, Oncosec, Pfizer, Roche, and Seagen; and speaker honoraria from MSD, Novartis, and Roche. Study funding to institution from MSD. EBG: Received grants and research support to the institution during the conduct of this study from Merck; has received grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Novartis, Dynavax, Mirati Therapeutics, and Iovance Biotherapeutics; and payment for advisory boards/steering committees from Dracen Pharmaceuticals, EMD Serono, and Novartis. Study funding to institution from MSD. MB: Received grants and non-financial support from Merck Sharp & Dohme during the conduct of this study; has received grants and non-financial support from AstraZeneca and Genentech/Roche; and grants from Bristol-Myers Squibb, Amgen, Pfizer, and Novartis. Study funding to institution from MSD. TK: Received lecture fees, honoraria, or other fees from MSD, Ono, Bristol-Myers Squibb, AstraZeneca, Chugai, Eli Lilly, Boehringer Ingelheim; and research funds from MSD, AstraZeneca, Takeda, Bristol-Myers Squibb, and Novartis. Study funding to institution from MSD. JY: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MCP: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FS: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MCG: Received grants and personal fees during the conduct of this study from MSD; has received grants and personal fees for clinical trials from AstraZeneca, Novartis, Bristol-Myers Squibb, Roche, Pfizer, Celgene, Bayer, and MSD; grants from Tiziana Life Sciences, Clovis, Merck Serono, GlaxoSmithKline, and Spectrum Pharmaceuticals; and personal fees from Eli Lilly, Boehringer Ingelheim, Otsuka Pharmaceutical Co., Ltd., Incyte, Inivata, Takeda, and Sanofi-Aventis. Study funding to institution from MSD., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)- Published
- 2021
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42. Neutrophil-to-Lymphocyte Ratio Is Superior to Other Leukocyte-Based Ratios as a Prognostic Predictor in Non-Small Cell Lung Cancer Patients with Radiosurgically Treated Brain Metastases Under Immunotherapy or Targeted Therapy.
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Cho A, Kranawetter B, Untersteiner H, Khalaveh F, Dorfer C, Rössler K, Zöchbauer-Müller S, Gatterbauer B, Hochmair MJ, and Frischer JM
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms mortality, Brain Neoplasms radiotherapy, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung radiotherapy, Carcinoma, Non-Small-Cell Lung secondary, Female, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Lung Neoplasms radiotherapy, Male, Middle Aged, Prognosis, Radiosurgery, Retrospective Studies, Survival Rate, Brain Neoplasms blood, Carcinoma, Non-Small-Cell Lung blood, Lung Neoplasms blood, Lymphocytes, Neutrophils
- Abstract
Objective: To investigate predictive value of preradiosurgery leukocyte-based prognostic ratios in a selected cohort of non-small cell lung cancer (NSCLC) patients with radiosurgery-treated brain metastases (BM) and concomitant immunotherapy (IT) or targeted therapy (TT)., Methods: We performed a retrospective analysis of 166 patients with NSCLC BM treated with Gamma Knife radiosurgery. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio were assessed within 14 days before radiosurgery., Results: In radiosurgically treated patients with NSCLC BM with concomitant IT or TT, estimated median survival after first Gamma Knife radiosurgery treatment was significantly longer in patients with NLR cutoff value <5 (P = 0.038). Consequently, the Cox regression model for NLR cutoff value groups revealed a significant hazard ratio of 1.519 (95% confidence interval 1.020-2.265, P = 0.040). In addition, each increase in NLR of 1 equaled an increase of 5.4% in risk of death (hazard ratio 1.054, 95% confidence interval 1.024-1.085, P < 0.001). After adjusting for sex, age, Karnofsky performance scale, and presence of extracranial metastases, NLR remained a significant and independent predictor for survival (hazard ratio 1.047, 95% confidence interval 1.017-1.078, P = 0.002). In contrast, platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio did not exhibit the same predictive value among patients with radiosurgery-treated BM with concomitant IT or TT., Conclusions: In patients with NSCLC BM treated with radiosurgery with concomitant IT or TT, preradiosurgery NLR represents a simple prognostic predictor for survival and is superior to other leukocyte-based ratios. NLR may be relevant for clinical decision making, therapeutic evaluation, patient counseling, and appropriate stratification of future clinical trials among patients with radiosurgery-treated BM., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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43. Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program.
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Illini O, Hochmair MJ, Fabikan H, Weinlinger C, Tufman A, Swalduz A, Lamberg K, Hashemi SMS, Huemer F, Vikström A, Wermke M, Absenger G, Addeo A, Banerji S, Calles A, Clarke S, Di Maio M, Durand A, Duruisseaux M, Itchins M, Kääränien OS, Krenn F, Laack E, de Langen AJ, Mohorcic K, Pall G, Passaro A, Prager G, Rittmeyer A, Rothenstein J, Schumacher M, Wöll E, and Valipour A
- Abstract
Introduction: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown., Methods: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021., Results: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases ( n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death., Conclusions: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated., Competing Interests: Conflict of interest statement: Oliver Illini, Received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Menarini, Merck Sharp & Dohme, Pfizer, and Roche. Maximilian Johannes Hochmair, Honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Hannah Fabikan, Speaker fee from Roche. Christoph Weinlinger, No conflict of interest. Amanda Tufman, Advisory Boards: Lilly, Pfizer, MSD, BMS, GSK, Celgene, Roche, Takeda, Boehringer Ingelheim, Amgen, AstraZeneca. Projects financed by AstraZeneca und Takeda. Aurélie Swalduz, Roche, Bristol-Myers Squibb, Takeda, Lilly, Pfizer, AstraZeneca, Boehringer-Ingelheim. Kristina Lamberg, Advisory boards: MSD and AstraZeneca. Sayed M.S. Hashemi, Advisory board/research grants: Abbvie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, GSK, MSD, Novartis, Roche, Takeda, Xcovery. Florian Huemer, Advisory Boards and Honoraria: MSD, BMS, Roche, Sanofi, Lilly, Takeda, Astra Zeneca, Boehringer Ingelheim. Anders Vikström, Ad-boards: AstraZeneca, Abbvie, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda. Lectures: AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche, Takeda. Grants: Boehringer-Ingelheim Consultancies: Astra Zeneca, Boehringer-Ingelheim, Roche. Martin Wermke, Received speaker fees and/or honoraria for advisory boards from BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, Astra Zeneca, Heidelberg Pharma. Gudrun Absenger, Honoraria from: AMGEN, AstraZeneca, BMS, Böhringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Alfredo Addeo, Personal fees from Bristol-Myers Squibb, AstraZeneca, Roche, Pfizer, Merck Sharp and Dohme, and Boehringer-Ingelheim for work performed outside of the current study. Shantanu Banerji, Honoraria for advisory board: AstraZeneca, Bayer, BMS, EMD-Serono, Merck, Novartis, Pfizer, Roche, Takeda Speaker Fees: None Research Funds: AstraZeneca. Antonio Calles, Honoraria/consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Takeda, Novartis, Merck Sharp & Dohme, and Bristol-Myers Squibb; Research grants from MSD and PharmaMar. Stephen Clarke, Advisory board and speaking remuneration from AstraZeneca. Massimo Di Maio, Honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro – GlaxoSmithKline. Alice Durand, No conflict of interest. Michaël Duruisseaux, Membership of an advisory council or committee for Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Merus, Amgen and Pfizer; consulting fees from Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, and Pfizer; research grants from Takeda, NanoString, and Blueprint. Malinda Itchins, AdBoard: Pfizer, Takeda. Consultancy: Roche, Merck. Honoraria: AZ, Pfizer, takeda, Roche, Novartis. Academic travel support: Roche, MSD. Okko-Sakari Kääränien, No conflict of interest associated with this study. Florian Krenn, Advisory Boards: Roche, MSD. Eckart Laack, Honoraria for advisory boards: AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda, MSD, Novartis, Lilly. Speaker fees. AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda, MSD, Novartis, Lilly. Research grants and clinical study: AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda, MSD, Novartis, Lilly. Adrianus Johannes de Langen, Research grants: BMS, MSD, AstraZeneca, Boehringer, Merus Non-financial support: Merck, Roche Advisory boards: Lilly, Bayer, MSD, AstraZeneca. Katja Mohorcic, Honoraria for ad-boards and speaker from MSD, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, BMS, Abbvie. Georg Pall, Speakers honoraria and advisory board-member: Eli Lilly, Roche. Antonio Passaro, Honoraria for consulting, advisory role or lectures from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer and Roche Genentech. Gerald Prager, Advisory Board Meetings/Symposiums: Merck, Roche, Amgen, Sanofi, Lilly, Servier, Taiho, Bayer, BMS, MSD, Celgene, Pierre Fabre, Terumo. Achim Rittmeyer, Grants as an advisor or speaker: AbbVie, Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer and Roche. Jeffrey Rothenstein, Advisory Boards: Amgen, AZ, BMS, Merck, Pfizer, Roche. Michael Schumacher, Consulting, speakers fee, advisory panel membership, travel grants: AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda, Roche, Amgen, Eli Lilly, MSD, BMS, Novartis. Ewald Wöll, Advisory boards or speaker fees: Amgen, Astra Zeneca, BMS, Celgen, Ebewe, Eli Lilly, Eisai, Janssen Cilag, Merck, MSD, Pierre Fabre, Pfizer, Ratiopharm, Roche, Sanofi Aventis. Arschang Valipour, Personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Merck, Novartis, and Roche for lectures and/or advisory boards outside of the submitted study., (© The Author(s), 2021.)
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- 2021
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44. Somatic Copy-Number Alterations in Plasma Circulating Tumor DNA from Advanced EGFR-Mutated Lung Adenocarcinoma Patients.
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Buder A, Heitzer E, Waldispühl-Geigl J, Weber S, Moser T, Hochmair MJ, Hackner K, Errhalt P, Setinek U, and Filipits M
- Subjects
- Acrylamides therapeutic use, Adenocarcinoma pathology, Adenocarcinoma of Lung metabolism, Adenocarcinoma of Lung pathology, Aged, Aged, 80 and over, Aniline Compounds therapeutic use, Biomarkers, Pharmacological blood, Carcinoma, Non-Small-Cell Lung pathology, Cell-Free Nucleic Acids blood, Cell-Free Nucleic Acids genetics, DNA Copy Number Variations genetics, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Humans, Liquid Biopsy methods, Lung pathology, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Progression-Free Survival, Protein Kinase Inhibitors therapeutic use, Adenocarcinoma of Lung genetics, Circulating Tumor DNA genetics
- Abstract
Background: To assess the clinical relevance of genome-wide somatic copy-number alterations (SCNAs) in plasma circulating tumor DNA (ctDNA) from advanced epidermal growth factor receptor ( EGFR )-mutated lung adenocarcinoma patients., Methods: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR., Results: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 31 (32%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before the initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 81%, p = 0.08) and was an independent predictor for shorter progression-free survival (adjusted HR 3.33, 95% CI 1.37-8.10, p = 0.008) and overall survival (adjusted HR 2.54, 95% CI 1.09-5.92, p = 0.03)., Conclusions: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach enables the comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.
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- 2021
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45. Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients.
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Hackner K, Buder A, Hochmair MJ, Strieder M, Grech C, Fabikan H, Burghuber OC, Errhalt P, and Filipits M
- Abstract
Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR -mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations., Methods: Twenty-eight patients with advanced EGFR -mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR)., Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80., Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone., Competing Interests: Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.H. has received honoraria from AstraZeneca and Roche. A.B. has received honoraria from AstraZeneca. M.J.H. has received honoraria from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche and had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, and Roche. O.C.B. has received honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Roche, and Takeda. P.E. has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Menarini, Merck Sharp & Dohme, Novartis, and Roche and had consulting or advisory roles with Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. M.F. has received honoraria from AstraZeneca, Bayer, Biomedica, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Myriad Genetics Inc, Pfizer, and Roche. H.F., C.G., and M.S. declare that they have no conflicts of interest that might be relevant to the contents of this article., (© The Author(s) 2021.)
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- 2021
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46. Alectinib following brigatinib: an efficient sequence for the treatment of advanced anaplastic lymphoma kinase-positive lung cancer patients.
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Hochmair MJ, Prosch H, Krenbek D, Weinlinger C, Fabikan H, and Valipour A
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- Adult, Carbazoles administration & dosage, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Middle Aged, Organophosphorus Compounds administration & dosage, Piperidines administration & dosage, Prognosis, Pyrimidines administration & dosage, Anaplastic Lymphoma Kinase metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Anaplastic lymphoma kinase (ALK)-translocations are present in up to 5% of non-small cell lung cancer (NSCLC), most of them being adenocarcinomas. Even though the availability of five potent ALK-inhibitors for the treatment of ALK-positive NSCLC patients, there is no consensus about the ideal therapy sequence. Alectinib has been so far successfully and routinely used as first-line therapy, especially in patients presenting central nervous system lesions; however, with the very recent European approval of brigatinib in the first line, a new treatment option is now available for ALK+ patient collective. In this case series, efficient systemic and intracranial responses to alectinib late-line treatment following brigatinib therapy are reported. This therapeutic sequence is going to gain therefore more importance in a near future., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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47. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.
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Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Każarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Thiyagarajah P, Jiang H, and Paz-Ares L
- Subjects
- Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carboplatin adverse effects, Cisplatin adverse effects, Disease Progression, Etoposide adverse effects, Female, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Progression-Free Survival, Small Cell Lung Carcinoma mortality, Small Cell Lung Carcinoma pathology, Time Factors, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin administration & dosage, Cisplatin administration & dosage, Etoposide administration & dosage, Lung Neoplasms drug therapy, Small Cell Lung Carcinoma drug therapy
- Abstract
Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone., Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m
2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872., Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each])., Interpretation: First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC., Funding: AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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48. The Allele Frequency of EGFR Mutations Predicts Survival in Advanced EGFR T790M-Positive Non-small Cell Lung Cancer Patients Treated with Osimertinib.
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Buder A, Hochmair MJ, and Filipits M
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- Acrylamides pharmacology, Adult, Aged, Aged, 80 and over, Aniline Compounds pharmacology, Carcinoma, Non-Small-Cell Lung mortality, ErbB Receptors metabolism, Female, Genotype, Humans, Lung Neoplasms mortality, Male, Middle Aged, Mutation, Protein Kinase Inhibitors pharmacology, Survival Analysis, Acrylamides therapeutic use, Aniline Compounds therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Gene Frequency genetics, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Background: The allele frequency of epidermal growth factor receptor (EGFR) mutations could be a potential molecular biomarker for the outcome of osimertinib therapy., Objective: The purpose of our study was to assess the clinical relevance of the allele frequency of EGFR mutations in plasma-based circulating tumor DNA (ctDNA) before starting osimertinib therapy in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who had progressed under treatment with EGFR tyrosine kinase inhibitors (TKIs)., Patients and Methods: We enrolled 141 patients with advanced EGFR T790M-positive NSCLC who underwent second-line osimertinib treatment. Plasma ctDNA was tested for EGFR-activating mutations (EGFR deletions in exon 19, L858R, L861Q, S768I) and T790M by means of droplet digital polymerase chain reaction (ddPCR)., Results: The allele frequency of EGFR-activating mutations in plasma ctDNA before osimertinib initiation ranged from 0 to 81,543 copies/ml and was independently associated with progression-free survival (PFS) and overall survival (OS) after adjusting for known clinicopathological risk factors (PFS: adjusted hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.15-1.39, P < 0.0001; OS: adjusted HR 1.32, 95% CI 1.18-1.47, P < 0.0001). The allele frequency of T790M in plasma ctDNA before starting osimertinib therapy ranged from 0 to 38,092 copies/ml. Multivariate analyses showed that a higher T790M allele frequency was associated with a trend towards a shorter PFS (adjusted HR 1.19, 95% CI 0.99-1.42, P = 0.05) and a significantly shorter OS (adjusted HR 1.25, 95% CI 1.02-1.53, P = 0.03) of the patients., Conclusion: A higher allele frequency of EGFR mutations, particularly EGFR-activating mutations, in plasma ctDNA is a poor prognostic marker. Further studies on the clinical utility of liquid biopsy are needed.
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- 2021
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49. Pre-radiosurgery leucocyte ratios and modified glasgow prognostic score predict survival in non-small cell lung cancer brain metastases patients.
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Cho A, Untersteiner H, Hirschmann D, Fitschek F, Dorfer C, Rössler K, Zöchbauer-Müller S, Gatterbauer B, Hochmair MJ, and Frischer JM
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms secondary, Brain Neoplasms surgery, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Female, Follow-Up Studies, Humans, Lung Neoplasms pathology, Lung Neoplasms surgery, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Blood Platelets pathology, Brain Neoplasms mortality, Carcinoma, Non-Small-Cell Lung mortality, Lung Neoplasms mortality, Lymphocytes pathology, Neutrophils pathology, Radiosurgery mortality
- Abstract
Introduction: The predictive value of the pre-radiosurgery Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR) and the modified Glasgow Prognostic Score (mGPS) was assessed for the first time in a homogenous group of NSCLC brain metastaes (BM) patients., Methods: We retrospectively evaluated 185 NSCLC-BM patients, who were treated with Gamma Knife Radiosurgery (GKRS). Patients with immunotherapy or targeted therapy were excluded. Routine laboratory parameters were reviewed within 14 days before GKRS1., Results: Median survival after GKRS1 was significantly longer in patients with NLR < 5 (p < 0.001), PLR < 180 (p = 0.003) and LMR ≥ 4 (p = 0.023). The Cox regression model for the continuous metric values revealed that each increase in the NLR of 1 equaled an increase of 4.3% in risk of death (HR: 1.043; 95%CI = 1.020-1.067, p < 0.001); each increase in the PLR of 10 caused an increase of 1.3% in risk of death (HR: 1.013; 95%CI = 1.004-1.021; p = 0.003) and each increase in the LMR of 1 equaled a decrease of 20.5% in risk of death (HR: 0.795; 95%CI = 0.697-0.907; p = 0.001). Moreover, the mGPS group was a highly significant predictor for survival after GKRS1 (p < 0.001) with a HR of 2.501 (95%CI = 1.582-3.954; p < 0.001). NLR, PLR, LMR values and mGPS groups were validated as independent prognostic factors for risk of death after adjusting for sex, KPS, age and presence of extracranial metastases., Conclusion: NLR, PLR, LMR and mGPS represent effective and simple tools to predict survival in NSCLC patients prior to radiosurgery for brain metastases.
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- 2021
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50. Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy.
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Cho A, Untersteiner H, Hirschmann D, Shaltout A, Göbl P, Dorfer C, Rössler K, Marik W, Kirchbacher K, Kapfhammer I, Zöchbauer-Müller S, Gatterbauer B, Hochmair MJ, and Frischer JM
- Abstract
The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3-11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT ( p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.
- Published
- 2020
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