30 results on '"Iveta Kudaba"'
Search Results
2. Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial
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Zsolt Markóczy, Veronika Sárosi, Iveta Kudaba, Gabriella Gálffy, Ülkü Yilmaz Turay, Ahmet Demirkazik, Gunta Purkalne, Attila Somfay, Zsolt Pápai-Székely, Erzsébet Rásó, and Gyula Ostoros
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Non-small cell lung cancer ,Lung adenocarcinoma ,EGFR ,Erlotinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection. Methods 651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS). Results 62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9–15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation. Conclusions Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure. Trial registration ClinicalTrials.gov Identifier: NCT01609543.
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- 2018
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3. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non–Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study
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Gilberto de Castro, Iveta Kudaba, Yi-Long Wu, Gilberto Lopes, Dariusz M. Kowalski, Hande Z. Turna, Christian Caglevic, Li Zhang, Boguslawa Karaszewska, Konstantin K. Laktionov, Vichien Srimuninnimit, Igor Bondarenko, Kaoru Kubota, Rinee Mukherjee, Jianxin Lin, Fabricio Souza, Tony S.K. Mok, and Byoung Chul Cho
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Cancer Research ,Oncology - Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically 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 report 5-year results from the phase III KEYNOTE-042 study (ClinicalTrials.gov identifier: NCT02220894 ). Eligible patients with locally advanced/metastatic non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations and with programmed death ligand-1 (PD-L1) tumor proportion score (TPS) ≥ 1% received pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin + paclitaxel or pemetrexed) for 4-6 cycles with optional maintenance pemetrexed. Primary end points were overall survival (OS) in PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups. Patients who completed 35 cycles of pembrolizumab with ≥ stable disease could begin second-course pembrolizumab upon progression. One thousand two hundred seventy‐four patients were randomly assigned (pembrolizumab, n = 637; chemotherapy, n = 637). Median follow-up time was 61.1 (range, 50.0-76.3) months. OS outcomes favored pembrolizumab ( v chemotherapy) regardless of PD-L1 TPS (hazard ratio [95% CI] for TPS ≥ 50%, 0.68 [0.57 to 0.81]; TPS ≥ 20%, 0.75 [0.64 to 0.87]; TPS ≥ 1%, 0.79 [0.70 to 0.89]), with estimated 5-year OS rates with pembrolizumab of 21.9%, 19.4%, and 16.6%, respectively. No new toxicities were identified. Objective response rate was 84.3% among 102 patients who completed 35 cycles of pembrolizumab and 15.2% among 33 patients who received second-course pembrolizumab. First-line pembrolizumab monotherapy continued to show durable clinical benefit versus chemotherapy after 5 years of follow-up in PD-L1–positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations and remains a standard of care.
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- 2023
4. Data from Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
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Lucjan Wyrwicz, Kohei Shitara, Josep Tabernero, Sukrut Shah, Pooja Bhagia, Razvan Cristescu, Julie Kobie, Deepti Aurora-Garg, Z. Alexander Cao, Zev A. Wainberg, Joseph Chao, Hugo R. Castro, Jeeyun Lee, Hyun Cheol Chung, Marcelo Garrido, Iveta Kudaba, Charles S. Fuchs, Yung-Jue Bang, Eric Van Cutsem, and Keun-Wook Lee
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Purpose:This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062.Patients and Methods:In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb.Results:TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non–MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated.Conclusions:This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.
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- 2023
5. Supplementary Figure from Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
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Lucjan Wyrwicz, Kohei Shitara, Josep Tabernero, Sukrut Shah, Pooja Bhagia, Razvan Cristescu, Julie Kobie, Deepti Aurora-Garg, Z. Alexander Cao, Zev A. Wainberg, Joseph Chao, Hugo R. Castro, Jeeyun Lee, Hyun Cheol Chung, Marcelo Garrido, Iveta Kudaba, Charles S. Fuchs, Yung-Jue Bang, Eric Van Cutsem, and Keun-Wook Lee
- Abstract
Supplementary Figure from Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
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- 2023
6. Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer
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Manuel Dómine Gómez, Tibor Csőszi, Rajesh K. Malik, Krasimir Nikolov, Iveta Kudaba, Davorin Radosavljevic, Jana Jaal, Janet K. Horton, Jie Xiao, and Janakiraman Subramanian
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Placebo ,chemotherapy ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Myeloid Cells ,Pyrroles ,Prospective Studies ,myelopreservation ,Cancer Therapy and Prevention ,Etoposide ,Aged ,myelosuppression ,Chemotherapy ,Myelosuppressive Chemotherapy ,trilaciclib ,business.industry ,Middle Aged ,medicine.disease ,Prognosis ,Chemotherapy regimen ,Hematologic Diseases ,Small Cell Lung Carcinoma ,Pyrimidines ,Cytoprotection ,Toxicity ,Female ,small cell lung cancer ,business ,myeloprotection ,Febrile neutropenia ,medicine.drug ,Follow-Up Studies - Abstract
Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC, and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared with placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after week 5 were significantly reduced with trilaciclib versus placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared with placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC. This article is protected by copyright. All rights reserved.
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- 2021
7. Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
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Keun-Wook Lee, Eric Van Cutsem, Yung-Jue Bang, Charles S. Fuchs, Iveta Kudaba, Marcelo Garrido, Hyun Cheol Chung, Jeeyun Lee, Hugo R. Castro, Joseph Chao, Zev A. Wainberg, Z. Alexander Cao, Deepti Aurora-Garg, Julie Kobie, Razvan Cristescu, Pooja Bhagia, Sukrut Shah, Josep Tabernero, Kohei Shitara, and Lucjan Wyrwicz
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Cancer Research ,Oncology ,Esophageal Neoplasms ,Stomach Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Microsatellite Instability ,Adenocarcinoma ,Antibodies, Monoclonal, Humanized - Abstract
Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non–MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.
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- 2022
8. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048)
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Barbara Burtness, Kevin J Harrington, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G M Hughes, Ricard Mesía, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Ruey-Long Hong, René González Mendoza, Ananya Roy, Yayan Zhang, Burak Gumuscu, Jonathan D Cheng, Fan Jin, Danny Rischin, Guillermo Lerzo, Marcelo Tatangelo, Mirta Varela, Juan Jose Zarba, Michael Boyer, Hui Gan, Bo Gao, Brett Hughes, Girish Mallesara, Anne Taylor, Martin Burian, Carlos Henrique Barrios, Dalvaro Oliveira de Castro Junior, Gilberto Castro, Fabio Andre Franke, Gustavo Girotto, Iane Pinto Figueiredo Lima, Ulisses Ribaldo Nicolau, Gustavo Dix Junqueira Pinto, Lucas Santos, Ana-Paula Victorino, Neil Chua, Felix Couture, Richard Gregg, Aaron Hansen, John Hilton, Joy McCarthy, Denis Soulieres, Rodrigo Ascui, Pablo Gonzalez, Luis Villanueva, Marco Torregroza, Angela Zambrano, Petra Holeckova, Zdenek Kral, Bohuslav Melichar, Jana Prausova, Milan Vosmik, Maria Andersen, Niels Gyldenkerne, Hannes Jurgens, Kadri Putnik, Petri Reinikainen, Viktor Gruenwald, Simon Laban, Gerasimos Aravantinos, Ioannis Boukovinas, Vassilis Georgoulias, Dora Kwong, Yousuf Al-Farhat, Tibor Csoszi, Jozsef Erfan, Geza Horvai, Laszlo Landherr, Eva Remenar, Agnes Ruzsa, Judit Szota, Salem Billan, Iris Gluck, Orit Gutfeld, Aron Popovtzer, Marco Benasso, Simona Bui, Vittorio Ferrari, Lisa Licitra, Franco Nole, Takashi Fujii, Yasushi Fujimoto, Nobuhiro Hanai, Hiroki Hara, Koji Matsumoto, Kenji Mitsugi, Nobuya Monden, Masahiro Nakayama, Kenji Okami, Nobuhiko Oridate, Kiyoto Shiga, Yasushi Shimizu, Masashi Sugasawa, Masanobu Takahashi, Shunji Takahashi, Kaoru Tanaka, Tsutomu Ueda, Hironori Yamaguchi, Tomoko Yamazaki, Ryuji Yasumatsu, Tomoya Yokota, Tomokazu Yoshizaki, Iveta Kudaba, Zinaida Stara, Soon Keat Cheah, Jose Aguilar Ponce, Rene Gonzalez Mendoza, Carlos Hernandez Hernandez, Francisco Medina Soto, Jan Buter, Ann Hoeben, S. Oosting, Karijn Suijkerbuijk, Aase Bratland, Marianne Brydoey, Renzo Alvarez, Luis Mas, Priscilla Caguioa, John Querol, Eugenio Emmanuel Regala, Maria Belen Tamayo, Ellie May Villegas, Andrzej Kawecki, Andrey Karpenko, Arkadiy Klochikhin, Alexey Smolin, Oleg Zarubenkov, Boon Cher Goh, Graham Cohen, Johanna du Toit, Christa Jordaan, Gregory Landers, Paul Ruff, Waldemar Szpak, Neonyana Tabane, Irene Brana, Lara Iglesias Docampo, Javier Lavernia, Ricard Mesia, Edvard Abel, Valentina Muratidu, Niels Nielsen, Valerie Cristina, Sacha Rothschild, Hung-Ming Wang, Muh-Hwa Yang, Su-Peng Yeh, Chia-Jui Yen, Nopadol Soparattanapaisarn, Virote Sriuranpong, Sercan Aksoy, Irfan Cicin, Meltem Ekenel, Hakan Harputluoglu, Ozgur Ozyilkan, Kevin Harrington, Sanjiv Agarwala, Haythem Ali, Robert Alter, Daniel Anderson, Justine Bruce, Nicholas Campbell, Miguel Conde, John Deeken, William Edenfield, Lawrence Feldman, Elizabeth Gaughan, Basem Goueli, Balazs Halmos, Upendra Hegde, Brian Hunis, Robert Jotte, Anand Karnad, Saad Khan, Noel Laudi, Douglas Laux, Danko Martincic, Steven McCune, Dean McGaughey, Krzysztof Misiukiewicz, Deborah Mulford, Eric Nadler, Johannes Nunnink, James Ohr, Meaghan O'Malley, Brian Patson, Doru Paul, Elizabeta Popa, Steven Powell, Rebecca Redman, Vincent Rella, Chaio Rocha Lima, Abirami Sivapiragasam, Yungpo Su, Ammar Sukari, Stuart Wong, Emrullah Yilmaz, Jeffrey Yorio, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Oncology ,Male ,Humanized/therapeutic use ,Antimetabolites ,Cetuximab ,Phases of clinical research ,Pembrolizumab ,030204 cardiovascular system & hematology ,Antineoplastic/therapeutic use ,Cetuximab/therapeutic use ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Monoclonal ,Squamous Cell Carcinoma of Head and Neck/drug therapy ,030212 general & internal medicine ,Antineoplastic Agents, Immunological/therapeutic use ,education.field_of_study ,General Medicine ,Middle Aged ,Antimetabolites, Antineoplastic/therapeutic use ,Progression-Free Survival ,Antibodies, Monoclonal, Humanized/therapeutic use ,Head and Neck Neoplasms ,Female ,Fluorouracil ,medicine.drug ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Population ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Fluorouracil/therapeutic use ,Antibodies ,03 medical and health sciences ,Immunological/therapeutic use ,Internal medicine ,medicine ,Humans ,Progression-free survival ,education ,Aged ,Performance status ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Head and Neck Neoplasms/drug therapy ,medicine.disease ,Interim analysis ,Head and neck squamous-cell carcinoma ,Antineoplastic Combined Chemotherapy Protocols/therapeutic use ,business - Abstract
BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.
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- 2019
9. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial
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Tony S K Mok, Yi-Long Wu, Iveta Kudaba, Dariusz M Kowalski, Byoung Chul Cho, Hande Z Turna, Gilberto Castro, Vichien Srimuninnimit, Konstantin K Laktionov, Igor Bondarenko, Kaoru Kubota, Gregory M Lubiniecki, Jin Zhang, Debra Kush, Gilberto Lopes, Grigory Adamchuk, Myung-Ju Ahn, Aurelia Alexandru, Ozden Altundag, Anna Alyasova, Orest Andrusenko, Keisuke Aoe, Antonio Araujo, Osvaldo Aren, Oscar Arrieta Rodriguez, Touch Ativitavas, Oscar Avendano, Fernando Barata, Carlos Henrique Barrios, Carlos Beato, Per Bergstrom, Daniel Betticher, Larisa Bolotina, Michiel Botha, Sayeuri Buddu, Christian Caglevic, Andres Cardona, Hugo Castro, Filiz Cay Senler, Carlos Alexandre Sydow Cerny, Alvydas Cesas, Gee-Chen Chan, Jianhua Chang, Gongyan Chen, Xi Chen, Susanna Cheng, Ying Cheng, Nelly Cherciu, Chao-Hua Chiu, Saulius Cicenas, Daniel Ciurescu, Graham Cohen, Marcos Andre Costa, Pongwut Danchaivijitr, Flavia De Angelis, Sergio Jobim de Azevedo, Mircea Dediu, Tsvetan Deliverski, Pedro Rafael Martins De Marchi, Flor de The Bustamante Valles, Zhenyu Ding, Boyan Doganov, Lydia Dreosti, Ricardo Duarte, Regina Edusma-Dy, Sergey Emelyanov, Mustafa Erman, Yun Fan, Luis Fein, Jifeng Feng, David Fenton, Gustavo Fernandes, Carlos Ferreira, Fabio Andre Franke, Helano Freitas, Yasuhito Fujisaka, Hector Galindo, Christina Galvez, Doina Ganea, Nuno Gil, Gustavo Girotto, Erdem Goker, Tuncay Goksel, Gonzalo Gomez Aubin, Luis Gomez Wolff, Hakan Griph, Mahmut Gumus, Jacqueline Hall, Gregory Hart, Libor Havel, Jianxing He, Yong He, Carlos Hernandez Hernandez, Venceslau Hespanhol, Tomonori Hirashima, Chung Man James Ho, Atsushi Horiike, Yukio Hosomi, Katsuyuki Hotta, Mei Hou, Soon Hin How, Te-Chun Hsia, Yi Hu, Masao Ichiki, Fumio Imamura, Oleksandr Ivashchuk, Yasuo Iwamoto, Jana Jaal, Jacek Jassem, Christa Jordaan, Rosalyn Anne Juergens, Diego Kaen, Ewa Kalinka-Warzocha, Nina Karaseva, Boguslawa Karaszewska, Andrzej Kazarnowicz, Kazuo Kasahara, Nobuyuki Katakami, Terufumi Kato, Tomoya Kawaguchi, Joo Hang Kim, Kazuma Kishi, Vitezslav Kolek, Marchela Koleva, Petr Kolman, Leona Koubkova, Ruben Kowalyszyn, Dariusz Kowalski, Krassimir Koynov, Doran Ksienski, Takayasu Kurata, Gerli Kuusk, Lyudmila Kuzina, Ibolya Laczo, Guia Elena Imelda Ladrera, Konstantin Laktionov, Gregory Landers, Sergey Lazarev, Guillermo Lerzo, Krzysztof Lesniewski Kmak, Wei Li, Chong Kin Liam, Igor Lifirenko, Oleg Lipatov, Xiaoqing Liu, Zhe Liu, Sing Hung Lo, Valeria Lopes, Karla Lopez, Shun Lu, Gaston Martinengo, Luis Mas, Marina Matrosova, Rumyana Micheva, Zhasmina Milanova, Lucian Miron, Tony Mok, Matias Molina, Shuji Murakami, Yasuharu Nakahara, Tien Quang Nguyen, Takashi Nishimura, Adrian Ochsenbein, Tatsuo Ohira, Ronny Ohman, Choo Khoon Ong, Gyula Ostoros, Xuenong Ouyang, Elena Ovchinnikova, Ozgur Ozyilkan, Lubos Petruzelka, Xuan Dung Pham, Pablo Picon, Bela Piko, Artem Poltoratsky, Olga Ponomarova, Patrice Popelkova, Gunta Purkalne, Shukui Qin, Rodryg Ramlau, Bernardo Rappaport, Felipe Rey, Eduardo Richardet, Jaromir Roubec, Paul Ruff, Andrii Rusyn, Hideo Saka, Jorge Salas, Mario Sandoval, Lucas Santos, Toshiyuki Sawa, Kasan Seetalarom, Mesut Seker, Nobuhiko Seki, Freddy Seolwane, Lucinda Shepherd, Sergii Shevnya, Andrea Kazumi Shimada, Yaroslav Shparyk, Ivan Sinielnikov, Daniela Sirbu, Oren Smaletz, Joao Paulo Holanda Soares, Aumkhae Sookprasert, Giovanna Speranza, Virote Sriuranpong, Zinaida Stara, Wu-Chou Su, Shunichi Sugawara, Waldemar Szpak, Kazuhisa Takahashi, Nagio Takigawa, Hiroshi Tanaka, Jerry Tan Chun Bing, Qiyou Tang, Pavel Taranov, Hermes Tejada, Lye Mun Tho, Yoshitaro Torii, Dmytro Trukhyn, Maria Turdean, Hande Turna, Grygoriy Ursol, Jaroslav Vanasek, Mirta Varela, Marcela Vallejo, Luis Vera, Ana-Paula Victorino, Tomas Vlasek, Ihor Vynnychenko, Buhai Wang, Jie Wang, Kai Wang, Yilong Wu, Kazuhiko Yamada, Chih-Hsin Yang, Takuma Yokoyama, Toshihide Yokoyama, Hiroshige Yoshioka, Fulden Yumuk, Angela Zambrano, Juan Jose Zarba, Oleg Zarubenkov, Marius Zemaitis, Li Zhang, Xin Zhang, Jun Zhao, Caicun Zhou, Jianying Zhou, Qing Zhou, and Alfred Zippelius
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medicine.medical_specialty ,Chemotherapy ,education.field_of_study ,Performance status ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Population ,Phases of clinical research ,General Medicine ,Pembrolizumab ,030204 cardiovascular system & hematology ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Carcinoma ,030212 general & internal medicine ,business ,Lung cancer ,education - Abstract
Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.
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- 2019
10. Pembrolizumab with or without chemotherapy versus chemotherapy alone for patients with PD-L1–positive advanced gastric or gastroesophageal junction adenocarcinoma: Update from the phase 3 KEYNOTE-062 trial
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Zev A. Wainberg, Kohei Shitara, Eric Van Cutsem, Lucjan Wyrwicz, Keun Wook Lee, Iveta Kudaba, Marcelo Garrido, Hyun Cheol Cheol Chung, Jeeyun Lee, Hugo Raul Castro-Salguero, Wasat Mansoor, Maria Ignez Braghiroli, Nina Karaseva, Eray Goekkurt, Hironaga Satake, Joseph Chao, Uma Kher, Sukrut Shah, Pooja Bhagia, and Josep Tabernero
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stomatognathic diseases ,Cancer Research ,Oncology ,neoplasms - Abstract
243 Background: KEYNOTE-062 (NCT02494583) is a global phase 3 study of pembrolizumab (pembro) as monotherapy and in combination with chemotherapy (chemo) versus chemo as first-line therapy for PD-L1–positive (combined positive score [CPS] ≥1) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. At the time of the protocol-specified final analysis, pembro was noninferior to chemo, with fewer adverse events (AEs) observed. Pembro or pembro + chemo was not superior to chemo for the overall survival (OS) and progression-free survival (PFS) end points tested. We present the results of KEYNOTE-062 after ̃25 additional months of follow-up (cutoff: April 19, 2021). Methods: Patients with previously untreated gastric or GEJ cancer were randomly assigned 1:1:1 to pembro 200 mg Q3W, pembro + chemo (cisplatin 80 mg/m2/day on day 1 + 5-FU 800 mg/m2/day on days 1-5 Q3W [or capecitabine 1000 mg/m2 twice daily on days 1-14 Q3W per local guidelines]), or placebo Q3W + chemo. Primary end points were OS in the CPS ≥1 and CPS ≥10 populations for pembro + chemo versus chemo and pembro versus chemo and PFS (RECIST v1.1; central review) in the CPS ≥1 and CPS ≥10 populations for pembro + chemo versus chemo. Safety was also evaluated. Results: At the time of data cutoff, 689 of 763 patients (90.3%) had died. Median follow-up (defined as time from randomization to data cutoff) was 54.3 months (range, 46.8-66.1). Pembro was noninferior to chemo for OS in the CPS ≥1 population (median, 10.6 vs 11.1 months; HR, 0.90; 95% CI, 0.75-1.08) but had a clinically meaningful OS benefit in the CPS ≥10 population (median, 17.4 vs 10.8 months; HR, 0.62; 95% CI, 0.45-0.86). 24-month OS rates (pembro vs chemo) were 26.6% versus 18.8% in the CPS ≥1 population and 39.1% versus 21.1% in the CPS ≥10 population. Pembro + chemo was not superior to chemo for OS in the CPS ≥1 (median, 12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.71-1.02) or the CPS ≥10 (median, 12.3 vs 10.8 months; HR, 0.76; 95% CI, 0.56-1.03) population. 24-month OS rates (pembro + chemo vs chemo) were 24.5% versus 18.8% in the CPS ≥1 population and 28.3% versus 21.1% in the CPS ≥10 population. Pembro + chemo did not significantly prolong PFS versus chemo in the CPS ≥1 (median, 6.9 vs 6.5 months; HR, 0.84; 95% CI, 0.70-1.01) or the CPS ≥10 (median, 5.8 vs 6.2 months; HR, 0.71; 95% CI, 0.52-0.96) population. Grade 3-5 treatment-related AEs rates were 17.3% (pembro), 73.2% (pembro + chemo), and 69.3% (chemo). Conclusions: After ̃25 additional months of follow-up, efficacy and safety outcomes with first-line pembro or pembro + chemo versus chemo in patients with gastric or GEJ adenocarcinoma enrolled in KEYNOTE-062 were consistent with the final analysis data. Clinical trial information: NCT02494583.
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- 2022
11. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial
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Yili Pritchett, Jana Jaal, Davey B. Daniel, Iveta Kudaba, Vladimer Kuchava, Joyce M Antal, Oleksandr Ivashchuk, Lowell L. Hart, Jessica A. Sorrentino, Igor Bondarenko, Jerome H. Goldschmidt, Amiran Matitashvili, Sreekanth Reddy, and Shannon R. Morris
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Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Phases of clinical research ,Placebo ,chemotherapy ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Atezolizumab ,Internal medicine ,small cell lung cancer (SCLC) ,Medicine ,myelopreservation ,Adverse effect ,Cancer Therapy and Prevention ,Etoposide ,myelosuppression ,Chemotherapy ,trilaciclib ,business.industry ,Carboplatin ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Absolute neutrophil count ,business ,medicine.drug - Abstract
Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy‐induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double‐blind, placebo‐controlled Phase II study in patients with newly diagnosed extensive‐stage small cell lung cancer (ES‐SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count
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- 2020
12. 363 KEYNOTE-042 5-year survival update: pembrolizumab versus chemotherapy in patients with previously untreated, PD-L1–positive, locally advanced or metastatic non–small-cell lung cancer
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Rinee Mukherjee, Li Zhang, Hande Turna, Byoung Chul Cho, Jianxin Lin, Tony Sk Mok, Gilberto de Castro, Vichien Srimuninnimit, Fabricio Souza, Iveta Kudaba, Boguslawa Karaszewska, Dariusz M. Kowalski, Gilberto Lopes, Igor Bondarenko, Konstantin Laktionov, Kaoru Kubota, Christian Caglevic, and Yi-Long Wu
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Oncology ,Cancer Research ,medicine.medical_specialty ,Randomization ,medicine.medical_treatment ,Immunology ,Locally advanced ,Pembrolizumab ,PD-L1 Positive ,chemistry.chemical_compound ,Internal medicine ,medicine ,Immunology and Allergy ,Lung cancer ,RC254-282 ,Pharmacology ,Chemotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Carboplatin ,Pemetrexed ,chemistry ,Molecular Medicine ,business ,medicine.drug - Abstract
BackgroundPrimary analysis of KEYNOTE-042 (NCT02220894), a global, randomized, phase 3 trial, showed that pembrolizumab significantly improved OS versus platinum-based chemotherapy in patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) without sensitizing EGFR/ALK alterations and with PD-L1 tumor proportion score (TPS) ≥50%, ≥20%, and ≥1% with fewer treatment-related AEs than chemotherapy. We report an updated analysis with ~5 years of follow-up.MethodsEligible adults were randomized 1:1 to receive pembrolizumab 200 mg Q3W for 35 cycles or investigator’s choice of chemotherapy (carboplatin + paclitaxel or pemetrexed) Q3W for 4–6 cycles with optional maintenance pemetrexed (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%; secondary endpoints included PFS and ORR per RECIST v1.1 by central review, and safety (secondary). Eligible patients randomized to pembrolizumab who completed 35 cycles with SD or better or stopped treatment after confirmed CR could begin a second course of pembrolizumab at the time of progression.Results1274 patients were randomized to pembrolizumab or chemotherapy (n = 637 each). Median (range) time from randomization to data cutoff (Apr 28, 2021) was 61.1 (50.0–76.3) months. OS outcomes favored the pembrolizumab group (vs chemotherapy alone) regardless of PD-L1 TPS (HR [95% CI] for TPS ≥50%, 0.68 [0.57–0.81]; TPS ≥20%, 0.75 [0.64–0.87]; TPS ≥1%, 0.79 [0.70–0.89]), with estimated 5-year OS rates (95% CI) of 21.9% (17.3%–26.9%), 19.4% (15.6%–23.4%) and 16.6% (13.7%–19.6%), respectively, in the pembrolizumab group (table 1). Median duration of response (DOR) was 28.1 vs 10.8 months in PD-L1 TPS ≥50% group, 27.7 vs 10.8 months in PD-L1 TPS ≥20% group and, 26.5 vs 8.4 months in PD-L1 TPS ≥1% for pembrolizumab group vs chemotherapy. Treatment-related grade 3–5 AEs occurred in 120 patients (18.9%) in the pembrolizumab group and 257 (41.8%) in the chemotherapy group. Among 102 patients who completed 35 cycles of pembrolizumab: ORR was 84.3%; estimated 4-year OS rate after completion of 35 cycles of pembrolizumab (ie, approximately 6 years after randomization) was 61.8%. Among 33 patients who received second-course pembrolizumab, ORR was 15.2%.Abstract 363 Table 1Key efficacy outcomes in the KEYNOTE-042 ITT populationConclusionsWith 5 years of follow-up, first-line pembrolizumab monotherapy continued to show substantial clinical benefit with higher 5-year OS rates, and durable response over chemotherapy in patients with PD-L1–positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations. First-line pembrolizumab remains a standard of care in patients with PD-L1 TPS ≥1%, as underscored by these long-term results.AcknowledgementsMedical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrialsgov, NCT02220894Ethics ApprovalThe protocol and all amendments were approved by the appropriate ethics committee at each center, the study was conducted in accordance with the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki. Patients provided written informed consent before enrollment.
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- 2021
13. FP13.04 KEYNOTE-042 3-Year Survival Update: 1L Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ Locally Advanced/Metastatic NSCLC
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Konstantin Laktionov, Y-L. Wu, Lifan Zhang, Vichien Srimuninnimit, G. De Castro, Hande Turna, Boguslawa Karaszewska, Byoung Chul Cho, Fábio Herrmann Coelho de Souza, Iveta Kudaba, Tony Mok, L. Yin, Igor Bondarenko, Christian Caglevic, G. Lopes, Dariusz M. Kowalski, Kaoru Kubota, and J. Lin
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Chemotherapy ,biology ,business.industry ,medicine.medical_treatment ,Locally advanced ,Pembrolizumab ,Internal medicine ,PD-L1 ,biology.protein ,Medicine ,business - Published
- 2021
14. 1442P Association of TMB using the Foundation Medicine Companion Diagnostic (F1CDx) with efficacy of first-line pembrolizumab (pembro) or pembro plus chemotherapy (pembro + chemo) versus chemo in patients with gastric cancer (gc) from KEYNOTE-062
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Zev A. Wainberg, J. Kobie, Iveta Kudaba, Joseph Chao, Deepti Aurora-Garg, K. Shitara, E. Van Cutsem, Y-J. Bang, J.W. Lee, Lucjan Wyrwicz, H.C. Chung, J. Tabernero, Marcelo Garrido, Sukrut Shah, Hugo Castro, Z.A. Cao, Charles S. Fuchs, K-W. Lee, Razvan Cristescu, and Pooja Bhagia
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,First line ,medicine.medical_treatment ,Foundation (evidence) ,Cancer ,Hematology ,Pembrolizumab ,medicine.disease ,Internal medicine ,Medicine ,In patient ,business ,Companion diagnostic - Published
- 2020
15. Pembrolizumab + chemotherapy for advanced G/GEJ adenocarcinoma (GC): The phase III KEYNOTE-062 study
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Joseph Chao, Maria Ignez Braghiroli, Charles S. Fuchs, Y-J. Bang, Sukrut Shah, Eray Goekkurt, E. Van Cutsem, J. Tabernero, Iveta Kudaba, H.C. Chung, Hugo Castro, Uma Kher, Wasat Mansoor, Zev A. Wainberg, Lucjan Wyrwicz, K.-W. Lee, K. Shitara, and Marcelo Garrido
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Internal medicine ,medicine.medical_treatment ,Medicine ,Adenocarcinoma ,Hematology ,Pembrolizumab ,business ,medicine.disease - Published
- 2019
16. Pembrolizumab with or without chemotherapy vs chemotherapy in patients with advanced G/GEJ cancer (GC) including outcomes according to Microsatellite Instability-High (MSI-H) status in KEYNOTE-062
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Marcelo Garrido, Lucjan Wyrwicz, Charles S. Fuchs, Soonmo Peter Kang, Y.-J. Bang, Sukrut Shah, Eray Goekkurt, J. Tabernero, H. Cheol Chung, K. Shitara, Maria Ignez Braghiroli, Hugo Castro, E. Van Cutsem, Zev A. Wainberg, K.-W. Lee, Joseph Chao, Wasat Mansoor, Uma Kher, and Iveta Kudaba
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0301 basic medicine ,business.industry ,HER2 negative ,Stock options ,Hematology ,Exploratory analysis ,Management ,03 medical and health sciences ,Safety profile ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Visual accommodation ,Medicine ,In patient ,business - Abstract
Background KEYNOTE-062 (NCT02494583) was a randomized, study of 1L pembrolizumab (P) or pembro + chemo (P+C) vs chemo (C) in patients (pts) with PD-L1 combined positive score ≥1 (CPS ≥1), HER2-negative, advanced GC. Methods Eligible pts were randomized 1:1:1 to P 200mg Q3W for up to 2 y, P+C (cisplatin 80mg/m2 + 5-FU 800mg/m2/d on d1-d5 Q3W [or capecitabine 1000mg/m2 BID on d1-d14 Q3W per local guideline]) or placebo Q3W + C. Primary endpoints were OS in CPS ≥1 and CPS ≥10 for P+C vs C and P vs C and PFS (RECIST v1.1; central review) in CPS ≥1 for P+C vs C. ORR (RECIST v1.1; central review) in CPS ≥1 for P+C vs C was the secondary endpoint. The final analysis cutoff date was 26 Mar 2019. Results 763 pts (281 with CPS ≥10) were randomized to P+C (257), P (256), or C (250) (Table). Median follow-up was 11.3mo. P was noninferior to C for OS in CPS ≥1 per prespecified margins. P vs C prolonged OS in CPS ≥10 (median 17.4 vs 10.8mo; HR 0.69; 95% CI 0.49-0.97) but wasn't tested per analysis plan. P+C vs C was not superior for OS in CPS ≥1 or CPS ≥10, with a favorable trend for P+C. In an exploratory analysis of pts with MSI-H tumors with CPS ≥1 (N=50), median OS was not reached vs 8.5mo for both P vs C (HR 0.29; 95% CI 0.11-0.81) and P+C vs C (HR 0.37; 95% CI 0.14-0.97). PFS was longer with P vs C (HR 0.72; 95% CI 0.31-1.68) and P+C vs C (HR 0.45; 95% CI 0.18-1.11). ORR was higher with P (57%) and P + C (65%) vs C (37%). Median DOR was 21.2mo with P, not reached (P + C) vs 7.0mo (C). Grade 3-5 drug-related AE rates were 17% (P), 73% (P+C), and 69% (C). Conclusions As 1L therapy for advanced GC, P was noninferior to C for OS in CPS ≥1 with clinically meaningful improvement for OS in CPS ≥10. P+C did not show superior OS and PFS in CPS ≥1 and OS in CPS ≥10. Clinical benefit was substantially enhanced in a small subset of pts with MSI-H tumors. The safety profile was more favorable for P vs C.TableLBA44TableCPS ≥1P+CCPCaMedian, mo (95% CI)N=257N=250N=256N=250OSa12.5 (10.8-13.9)/ 11.1 (9.2-12.8)10.6 (7.7-13.8)/11.1 (9.2-12.8)HR (95% CI)/ b99.2% CI0.85 (0.70-1.03)0.91 (0.74-1.10)P=0.0460.91b (0.69-1.18); NI margin=1.2PFSa6.9 (5.7-7.3)/ 6.4 (5.7-7.0)2.0 (1.5-2.8)/6.4 (5.7-7.0)HR (95% CI)0.84 (0.70-1.02); P=0.0391.66 (1.37-2.01)MSI-HN=17/N=19N=14/N=19OSaNot reached (3.6-NR)/8.5 (5.3-20.8)Not reached (10.7-NR)/8.5 (5.3-20.8)ORR, %64.7/36.857.1/36.8PFSaNot reached (3.6-NR)/6.6 (4.4-8.3)11.2 (1.5-NR)/6.6 (4.4-8.3)DOR, median, mo (range)NR (1.6+ to 34.5+)/7.0 (2.0-30.4+)21.2 (1.4+ to 33.6+)/7.0 (2.0-30.4+) Clinical trial identification NCT02494583. Editorial acknowledgement Medical writing assistance was provided by Luana Atherly-Henderson, an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA. Legal entity responsible for the study Merck & Co., Inc. Funding Merck & Co., Inc. Disclosure K. Shitara: Honoraria (institution): Novartis; Honoraria (institution): AbbVie; Honoraria (institution): Yakult; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical ; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma. E. Van Cutsem: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck Serano; Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy: Samyang Biopharma . C.S. Fuchs: Leadership role: CytomX Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Unum Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho. L. Wyrwicz: Honoraria (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): BMS; Licensing / Royalties: Cervico. K.W. Lee: Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Green Cross Corp.; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Pfizer. M. Garrido: Advisory / Consultancy: MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Roche. H. Cheol Chung: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (institution): Foundation medicine; Advisory / Consultancy: Taiho; Advisory / Consultancy: Celltrione; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Research grant / Funding (institution): GSK; Research grant / Funding (institution): BMS-Ono; Research grant / Funding (institution): Taiho. H.R. Castro: Research grant / Funding (institution): Merck. W. Mansoor: Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: BMS. M.I.F.M. Braghiroli: Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Merck; Research grant / Funding (institution): AstraZeneca. E. Goekkurt: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. J. Chao: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: FivePrime Therapeutics; Research grant / Funding (institution): Novonco Therapeutics. Z.A. Wainberg: Advisory / Consultancy: Aduro Bio; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Five Prime Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sirtex Medical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon. U. Kher: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S. Shah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S..P. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment, Non-remunerated activity/ies, Patent: Merck & Co., Inc.. J. Tabernero: Advisory / Consultancy: Array Bio; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.
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- 2019
17. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study
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Stefano Iacobelli, Malgorzata Foszczynska-Kloda, Soo-Chin Lee, Richard A. Michaelson, Juan Lacava, Raymond Smith, Vichien Srimuninnimit, Mauricio Kotliar, William Audeh, Damir Vrbanec, Young-Hyuck Im, Paola Edith Price, Maria Del Pilar, Barbara Bower, Tadeusz Pienkowski, Jedzada Maneecahvakajorn, Seppo Pyrhoenen, Alexander Marmé, Saverio Cinieri, Vladimir Semiglazov, Luciano Latini, Luis Miguel, Thitiya Sirisinha, Mario Matwiejuk, Jose Luiz Pedrini, John Allan Ellerton, Maik Hauschild, Xiaojia Wang, Christoph Maintz, Joohyuk Sohn, Estefania Monturus, Kenjiro Aogi, Eugeny Gotovkin, Ron Blachy, Douglas Otero Reye, Rita Blanchard, Bahriye Aktas, Adam Knott, Norberto Batista Lopez, L Roman, Reiki Nishimura, Piotr Tomczak, Duncan Wheatley, Emilio Alba Conejo, Yoshinori Itoh, Giraldo Kato, Petar Stefanovski, Rosa Jochim, Christoph Thomssen, Brigitte Van Eyll, Yutaka Tokuda, S O'Reilly, Paulette Blanchet, Ion Boiangiu, Nikola Vasev, Sherko Kümmel, Julie Taguchi, Do Youn Oh, David Miles, Jurandyr Andrade, Nora Giacomi, Volkmar Mueller, Eduardo Côrtes, Paula Klein, Eleonora Restuccia, Xuenong Ouyang, Leanne Budde, Andre Kallab, Elżbieta Starosławska, Takayuki Ueno, Taral Patel, Jun Horiguchi, Gilson Delgado, Sue Prill, Carol Peterson, Lourdes Calvo, Andreas Kirsch, Gustavo Ismael, Liwei Wang, Veena Charu, Dino Amadori, Pirkko Kellokumpu-Lehtinen, Brooke R. Daniel, Frank Senecal, Sanjay Yadav, Vera Gorbunova, Mikhail Kopp, Patrapim Sunpaweravong, Hiroji Iwata, Frank Priou, Kazuhiko Nakagami, Alejandra Perez, Michael R. Clemens, Marcus Schmidt, Denise A. Yardley, Birgitta Wesenberg, Priscilla Caguioa, Haruki Ogata, An Nguyen, Sung Bae Kim, Tsz-Kok Yau, Vladimir Merculov, Mikhail Lichinitser, Valorie Chan, Yoshiaki Rai, Neville Davidson, Walter E. Aulitzky, Gloria Martinez, Koji Takeda, Sherene Loi, Junichiro Watanabe, Louis Fehrenbacher, Gunta Purkalne, Shaker R. Dakhil, Claudia Schumacher, Rizvana Ahmad, Winnie Yeo, Christine Brezden-Masley, Alison Jones, Seock-Ah Im, Zetina Toache, Jeffrey Hargis, Celia Tosello, Tania Soria, Catia Angiolini, Maria De Fatima Gaui, Ravi Patel, Christopher Lobo, Andreas Schneeweiss, Priyanka Sharma, Cesar Estuardo, Randall Thomas, Adam Brufsky, Virote Sriuranpong, Zhenzhou Shen, Sandra Franco, Clive Mulatero, Wojciech Polkowski, Maria Alejandra Bartoli, Shigehira Saji, Patrick J. Flynn, Kimberly L. Blackwell, Gladys Rodriguez, Robert Robles, Timothy J. O'Rourke, Fabio Franke, Gabriel Tellez-Trevilla, Robert R. Carroll, Laura Biganzoli, Cheng Ying, Peter A. Kaufman, Mark Karwal, Mirta Varela, Darcy Spicer, Jonathan Polikoff, Roberto Hegg, Jungsil Ro, Pedro Sánchez-Rovira, Takahiro Nakayama, Edda Simoncini, María Bianconi, Liljana Kostovska-Maneva, Hugo Castro, Elza Grincuka, Jeff Neidhart, Anne Robinson, Nathan B. Green, Robert Hermann, Laura Assersohn, Teresa Gamucci, Dennis Tudtud, Nobuaki Sato, Antonio Gonzalez Martin, Victor Hugo Alencar, Jess Armor, Bruno Coudert, Nuria Ribelles, Eva Ciruelos, Daniel Cubero, Iveta Kudaba, Eduardo Cronemberger, Norikazu Masuda, Norio Kohno, Sergio J Azevedo, Vadim Shirinkin, Miguel Gil I Gil, Serafin Morales, Hirofumi Fujii, Chris Gallagher, Hernandez Monroy, Katsumasa Kuroi, Rodrigo Moura, Richy Agajanian, Zeljko Soldic, Jean-Marc Ferrero, Kenichi Inoue, Mark C. Benyunes, Davi Jendiroba, Filippo Montemurro, Masahiro Kashiwaba, Robert Quackenbush, Koichiro Tsugawa, Paulo M. Hoff, Eva-Maria Grischke, Susana De La Cruz, Vincent Hansen, Marianna Bitina, Carolyn B. Hendricks, Javier Cortes, Zee Wan Wong, Igor Kiselev, David Waterhouse, Javier Hornedo Muguiro, Mario Campone, Marianne Just, Emma Clark, Rodrigo Pereira, Sandra M Swain, Ruemu E. Birhiray, Helio Pinczowski, and Wichit Arpornwirat
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Receptor, ErbB-2 ,Population ,Phases of clinical research ,Breast Neoplasms ,Docetaxel ,Placebo ,Antibodies, Monoclonal, Humanized ,Loading dose ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Trastuzumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Neoplasm Metastasis ,education ,Aged ,education.field_of_study ,business.industry ,Middle Aged ,Survival Analysis ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Pertuzumab ,business ,medicine.drug - Abstract
Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190 . Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.
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- 2019
18. MO01.41 Using an Exploratory Composite Endpoint to Evaluate the Myelopreservation Benefits of Trilaciclib in Patients with Small Cell Lung Cancer
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Janet K. Horton, K. Nikolov, M.D. Gómez, Davorin Radosavljevic, Iveta Kudaba, Rajesh K. Malik, Jie Xiao, Jana Jaal, Janakiraman Subramanian, and T. Csőszi
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,In patient ,Non small cell ,business - Published
- 2021
19. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer
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Nina A. Karaseva, Sukrut Shah, Lucjan Wyrwicz, Joseph Chao, Christian Caglevic, Kohei Shitara, Luis Villanueva, Eric Van Cutsem, Al B. Benson, Eray Goekkurt, Wasat Mansoor, Marcelo Garrido, Iveta Kudaba, Keun Wook Lee, Jeeyun Lee, Maria Alsina, Andrew H. Ko, Charles S. Fuchs, S. Peter Kang, Josep Tabernero, Hugo Castro, Hironaga Satake, Uma Kher, Yung-Jue Bang, Maria Ignez Braghiroli, Peter C. Enzinger, Zev A. Wainberg, and Hyun Cheol Chung
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,law.invention ,Capecitabine ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Stomach Neoplasms ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Aged ,Aged, 80 and over ,Chemotherapy ,business.industry ,Middle Aged ,Chemotherapy regimen ,Clinical trial ,Oncology ,Docetaxel ,Fluorouracil ,030220 oncology & carcinogenesis ,Female ,Esophagogastric Junction ,business ,medicine.drug - Abstract
Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583
- Published
- 2020
20. 1459P Albumin as a simple criterion to reduce early mortality (EM) in gastric cancer (GC) trials
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E. van Custem, Pooja Bhagia, Marcelo Garrido, Sukrut Shah, K-W. Lee, Lucjan Wyrwicz, C. Shih, Charles S. Fuchs, Mustafa Ozguroglu, Zev A. Wainberg, M. Di Bartolomeo, Z.A. Cao, H.C. Chung, J. Tabernero, Junshui Ma, Christian Caglevic, J.W. Lee, K. Shitara, Iveta Kudaba, and Joseph Chao
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Oncology ,medicine.medical_specialty ,business.industry ,Simple (abstract algebra) ,Internal medicine ,medicine ,Albumin ,Cancer ,Hematology ,business ,medicine.disease - Published
- 2020
21. Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial
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Gabriella Gálffy, Zsolt Papai-Szekely, Iveta Kudaba, Zsolt Markóczy, Ahmet Demirkazik, Ülkü Yilmaz Turay, Erzsébet Rásó, Gyula Ostoros, Veronika Sárosi, Gunta Purkalne, and Attila Somfay
- Subjects
0301 basic medicine ,Oncology ,Lung adenocarcinoma ,Male ,Cancer Research ,Lung Neoplasms ,DNA Mutational Analysis ,0302 clinical medicine ,Non-small cell lung cancer ,Clinical endpoint ,Epidermal growth factor receptor ,Erlotinib Hydrochloride ,Lung ,Aged, 80 and over ,biology ,Exons ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Progression-Free Survival ,ErbB Receptors ,Treatment Outcome ,Erlotinib ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,medicine.drug ,Research Article ,Adult ,medicine.medical_specialty ,EGFR ,Adenocarcinoma of Lung ,lcsh:RC254-282 ,White People ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Humans ,Progression-free survival ,Genetic Testing ,Protein Kinase Inhibitors ,Aged ,Performance status ,business.industry ,medicine.disease ,Clinical trial ,030104 developmental biology ,Mutation ,biology.protein ,Feasibility Studies ,business ,Follow-Up Studies - Abstract
Background Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection. Methods 651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS). Results 62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9–15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation. Conclusions Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure. Trial registration ClinicalTrials.gov Identifier: NCT01609543.
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- 2018
22. Pembrolizumab with or without chemotherapy versus chemotherapy for first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The Phase 3 KEYNOTE-062 Study
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Maria Ignez Braghiroli, Soonmo Peter Kang, Lucjan Wyrwicz, Joseph Chao, Eray Goekkurt, Marcelo Garrido, Y-J. Bang, K. Shitara, E. Van Cutsem, Iveta Kudaba, Wasat Mansoor, K.-W. Lee, H. Castro Salguero, H.C. Chung, Uma Kher, J. Tabernero, Charles S. Fuchs, Zev A. Wainberg, and Sukrut Shah
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Hematology ,Pembrolizumab ,medicine.disease ,Gastroesophageal Junction ,Chemotherapy regimen ,First line treatment ,Internal medicine ,medicine ,Adenocarcinoma ,Esophagogastric junction ,business - Published
- 2019
23. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study
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Soonmo Peter Kang, Marcelo Garrido, Hyun Cheol Chung, Lucjan Wyrwicz, Iveta Kudaba, Sukrut Shah, Zev A. Wainberg, Wasat Mansoor, Kohei Shitara, Charles S. Fuchs, Joseph Chao, Uma Kher, Keun Wook Lee, Yung-Jue Bang, Eray Goekkurt, Eric Van Cutsem, Hugo Raul Castro Salguero, Maria Ignez Braghiroli, and Josep Tabernero
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Pembrolizumab ,medicine.disease ,Gastroesophageal Junction ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adenocarcinoma ,business ,030215 immunology - Abstract
LBA4007 Background: KEYNOTE062 (NCT02494583) was a randomized, active controlled study of 1L P or P+C vs C in pts with PD-L1 combined positive score ≥1 (CPS ≥1), HER2-negative, advanced GC. Methods: Eligible pts were randomized 1:1:1 to P 200 mg Q3W for up to 2 y, P+C (cisplatin 80 mg/m2 + 5-FU 800 mg/m2/d on d1-d5 Q3W [or capecitabine 1000 mg/m2 BID on d1-d14 Q3W per local guideline]) or placebo Q3W + C. Randomization was stratified by region, disease status, and fluoropyrimidine treatment. Primary endpoints were OS in CPS ≥1 and CPS ≥10 for P+C vs C and P vs C and PFS (RECIST v1.1; central review) in CPS ≥1 for P+C vs C. ORR (RECIST v1.1; central review) in CPS ≥1 for P+C vs C was the secondary endpoint. Final analysis cutoff date was 26 Mar 2019. Results: 763 pts (281 with CPS ≥10) were randomized to P+C (257), P (256), or C (250) (Table). Median follow-up was 11.3 mo. P was noninferior to C for OS in CPS ≥1 per prespecified margins. P vs C prolonged OS in CPS ≥10 (median 17.4 vs 10.8 mo; HR 0.69; 95% CI 0.49-0.97) but wasn’t tested per analysis plan. P+C vs C was not superior for OS in CPS ≥1 or CPS ≥10, with a favorable trend for P+C. P+C did not significantly prolong PFS in CPS ≥1. ORR was higher for P+C vs C. Grade 3-5 drug-related AE rates were 17% (P), 73% (P+C), and 69% (C). Conclusions: As 1L therapy for advanced GC, P was noninferior to C for OS in CPS ≥1 with clinically meaningful improvement for OS in CPS ≥10. P+C did not show superior OS and PFS in CPS ≥1 and OS in CPS ≥10. The safety profile was more favorable for P vs C. Clinical trial information: NCT02494583. [Table: see text]
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- 2019
24. Final analysis of the phase III KEYNOTE-042 study: Pembrolizumab (Pembro) versus platinum-based chemotherapy (Chemo) as first-line therapy for patients (Pts) with PD-L1–positive locally advanced/metastatic NSCLC
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Hande Turna, Konstantin Laktionov, L. Yin, Christian Caglevic, Tony Mok, Vichien Srimuninnimit, Y-L. Wu, Iveta Kudaba, Igor Bondarenko, J. Penrod, G. Lopes, Byoung Chul Cho, T. Dang, Dariusz M. Kowalski, G. De Castro, Boguslawa Karaszewska, and Kaoru Kubota
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Brachial Plexus Neuritis ,Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Locally advanced ,Hematology ,Pembrolizumab ,Chemotherapy regimen ,PD-L1 Positive ,First line therapy ,Internal medicine ,medicine ,business - Published
- 2019
25. Renal Cell Carcinoma – How Can We Predict its Outcomes in Clinical Practice?
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V. Lietuvietis, Alinta Hegmane, Iveta Kudaba, and I. Vaivode
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Clinical Practice ,Oncology ,medicine.medical_specialty ,business.industry ,Renal cell carcinoma ,Internal medicine ,medicine ,General Materials Science ,business ,medicine.disease ,Prognostic models - Abstract
Summary Morbidity and mortality data of RCC (renal cell carcinoma) differs a lot among the European countries. In Latvia a growing trend in both incidence and mortality rates is still observed. The expanding availability of multiple treatment strategies has increased the importance of skilled individualized outcome prediction for patients. Several prognostic factors are available in RCC including anatomical, histological, clinical and molecular ones, but none of them is very precise, when used alone. Therefore increasing number of prognostic systems has been created in local and metastatic disease to increase predictive accuracy. In order to encourage the clinicians to use the available models in their routine practice, we tried to select the most relevant ones and include them in a simple algorithm to be used in common clinical scenarios throughout entire history of the disease in patients with RCC
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- 2013
26. Absence of pharmacokinetic drug–drug interaction of pertuzumab with trastuzumab and docetaxel
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Maik Hauschild, Bert L. Lum, Taral Patel, Graham Ross, Amit Garg, Jean-Francois Marier, Mike Brewster, Sandra M. Swain, Javier Cortes, Elza Grincuka, Jennifer Visich, V. McNally, My My Trinh, Norikazu Masuda, José Baselga, Ihsan Nijem, and Iveta Kudaba
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Oncology ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-2 ,Population ,Cmax ,Breast Neoplasms ,Docetaxel ,Antibodies, Monoclonal, Humanized ,Models, Biological ,Drug Administration Schedule ,Cmin ,Pharmacokinetics ,Trastuzumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Drug Interactions ,Pharmacology (medical) ,Neoplasm Metastasis ,skin and connective tissue diseases ,education ,neoplasms ,Pharmacology ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Female ,Taxoids ,Pertuzumab ,business ,medicine.drug - Abstract
Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.
- Published
- 2013
27. PS1 Phase 3 KEYNOTE-042 Study: Pembrolizumab vs Platinum-Based Chemotherapy as 1l Therapy for Advanced NSCLC with a PD-L1 TPS ≥1%
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Tony Mok, Byoung Chul Cho, Igor Bondarenko, G. Lopes, Dariusz M. Kowalski, Y-L. Wu, Kaoru Kubota, Debra Kush, Vichien Srimuninnimit, G. De Castro, Gregory M. Lubiniecki, Hande Turna, Konstantin Laktionov, Jin Zhang, and Iveta Kudaba
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,Chemotherapy ,medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,chemistry.chemical_element ,Pembrolizumab ,chemistry ,PD-L1 ,Internal medicine ,Phase (matter) ,biology.protein ,medicine ,Platinum ,business - Published
- 2018
28. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study
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Yi-Long Wu, Gilberto de Castro, Dariusz M. Kowalski, Kaoru Kubota, Debra Kush, Igor Bondarenko, Gilberto Lopes, Vichien Srimuninnimit, Gregory M. Lubiniecki, Tony Mok, Byoung Chul Cho, Iveta Kudaba, and Jin Zhang
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Randomization ,business.industry ,medicine.medical_treatment ,Pembrolizumab ,Interim analysis ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Pemetrexed ,chemistry ,Paclitaxel ,030220 oncology & carcinogenesis ,Internal medicine ,Clinical endpoint ,Medicine ,business ,medicine.drug - Abstract
LBA4 Background: In KEYNOTE-024, pembro significantly improved PFS (primary end point) and OS (secondary end-point) over chemo as first-line therapy for metastatic NSCLC without targetable alterations and PD-L1 TPS ≥50%. In KEYNOTE-042, we compared pembro with chemo at the lower TPS of ≥1% (NCT02220894). Methods: Eligible patients (pts) were randomized 1:1 to ≤35 cycles of pembro 200 mg Q3W or investigator’s choice of ≤6 cycles of paclitaxel + carboplatin or pemetrexed (peme) + carboplatin with optional peme maintenance (nonsquamous only). Randomization was stratified by region (east Asia vs non-east Asia), ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and TPS (≥50% vs 1-49%). Primary end-points were OS in pts with TPS ≥50%, ≥20%, and ≥1%. OS differences were assessed sequentially using the stratified log-rank test. Efficacy boundaries at the prespecified second interim analysis were one-sided P = .0122, .01198, and .01238, respectively. Results: 1274 pts were randomized: 637 to each arm. 599 pts (47.0%) had TPS ≥50%, 818 (64.2%) had TPS ≥20%. After 12.8-mo median follow-up, 13.7% were still on pembro and 4.9% were receiving peme maintenance. Pembro significantly improved OS in pts with TPS ≥50% (HR 0.69), TPS ≥20% (HR 0.77), and TPS ≥1% (HR 0.81) (Table). Grade 3-5 drug-related AEs were less frequent with pembro (17.8% vs 41.0%). The external DMC recommended continuing the trial to evaluate PFS (secondary end-point). Conclusion: KEYNOTE-042 is the first study with a primary end-point of OS to demonstrate superiority of pembro over platinum-based chemo in pts with previously untreated advanced/metastatic NSCLC without sensitizing EGFR or ALK alterations and a PD-L1 TPS ≥1%. These data confirm and potentially extend the role of pembro monotherapy as a standard first-line treatment for PD-L1-expressing advanced/metastatic NSCLC. Clinical trial information: NCT02220894. [Table: see text]
- Published
- 2018
29. Prognostic and Predictive Significance of Breast Cancer Stem Cells
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Talivaldis Freivalds, Zane Simsone, Juris Berzins, and Iveta Kudaba
- Subjects
CA15-3 ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Metastasis ,Radiation therapy ,Breast cancer ,Cancer stem cell ,Immunology ,Cancer cell ,medicine ,Cancer research ,General Materials Science ,Stem cell ,skin and connective tissue diseases ,business - Abstract
Summary The existence of tumorigenic (stem) cells has been first described in acute myeloid leukemia (AML), and afterwards in some solid tumors. Recently, they were identified also in breast cancer showing high levels of CD44 surface marker and low level or lacking of CD24. Latest development revealed also significance of presence of ALDH1+ in this certain subpopulation of cells. These cells – CD44+/CD24- with ALDH1 have additional capability to induce tumors in NOD/SCID mice, have been extensively investigated in human tumors, and are claimed by some investigators to be responsible for cancer growth, relapse, resistance to chemotherapy, endocrine and radiation treatment, as well as widespread metastasis in breast cancer patients. However, the hope to solve the problem of breast cancer treatment focusing all attention to breast cancer stem cells (BCSC) has not yet been entirely successful and rather speculative. Investigations in animal models and human breast cancer cells grown as single cell suspensions or mammospheres in vitro have enlighted some of the latter problems, but the results until now are scarce and contradictory. In our review we have focused only on problems of vital interest for clinical practice, trying to elucidate the significance of breast cancer stem cells (or broadly speaking tumorigenic breast cancer cells) for prognostic and predictive significance in breast cancer treatment and prognosis. As a rule, BCSC are immunohistochemically detectable, having CD44+/CD24-/ low or ALDH1+ as a surface markers, they as a rule present a subpopulation of cells with intrinsic resistance to chemotherapy, some of them (CD44+/CD24 -/ low ) to radiotherapy; as to endocrine treatment, no satisfactory data are available until now. The BCSC problem remains unsolved, in vitro, in vivo or using them as indicators for treatment strategy. More data are to be needed for definite answers to many questions put forward by investigators and clinicians.
- Published
- 2011
30. The utility of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in the investigation of patients with disseminated carcinoma of unknown primary origin
- Author
-
Danny Rischin, Iveta Kudaba, Josephine Stewart, Rodney J. Hicks, and Clare L. Scott
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Fluorodeoxyglucose F18 ,medicine ,Retrospective analysis ,Humans ,Radiology, Nuclear Medicine and imaging ,In patient ,Aged ,Retrospective Studies ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Carcinoma ,Middle Aged ,Oncology ,Positron emission tomography ,Positron-Emission Tomography ,Unknown primary ,Neoplasms, Unknown Primary ,Female ,Radiology ,Nuclear medicine ,business ,Disseminated Carcinoma ,Follow-Up Studies - Abstract
A retrospective analysis of the use of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) positron emission tomography (PET) was performed in patients with histologically proven disseminated carcinoma of unknown primary tumor (CUP).The records of 31 patients with CUP, excluding patients with isolated neck metastases, were reviewed to identify the ability of PET to detect the putative primary site (PPS) and/or to change therapeutic management.In eight out of 31 cases (26%), a PPS was confirmed, either definitively (one pathologically, one radiologically) (true positive) or clinically (six cases). For three cases (10%), histological evidence of a primary tumor distant from the PPS was found (false positive). In a further seven cases (23%), the PPS remained unconfirmed, whereas for 13 cases (42%) no PPS was identified. In five out of seven patients in whom the PET suggested a high probability of having identified the primary site, the PPS was confirmed definitively or clinically. PET altered clinical management in at least 12 cases (38%).PET contributed to the management of previously extensively investigated patients with CUP. Identification of a PPS and/or change in management was documented in 38% of cases, the majority of which were lung or pancreatic cancer. These findings are worthy of evaluation in a prospective study.
- Published
- 2005
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