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1. Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies

Author

Figarol, Sarah, Delahaye, Célia, Gence, Rémi, Doussine, Aurélia, Cerapio, Juan Pablo, Brachais, Mathylda, Tardy, Claudine, Béry, Nicolas, Asslan, Raghda, Colinge, Jacques, Villemin, Jean-Philippe, Maraver, Antonio, Ferrer, Irene, Paz-Ares, Luis, Kessler, Linda, Burrows, Francis, Lajoie-Mazenc, Isabelle, Dongay, Vincent, Morin, Clara, Florent, Amélie, Pagano, Sandra, Taranchon-Clermont, Estelle, Casanova, Anne, Pradines, Anne, Mazieres, Julien, Favre, Gilles, and Calvayrac, Olivier

Published
2024
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2. Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study

Author

Xie, Mingchao, Vuko, Miljenka, Rodriguez-Canales, Jaime, Zimmermann, Johannes, Schick, Markus, O’Brien, Cathy, Paz-Ares, Luis, Goldman, Jonathan W., Garassino, Marina Chiara, Gay, Carl M., Heymach, John V., Jiang, Haiyi, Barrett, J. Carl, Stewart, Ross A., Lai, Zhongwu, Byers, Lauren A., Rudin, Charles M., and Shrestha, Yashaswi

Published
2024
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3. CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials

Author

Segal, Neil H., Melero, Ignacio, Moreno, Victor, Steeghs, Neeltje, Marabelle, Aurelien, Rohrberg, Kristoffer, Rodriguez-Ruiz, Maria E., Eder, Joseph P., Eng, Cathy, Manji, Gulam A., Waterkamp, Daniel, Leutgeb, Barbara, Bouseida, Said, Flinn, Nick, Das Thakur, Meghna, Elze, Markus C., Koeppen, Hartmut, Jamois, Candice, Martin-Facklam, Meret, Lieu, Christopher H., Calvo, Emiliano, Paz-Ares, Luis, Tabernero, Josep, and Argilés, Guillem

Published
2024
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4. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab as first-line treatment for metastatic non-small cell lung cancer with high levels of programmed death-ligand 1: a randomized, double-blind phase 2 study

Author

Tokito, Takaaki, Kolesnik, Oleksii, Sørensen, Jens, Artac, Mehmet, Quintela, Martín Lázaro, Lee, Jong-Seok, Hussein, Maen, Pless, Miklos, Paz-Ares, Luis, Leopold, Lance, Daniel, Jeannie, Munteanu, Mihaela, Samkari, Ayman, Xu, Lu, and Butts, Charles

Published
2024
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5. Efficient Identification of Patients With NTRK Fusions Using a Supervised Tumor-Agnostic Approach

Author

Hernandez, Susana, Conde, Esther, Molero, Aida, Suarez-Gauthier, Ana, Martinez, Rebeca, Alonso, Marta, Plaza, Carlos, Camacho, Carmen, Chantada, Debora, Juaneda-Magdalena, Laura, Garcia-Toro, Enrique, Saiz-Lopez, Patricia, Rojo, Federico, Abad, Mar, Boni, Valentina, del Carmen, Sofia, Regojo, Rita Maria, Sanchez-Frias, Marina Esther, Teixido, Cristina, Paz-Ares, Luis, and Lopez-Rios, Fernando

Subjects
Thermo Fisher Scientific Inc., Bayer AG, Hoffmann-La Roche Inc. Roche Molecular Systems, Ventana Medical Systems Inc., Biological products industry, Immunohistochemistry, Genes, Colorectal cancer, Thyroid diseases, Muscle proteins, Lung cancer, Algorithms, Pharmaceutical industry, Sarcoma, Scientific equipment and supplies industry, Medical test kit industry, Medical equipment and supplies industry, Cancer, Algorithm, Health
Abstract

* Context.--The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated as predictive biomarkers in a 'tumor-agnostic' manner. However, the identification of these patients is extremely challenging because the overall frequency of NTRK fusions is below 1%. Academic groups and professional organizations have released recommendations on the algorithms to detect NTRK fusions. The European Society for Medical Oncology proposal encourages the use of next-generation sequencing (NGS) if available, or alternatively immunohistochemistry (IHC) could be used for screening with NGS confirmation of all positive IHC results. Other academic groups have included histologic and genomic information in the testing algorithm. Objective.--To apply some of these triaging strategies for a more efficient identification of NTRK fusions within a single institution, so pathologists can gain practical insight on how to start looking for NTRK fusions. Design.--A multiparametric strategy combining histologic (secretory carcinomas of the breast and salivary gland; papillary thyroid carcinomas; infantile fibrosarcoma) and genomic (driver-negative non-small cell lung carcinomas, microsatellite instability-high colorectal adenocarcinomas, and wild-type gastrointestinal stromal tumors) triaging was put forward. Results.--Samples from 323 tumors were stained with the VENTANA pan-TRK EPR17341 Assay as a screening method. All positive IHC cases were simultaneously studied by 2 NGS tests, Oncomine Comprehensive Assay v3 and FoundationOne CDx. With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients. Conclusions.--Based on our findings, we propose a multiparametric strategy (ie, 'supervised tumor-agnostic approach') when pathologists start searching for NTRK fusions., In solid tumors, actionable gene fusions can be identified in a wide range of cancer types. (1) The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated [...]

Published
2024
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6. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author

Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, and Martin, Stewart G

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Ovarian Cancer, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Tumor Suppressor Protein p53, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Carcinoma, Endometrioid, ovarian cancer, high-grade serous carcinoma, endometrioid, clear cell, TP53, p53, prognosis, AOCS Group, Clinical sciences
Abstract

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Published
2023

7. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial

Author

Desai, Jayesh, Alonso, Guzman, Kim, Se Hyun, Cervantes, Andres, Karasic, Thomas, Medina, Laura, Shacham-Shmueli, Einat, Cosman, Rasha, Falcon, Alejandro, Gort, Eelke, Guren, Tormod, Massarelli, Erminia, Miller, Jr., Wilson H., Paz-Ares, Luis, Prenen, Hans, Amatu, Alessio, Cremolini, Chiara, Kim, Tae Won, Moreno, Victor, Ou, Sai-Hong I., Passardi, Alessandro, Sacher, Adrian, Santoro, Armando, Stec, Rafal, Ulahannan, Susanna, Arbour, Kathryn, Lorusso, Patricia, Luo, Jia, Patel, Manish R., Choi, Yoonha, Shi, Zhen, Mandlekar, Sandhya, Lin, Mark T., Royer-Joo, Stephanie, Chang, Julie, Jun, Tomi, Dharia, Neekesh V., Schutzman, Jennifer L., and Han, Sae-Won

Published
2024
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8. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author

Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Clinical Research, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, Prognosis, Survival Analysis, RNA, Messenger, Cystadenocarcinoma, Serous, Biomarkers, Tumor, Forkhead Transcription Factors, AOCs group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Published
2023

10. RET Fusion Testing in Patients With NSCLC: The RETING Study

Author

Conde, Esther, Hernandez, Susana, Rodriguez Carrillo, Jose Luis, Martinez, Rebeca, Alonso, Marta, Curto, Daniel, Jimenez, Beatriz, Caminoa, Alejandra, Benito, Amparo, Garrido, Pilar, Clave, Sergi, Arriola, Edurne, Esteban-Rodriguez, Isabel, De Castro, Javier, Sansano, Irene, Felip, Enriqueta, Rojo, Federico, Dómine, Manuel, Abdulkader, Ihab, Garcia-Gonzalez, Jorge, Teixido, Cristina, Reguart, Noemi, Compañ, Desamparados, Insa, Amelia, Mancheño, Nuria, Palanca, Sarai, Juan-Vidal, Oscar, Baixeras, Nuria, Nadal, Ernest, Cebollero, Maria, Calles, Antonio, Martin, Paloma, Salas, Clara, Provencio, Mariano, Aranda, Ignacio, Massuti, Bartomeu, Lopez-Vilaro, Laura, Majem, Margarita, Paz-Ares, Luis, and Lopez-Rios, Fernando

Published
2024
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11. Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer

Author

Li, Bob T, Smit, Egbert F, Goto, Yasushi, Nakagawa, Kazuhiko, Udagawa, Hibiki, Mazières, Julien, Nagasaka, Misako, Bazhenova, Lyudmila, Saltos, Andreas N, Felip, Enriqueta, Pacheco, Jose M, Pérol, Maurice, Paz-Ares, Luis, Saxena, Kapil, Shiga, Ryota, Cheng, Yingkai, Acharyya, Suddhasatta, Vitazka, Patrik, Shahidi, Javad, Planchard, David, and Jänne, Pasi A

Subjects
Clinical Research, Clinical Trials and Supportive Activities, Lung, Lung Cancer, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Camptothecin, Carcinoma, Non-Small-Cell Lung, Female, Follow-Up Studies, Humans, Immunoconjugates, Lung Diseases, Interstitial, Lung Neoplasms, Male, Middle Aged, Pneumonia, Progression-Free Survival, Receptor, ErbB-2, Trastuzumab, DESTINY-Lung01 Trial Investigators, Receptor, erbB-2, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundHuman epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.MethodsWe conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.ResultsA total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.ConclusionsTrastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).

Published
2022

12. Abemaciclib in combination with pembrolizumab for HR+, HER2− metastatic breast cancer: Phase 1b study

Author

Rugo, Hope S, Kabos, Peter, Beck, J Thad, Jerusalem, Guy, Wildiers, Hans, Sevillano, Elena, Paz-Ares, Luis, Chisamore, Michael J, Chapman, Sonya C, Hossain, Anwar M, Chen, Yanyun, and Tolaney, Sara M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Patient Safety, Cancer, Clinical Trials and Supportive Activities, Genetics, Clinical Research, Breast Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Clinical sciences, Oncology and carcinogenesis, Epidemiology
Abstract

This nonrandomized, open-label, multi-cohort Phase 1b study (NCT02779751) investigated the safety and efficacy of abemaciclib plus pembrolizumab with/without anastrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) without prior CDK4 and 6 inhibitor exposure. Patients were divided into two cohorts: treatment naïve (cohort 1) and pretreated (cohort 2). Patients received abemaciclib plus pembrolizumab with (cohort 1) or without (cohort 2) anastrozole over 21-day cycles. The primary objective was safety, and secondary objectives included efficacy and pharmacokinetics (PK). Cohort 1/2 enrolled 26/28 patients, respectively. Neutropenia (30.8/28.6%), AST increase (34.6/17.9%), ALT increase (42.3/10.7%), and diarrhea (3.8/10.7%) were the most frequent grade ≥3 adverse events in cohort 1/2, respectively. A total of two deaths occurred, which investigators attributed to treatment-related adverse events (AEs), both in cohort 1. Higher rates of all grade and grade ≥3 interstitial lung disease (ILD)/pneumonitis were observed compared to previously reported with abemaciclib and pembrolizumab monotherapy. The PK profiles were consistent between cohorts and with previous monotherapy studies. In cohorts 1/2, the overall response rate and disease control rate were 23.1/28.6% and 84.6/82.1%, respectively. Median progression-free survival and overall survivals were 8.9 (95% CI: 3.9-11.1) and 26.3 months (95% CI: 20.0-31.0) for cohort 2; cohort 1 data are immature. Abemaciclib plus pembrolizumab demonstrated antitumor activity, but high rates of ILD/pneumonitis and severe transaminase elevations occurred with/without anastrozole compared to the previous reporting. Benefit/risk analysis does not support further evaluation of this combination in the treatment of HR+, HER2- MBC.

Published
2022

13. Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

Author

de Jager, Vincent D., Timens, Wim, Bayle, Arnaud, Botling, Johan, Brcic, Luka, Büttner, Reinhard, Fernandes, Maria Gabriela O., Havel, Libor, Hochmair, Maximilian J., Hofman, Paul, Janssens, Annelies, Johansson, Mikael, van Kempen, Léon, Kern, Izidor, Lopez-Rios, Fernando, Lüchtenborg, Margreet, Machado, José Carlos, Mohorcic, Katja, Paz-Ares, Luis, Popat, Sanjay, Ryška, Aleš, Taniere, Phillipe, Wolf, Jürgen, Schuuring, Ed, and van der Wekken, Anthonie J.

Published
2024
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14. Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study

Author

Vokes, Everett E., Mornex, Francoise, Sezer, Ahmet, Cheng, Ying, Fang, Jian, Baz, David Vicente, Cil, Timucin, Adjei, Alex A., Ahn, Myung-Ju, Barlesi, Fabrice, Felip, Enriqueta, Garon, Edward B., Audhuy, Francois, Ito, Rena, Sato, Masashi, Eggleton, S. Peter, Martin, Claudio Marcelo, Reck, Martin, Robinson, Clifford G., and Paz-Ares, Luis

Published
2024
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15. Long-Term Survival Outcomes With First-Line Nivolumab Plus Ipilimumab–Based Treatment in Patients With Metastatic NSCLC and Tumor Programmed Death-Ligand 1 Lower Than 1%: A Pooled Analysis

Author

Peters, Solange, Paz-Ares, Luis G., Reck, Martin, Carbone, David P., Brahmer, Julie R., Borghaei, Hossein, Lu, Shun, O’Byrne, Kenneth J., John, Thomas, Ciuleanu, Tudor-Eliade, Schenker, Michael, Bernabe Caro, Reyes, Nishio, Makoto, Cobo, Manuel, Lee, Jong-Seok, Zurawski, Bogdan, Pluzanski, Adam, Aoyama, Takekazu, Tschaika, Marina, Devas, Vipul, Grootendorst, Diederik J., and Ramalingam, Suresh S.

Published
2024
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16. Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer

Author

Macaya, Irati, Roman, Marta, Welch, Connor, Entrialgo-Cadierno, Rodrigo, Salmon, Marina, Santos, Alba, Feliu, Iker, Kovalski, Joanna, Lopez, Ines, Rodriguez-Remirez, Maria, Palomino-Echeverria, Sara, Lonfgren, Shane M., Ferrero, Macarena, Calabuig, Silvia, Ludwig, Iziar A., Lara-Astiaso, David, Jantus-Lewintre, Eloisa, Guruceaga, Elizabeth, Narayanan, Shruthi, Ponz-Sarvise, Mariano, Pineda-Lucena, Antonio, Lecanda, Fernando, Ruggero, Davide, Khatri, Purvesh, Santamaria, Enrique, Fernandez-Irigoyen, Joaquin, Ferrer, Irene, Paz-Ares, Luis, Drosten, Matthias, Barbacid, Mariano, Gil-Bazo, Ignacio, and Vicent, Silve

Published
2023
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18. Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1–High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial

Author

Cho, Byoung Chul, Lee, Jong Seok, Wu, Yi-Long, Cicin, Irfan, Dols, Manuel Cobo, Ahn, Myung-Ju, Cuppens, Kristof, Veillon, Rémi, Nadal, Ernest, Dias, Josiane Mourão, Martin, Claudio, Reck, Martin, Garon, Edward B., Felip, Enriqueta, Paz-Ares, Luis, Mornex, Francoise, Vokes, Everett E., Adjei, Alex A., Robinson, Clifford, Sato, Masashi, Vugmeyster, Yulia, Machl, Andreas, Audhuy, Francois, Chaudhary, Surendra, and Barlesi, Fabrice

Published
2023
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19. Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B

Author

Le, Xiuning, Paz-Ares, Luis G., Van Meerbeeck, Jan, Viteri, Santiago, Galvez, Carlos Cabrera, Smit, Egbert F., Garassino, Marina, Veillon, Remi, Baz, David Vicente, Pradera, Jose Fuentes, Sereno, María, Kozuki, Toshiyuki, Kim, Young-Chul, Yoo, Seung Soo, Han, Ji-Youn, Kang, Jin-Hyoung, Son, Choon-Hee, Choi, Yoon Ji, Stroh, Christopher, Juraeva, Dilafruz, Vioix, Helene, Bruns, Rolf, Otto, Gordon, Johne, Andreas, and Paik, Paul K.

Published
2023
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20. Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

Author

Reck, Martin, Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Schenker, Michael, Zurawski, Bogdan, Kim, Sang-We, Mahave, Mauricio, Alexandru, Aurelia, Peters, Solange, Pluzanski, Adam, Caro, Reyes Bernabe, Linardou, Helena, Burgers, Jacobus A., Nishio, Makoto, Martinez-Marti, Alex, Azuma, Koichi, Axelrod, Rita, Paz-Ares, Luis G., Ramalingam, Suresh S., Borghaei, Hossein, O’Byrne, Kenneth J., Li, Li, Bushong, Judith, Gupta, Ravi G., Grootendorst, Diederik J., Eccles, Laura J., and Brahmer, Julie R.

Published
2023
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21. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Author

Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N, Chow, Christine, Nazeran, Tayyebeh M, Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D, Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y, McCauley, Bryan M, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, and Brenton, James D

Subjects
Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

BackgroundPTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.MethodsTumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.ResultsDownregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value

Published
2020

22. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials

Author

Doebele, Robert C, Drilon, Alexander, Paz-Ares, Luis, Siena, Salvatore, Shaw, Alice T, Farago, Anna F, Blakely, Collin M, Seto, Takashi, Cho, Byung Chul, Tosi, Diego, Besse, Benjamin, Chawla, Sant P, Bazhenova, Lyudmila, Krauss, John C, Chae, Young Kwang, Barve, Minal, Garrido-Laguna, Ignacio, Liu, Stephen V, Conkling, Paul, John, Thomas, Fakih, Marwan, Sigal, Darren, Loong, Herbert H, Buchschacher, Gary L, Garrido, Pilar, Nieva, Jorge, Steuer, Conor, Overbeck, Tobias R, Bowles, Daniel W, Fox, Elizabeth, Riehl, Todd, Chow-Maneval, Edna, Simmons, Brian, Cui, Na, Johnson, Ann, Eng, Susan, Wilson, Timothy R, Demetri, George D, and investigators, trial

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Neurosciences, Cancer, Clinical Research, Clinical Trials and Supportive Activities, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Aged, Antineoplastic Agents, Benzamides, Biomarkers, Tumor, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Female, Gene Fusion, Humans, Indazoles, Male, Membrane Glycoproteins, Middle Aged, Neoplasm Metastasis, Neoplasms, Protein Kinase Inhibitors, Receptor, trkA, Receptor, trkB, Receptor, trkC, Receptors, Nerve Growth Factor, Time Factors, Treatment Outcome, trial investigators, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundEntrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.MethodsAn integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).FindingsPatients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.InterpretationEntrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.FundingIgnyta/F Hoffmann-La Roche.

Published
2020

23. First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations

Author

Paz-Ares, Luis G., Ciuleanu, Tudor-Eliade, Cobo, Manuel, Bennouna, Jaafar, Schenker, Michael, Cheng, Ying, Juan-Vidal, Oscar, Mizutani, Hideaki, Lingua, Alejo, Reyes-Cosmelli, Felipe, Reinmuth, Niels, Menezes, Juliana, Jassem, Jacek, Protsenko, Svetlana, Richardet, Eduardo, Felip, Enriqueta, Feeney, Kynan, Zurawski, Bogdan, Alexandru, Aurelia, de la Mora Jimenez, Emmanuel, Dakhil, Shaker, Lu, Shun, Reck, Martin, John, Thomas, Hu, Nan, Zhang, Xiaoqing, Sylvester, Judi, Eccles, Laura J., Grootendorst, Diederik J., Balli, David, Neely, Jaclyn, and Carbone, David P.

Published
2023
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24. Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817

Author

Paz-Ares, Luis G., Ciuleanu, Tudor-Eliade, Pluzanski, Adam, Lee, Jong-Seok, Gainor, Justin F., Otterson, Gregory A., Audigier-Valette, Clarisse, Ready, Neal, Schenker, Michael, Linardou, Helena, Caro, Reyes Bernabe, Provencio, Mariano, Zurawski, Bogdan, Lee, Ki Hyeong, Kim, Sang-We, Caserta, Claudia, Ramalingam, Suresh S., Spigel, David R., Brahmer, Julie R., Reck, Martin, O’Byrne, Kenneth J., Girard, Nicolas, Popat, Sanjay, Peters, Solange, Memaj, Arteid, Nathan, Faith, Aanur, Nivedita, and Borghaei, Hossein

Published
2023
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25. Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial

Author

Subbiah, Vivek, Cassier, Philippe A., Siena, Salvatore, Garralda, Elena, Paz-Ares, Luis, Garrido, Pilar, Nadal, Ernest, Vuky, Jacqueline, Lopes, Gilberto, Kalemkerian, Gregory P., Bowles, Daniel W., Seetharam, Mahesh, Chang, Jianhua, Zhang, Hui, Green, Jennifer, Zalutskaya, Alena, Schuler, Martin, Fan, Yun, and Curigliano, Giuseppe

Published
2022
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26. Antitumor activity of an engineered decoy receptor targeting CLCF1–CNTFR signaling in lung adenocarcinoma

Author

Kim, Jun W, Marquez, Cesar P, Kostyrko, Kaja, Koehne, Amanda L, Marini, Kieren, Simpson, David R, Lee, Alex G, Leung, Stanley G, Sayles, Leanne C, Shrager, Joseph, Ferrer, Irene, Paz-Ares, Luis, Gephart, Melanie Hayden, Vicent, Silvestre, Cochran, Jennifer R, and Sweet-Cordero, E Alejandro

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Lung Cancer, Lung, Aetiology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Adenocarcinoma of Lung, Animals, Cell Line, Tumor, Cell Proliferation, Ciliary Neurotrophic Factor Receptor alpha Subunit, Cytokines, Gene Expression Regulation, Neoplastic, Humans, Interleukins, Mice, Mutation, Protein Binding, Proto-Oncogene Proteins p21(ras), Signal Transduction, Tumor Microenvironment, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.

Published
2019

27. First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy

Author

Munster, Pamela, Mita, Monica, Mahipal, Amit, Nemunaitis, John, Massard, Christophe, Mikkelsen, Tom, Cruz, Cristina, Paz-Ares, Luis, Hidalgo, Manuel, Rathkopf, Dana, Blumenschein, George, Smith, David C, Eichhorst, Barbara, Cloughesy, Tim, Filvaroff, Ellen H, Li, Shaoyi, Raymon, Heather, de Haan, Hans, Hege, Kristen, and Bendell, Johanna C

Subjects
Clinical Research, Rare Diseases, Brain Disorders, Orphan Drug, Cancer, Clinical Trials and Supportive Activities, Patient Safety, Hematology, Pediatric Cancer, Pediatric, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, CC-115, mTORC1/mTORC2, mTOR inhibitor, DNA-PK inhibitor, Phase I study, Oncology and Carcinogenesis
Abstract

PurposeThis first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.Patients and methodsPatients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.ResultsForty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.ConclusionCC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.Clinical trial registrationNCT01353625.

Published
2019

28. A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms.

Author

Wolin, Edward, Mita, Alain, Mahipal, Amit, Meyer, Tim, Bendell, Johanna, Nemunaitis, John, Munster, Pam N, Paz-Ares, Luis, Filvaroff, Ellen H, Li, Shaoyi, Hege, Kristen, de Haan, Hans, and Mita, Monica

Subjects
Humans, Neuroendocrine Tumors, Carcinoid Tumor, Gastrointestinal Neoplasms, Pyrazines, Administration, Oral, Cohort Studies, Maximum Tolerated Dose, Adult, Aged, Middle Aged, Female, Male, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Administration, Oral, General Science & Technology
Abstract

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

Published
2019

29. YES1 Is a Druggable Oncogenic Target in SCLC

Author

Redin, Esther, Garrido-Martin, Eva M., Valencia, Karmele, Redrado, Miriam, Solorzano, Jose Luis, Carias, Rafael, Echepare, Mirari, Exposito, Francisco, Serrano, Diego, Ferrer, Irene, Nunez-Buiza, Angel, Garmendia, Irati, García-Pedrero, Juana M., Gurpide, Alfonso, Paz-Ares, Luis, Politi, Katerina, Montuenga, Luis M., and Calvo, Alfonso

Published
2022
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30. Durvalumab After Sequential Chemoradiotherapy in Stage III, Unresectable NSCLC: The Phase 2 PACIFIC-6 Trial

Author

Garassino, Marina C., Mazieres, Julien, Reck, Martin, Chouaid, Christos, Bischoff, Helge, Reinmuth, Niels, Cove-Smith, Laura, Mansy, Talal, Cortinovis, Diego, Migliorino, Maria R., Delmonte, Angelo, Sánchez, José Garcia, Chara Velarde, Luis Enrique, Bernabe, Reyes, Paz-Ares, Luis, Perez, Ignacio Diaz, Trunova, Nataliya, Foroutanpour, Kayhan, and Faivre-Finn, Corinne

Published
2022
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31. Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Author

Monteiro, Cátia, Miarka, Lauritz, Perea-García, María, Priego, Neibla, García-Gómez, Pedro, Álvaro-Espinosa, Laura, de Pablos-Aragoneses, Ana, Yebra, Natalia, Retana, Diana, Baena, Patricia, Fustero-Torre, Coral, Graña-Castro, Osvaldo, Troulé, Kevin, Caleiras, Eduardo, Tezanos, Patricia, Muela, Pablo, Cintado, Elisa, Trejo, José Luis, Sepúlveda, Juan Manuel, González-León, Pedro, Jiménez-Roldán, Luis, Moreno, Luis Miguel, Esteban, Olga, Pérez-Núñez, Ángel, Hernández-Lain, Aurelio, Mazarico Gallego, José, Ferrer, Irene, Suárez, Rocío, Garrido-Martín, Eva M., Paz-Ares, Luis, Dalmasso, Celine, Cohen-Jonathan Moyal, Elizabeth, Siegfried, Aurore, Hegarty, Aisling, Keelan, Stephen, Varešlija, Damir, Young, Leonie S., Mohme, Malte, Goy, Yvonne, Wikman, Harriet, Fernández-Alén, Jose, Blasco, Guillermo, Alcázar, Lucía, Cabañuz, Clara, Grivennikov, Sergei I., Ianus, Andrada, Shemesh, Noam, Faria, Claudia C., Lee, Rebecca, Lorigan, Paul, Le Rhun, Emilie, Weller, Michael, Soffietti, Riccardo, Bertero, Luca, Ricardi, Umberto, Bosch-Barrera, Joaquim, Sais, Elia, Teixidor, Eduard, Hernández-Martínez, Alejandro, Calvo, Alfonso, Aristu, Javier, Martin, Santiago M., Gonzalez, Alvaro, Adler, Omer, Erez, Neta, and Valiente, Manuel

Published
2022
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32. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial

Author

Paz-Ares, Luis G., Ramalingam, Suresh S., Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Urban, Laszlo, Caro, Reyes Bernabe, Park, Keunchil, Sakai, Hiroshi, Ohe, Yuichiro, Nishio, Makoto, Audigier-Valette, Clarisse, Burgers, Jacobus A., Pluzanski, Adam, Sangha, Randeep, Gallardo, Carlos, Takeda, Masayuki, Linardou, Helena, Lupinacci, Lorena, Lee, Ki Hyeong, Caserta, Claudia, Provencio, Mariano, Carcereny, Enric, Otterson, Gregory A., Schenker, Michael, Zurawski, Bogdan, Alexandru, Aurelia, Vergnenegre, Alain, Raimbourg, Judith, Feeney, Kynan, Kim, Sang-We, Borghaei, Hossein, O'Byrne, Kenneth John, Hellmann, Matthew D., Memaj, Arteid, Nathan, Faith Ellen, Bushong, Judith, Tran, Phuong, Brahmer, Julie R., and Reck, Martin

Published
2022
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33. Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

Author

Garassino, Marina C., Gadgeel, Shirish, Novello, Silvia, Halmos, Balazs, Felip, Enriqueta, Speranza, Giovanna, Hui, Rina, Garon, Edward B., Horinouchi, Hidehito, Sugawara, Shunichi, Rodriguez-Abreu, Delvys, Reck, Martin, Cristescu, Razvan, Aurora-Garg, Deepti, Loboda, Andrey, Lunceford, Jared, Kobie, Julie, Ayers, Mark, Piperdi, Bilal, Pietanza, M. Catherine, and Paz-Ares, Luis

Published
2022
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34. Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study

Author

Kim, Edward S, Kelly, Karen, Paz-Ares, Luis G, Garrido, Pilar, Jalal, Shadia, Mahadevan, Daruka, Gutierrez, Martin, Provencio, Mariano, Schaefer, Eric, Shaheen, Monte, Johnston, Erica L, Turner, P Kellie, Kambhampati, Siva Rama Prasad, Beckmann, Richard, Hossain, Anwar, John, William J, and Goldman, Jonathan W

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Lung, Clinical Trials and Supportive Activities, Digestive Diseases, Cancer, Lung Cancer, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Aminopyridines, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Carcinoma, Non-Small-Cell Lung, Drug Administration Schedule, Female, Humans, Lung Neoplasms, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Staging, Treatment Outcome, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC.Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules.Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively.Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543-51. ©2018 AACR.

Published
2018

35. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Author

Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, and Goode, Ellen L

Subjects
Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Tissue Array Analysis, Immunohistochemistry, Survival Analysis, Adult, Aged, Middle Aged, Female, Toll-Like Receptor 4, Myeloid Differentiation Factor 88, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Medical and Health Sciences
Abstract

ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and methodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P

Published
2018

36. First-line avelumab plus chemotherapy in patients with advanced solid tumors: results from the phase 1b/2 JAVELIN Chemotherapy Medley study

Author

Wheatley, Duncan A., primary, Berardi, Rossana, additional, Climent Duran, Miguel A., additional, Tomiak, Anna, additional, Greystoke, Alastair P., additional, Joshua, Anthony M., additional, Arkenau, Hendrik-Tobias, additional, Géczi, Lajos, additional, Garcia-Corbacho, Javier, additional, Paz-Ares, Luis G., additional, Hussain, Syed A., additional, Petruželka, Lubos, additional, Delmonte, Angelo, additional, Chappey, Colombe, additional, Masters, Joanna C., additional, Michelon, Elisabete, additional, Murphy, Danielle A., additional, Mwewa, Sandrine, additional, Cesari, Rossano, additional, and Doger de Speville, Bernard, additional

Published
2024
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37. Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407

Author

Powell, Steven F., Rodríguez-Abreu, Delvys, Langer, Corey J., Tafreshi, Ali, Paz-Ares, Luis, Kopp, Hans-Georg, Rodríguez-Cid, Jeronimo, Kowalski, Dariusz M., Cheng, Ying, Kurata, Takayasu, Awad, Mark M., Lin, Jinaxin, Zhao, Bin, Pietanza, M. Catherine, Piperdi, Bilal, and Garassino, Marina C.

Published
2021
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39. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

Author

Paz-Ares, Luis, Vicente, David, Tafreshi, Ali, Robinson, Andrew, Soto Parra, Hector, Mazières, Julien, Hermes, Barbara, Cicin, Irfan, Medgyasszay, Balazs, Rodríguez-Cid, Jerónimo, Okamoto, Isamu, Lee, SungSook, Ramlau, Rodryg, Vladimirov, Vladimir, Cheng, Ying, Deng, Xuan, Zhang, Ying, Bas, Tuba, Piperdi, Bilal, and Halmos, Balazs

Published
2020
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42. Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

Author

Remon, Jordi, Passiglia, Francesco, Ahn, Myung-Ju, Barlesi, Fabrice, Forde, Patrick M., Garon, Edward B., Gettinger, Scott, Goldberg, Sarah B., Herbst, Roy S., Horn, Leora, Kubota, Kaoru, Lu, Shun, Mezquita, Laura, Paz-Ares, Luis, Popat, Sanjay, Schalper, Kurt A., Skoulidis, Ferdinandos, Reck, Martin, Adjei, Alex A., and Scagliotti, Giorgio V.

Published
2020
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43. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy

Author

Travis, William D., Dacic, Sanja, Wistuba, Ignacio, Sholl, Lynette, Adusumilli, Prasad, Bubendorf, Lukas, Bunn, Paul, Cascone, Tina, Chaft, Jamie, Chen, Gang, Chou, Teh-Ying, Cooper, Wendy, Erasmus, Jeremy J., Ferreira, Carlos Gil, Goo, Jin-Mo, Heymach, John, Hirsch, Fred R., Horinouchi, Hidehito, Kerr, Keith, Kris, Mark, Jain, Deepali, Kim, Young T., Lopez-Rios, Fernando, Lu, Shun, Mitsudomi, Tetsuya, Moreira, Andre, Motoi, Noriko, Nicholson, Andrew G., Oliveira, Ricardo, Papotti, Mauro, Pastorino, Ugo, Paz-Ares, Luis, Pelosi, Giuseppe, Poleri, Claudia, Provencio, Mariano, Roden, Anja C., Scagliotti, Giorgio, Swisher, Stephen G., Thunnissen, Erik, Tsao, Ming S., Vansteenkiste, Johan, Weder, Walter, and Yatabe, Yasushi

Published
2020
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44. Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma

Author

Mur, Emilie Bousquet, Bernardo, Sara, Papon, Laura, Mancini, Maicol, Fabbrizio, Eric, Goussard, Marion, Ferrer, Irene, Giry, Anais, Quantin, Xavier, Pujol, Jean-Louis, Calvayrac, Olivier, Moll, Herwig P., Glasson, Yael, Pirot, Nelly, Turtoi, Andrei, Canamero, Marta, Wong, Kwok-Kin, Yarden, Yosef, Casanova, Emilio, Soria, Jean-Charles, Colinge, Jacques, Siebel, Christian W., Mazieres, Julien, Favre, Gilles, Paz-Ares, Luis, and Maraver, Antonio

Subjects
Cancer treatment -- Health aspects, Adenocarcinoma -- Development and progression -- Health aspects, Osimertinib -- Health aspects, Tyrosine -- Health aspects, Antineoplastic agents -- Health aspects, Phenols (Class of compounds) -- Health aspects, Gefitinib, Chemotherapy, Tumors, Diseases, Health care industry
Abstract

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as [EGFR.sup.T790M] and [EGFR.sup.C7975]. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in [EGFR.sup.T790M] and [EGFR.sup.C7975] tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor-resistant tumors, with [EGFR.sup.T790M] and [EGFR.sup.C7975] mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib- treated patients after disease progression., Introduction Lung cancer kills approximately 1 million people every year worldwide and is the leading cause of death by cancer in the world. Lung cancer consists of 2 main types: [...]

Published
2020
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45. Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

Author

Conde, Esther, Hernandez, Susana, Martinez, Rebeca, Angulo, Barbara, De Castro, Javier, Collazo-Lorduy, Ana, Jimenez, Beatriz, Muriel, Alfonso, Mate, Jose Luis, Moran, Teresa, Aranda, Ignacio, Massuti, Bartomeu, Rojo, Federico, Domine, Manuel, Sansano, Irene, Garcia, Felip, Felip, Enriqueta, Mancheño, Nuria, Juan, Oscar, Sanz, Julian, Gonzalez-Larriba, Jose Luis, Atienza-Cuevas, Lidia, Arriola-Arellano, Esperanza, Abdulkader, Ihab, Garcia-Gonzalez, Jorge, Camacho, Carmen, Rodriguez-Abreu, Delvys, Teixido, Cristina, Reguart, Noemi, Gonzalez-Piñeiro, Ana, Lazaro-Quintela, Martin, Lozano, Maria Dolores, Gurpide, Alfonso, Gomez-Roman, Javier, Lopez-Brea, Marta, Pijuan, Lara, Salido, Marta, Arriola, Edurne, Company, Amparo, Insa, Amelia, Esteban-Rodriguez, Isabel, Saiz, Monica, Azkona, Eider, Alvarez, Ramiro, Artal, Angel, Plaza, Maria Luz, Aguiar, David, Enguita, Ana Belen, Benito, Amparo, Paz-Ares, Luis, Garrido, Pilar, and Lopez-Rios, Fernando

Published
2019
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48. Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden

Author

Paz-Ares, Luis, primary, Garassino, Marina Chiara, additional, Chen, Yuanbin, additional, Reinmuth, Niels, additional, Hotta, Katsuyuki, additional, Poltoratskiy, Artem, additional, Trukhin, Dmytro, additional, Hochmair, Maximilian J., additional, Özgüroğlu, Mustafa, additional, Ji, Jun Ho, additional, Statsenko, Galina, additional, Conev, Nikolay, additional, Bondarenko, Igor, additional, Havel, Libor, additional, Losonczy, György, additional, Xie, Mingchao, additional, Lai, Zhongwu, additional, Godin-Heymann, Nadia, additional, Mann, Helen, additional, Jiang, Haiyi, additional, Shrestha, Yashaswi, additional, and Goldman, Jonathan W., additional

Published
2023
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49. Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study

Author

Vokes, Everett E., primary, Mornex, Francoise, additional, Sezer, Ahmet, additional, Cheng, Ying, additional, Fang, Jian, additional, Baz, David Vicente, additional, Cil, Timucin, additional, Adjei, Alex A., additional, Ahn, Myung-Ju, additional, Barlesi, Fabrice, additional, Felip, Enriqueta, additional, Garon, Edward B., additional, Audhuy, Francois, additional, Ito, Rena, additional, Sato, Masashi, additional, Eggleton, S. Peter, additional, Martin, Claudio Marcelo, additional, Reck, Martin, additional, Robinson, Clifford G., additional, and Paz-Ares, Luis, additional

Published
2023
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