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1. Response to Mobocertinib in a patient with advanced Non-Small Cell Lung Cancer harboring EGFR exon 20 insertion after several therapies including Amivantamab

Author

Elena Corral de la Fuente, María Eugenia Olmedo García, Inmaculada Orejana Martín, Amparo Benito Berlinches, Ana Gómez Rueda, Yolanda Lage Alfranca, and Pilar Garrido

Subjects
EGFR, Exon20 insertions, Non-Small Cell lung cancer, Mobocertinib, targeted therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Patients harboring EGFR exon 20 insertion (EGFRex20ins) advanced Non-Small Cell Lung Cancer (NSCLC) represent a poor prognosis population of oncogene-addicted cancers in need of targeted therapy, since they are resistant to available EGFR tyrosine kinase inhibitor (TKIs) and there is limited efficacy data of immunotherapy.New drugs targeting EGFRex20ins are under development, such as mobocertinib, an antiEGFR TKI or amivantamab, a bispecific antibody targeting EGFR and MET, which have shown promising results in pre-treated patients. The activity of mobocertinib after treatment with amivantamab and vice versa is currently unknown.We present a 49-year-old, non-smoking woman with advanced EGFRex20ins NSCLC who had a significant response to mobocertinib after several treatments, including amivantamab. We discuss new treatments in development for patients with EGFRex20ins NSCLC.

Published
2022
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2. Efficacy of immunotherapy in sarcomatoid lung cancer, a case report and literature review

Author

Magda Palka Kotlowska, Ana Gómez Rueda, María Eugenia Olmedo, Amparo Benito, Almudena Santón Roldán, Maria Angeles Fernandez Méndez, Luis Gorospe, José Palacios, and Pilar Garrido López

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Sarcomatoid carcinoma is a subtype of non-small cell lung cancer (NSCLC) characterized by mesenchymal – epithelial transition component and awful prognosis. In this report, based on a case of stage IV lung sarcomatoid carcinoma with an extraordinary evolution and survival over 4 years, we address unresolved questions about the treatment of this cancer. We also make a literature review about the key factors that characterize this histology and that should be considered when treating those patients. Sarcomatoid carcinoma presents with mutations as KRAS, EGFR, ALK or MET in up to 70% of cases, and an important expression of PD-L1 (also called B7-H1), which can influence treatment of those patients with new drugs as immune checkpoint inhibitors. Immunotherapy has changed the horizon of patients with stage IV lung cancers without driver mutations, as their survival has improved extraordinary. Moreover, radical treatments are being considered in long survivors with oligometastatic disease. In this report, we review targeted and radical therapy, treatment duration and the mechanisms responsible of disease evolution of sarcomatoid tumors. Keywords: Sarcomatoid, Pleomorphic, Immunotherapy, Long survivor, Lung cancer

Published
2019
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6. Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design

Author

Tuochuan Dong, Tony Sk Mok, Jay M. Lee, Masahiro Tsuboi, Cecile Blin, Ana Gómez-Rueda, Edward S. Kim, Vanessa Q. Passos, Vanessa Rodrik-Outmezguine, Pilar Garrido, Luis Gorospe, Jean-Louis Pujol, Amparo Benito, and Nicolas Moreno

Subjects
Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Adolescent, medicine.medical_treatment, Interleukin-1beta, Programmed Cell Death 1 Receptor, Disease, Pembrolizumab, Antibodies, Monoclonal, Humanized, Young Adult, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Humans, Medicine, Pneumonectomy, Lung cancer, Lung, Neoplasm Staging, Randomized Controlled Trials as Topic, business.industry, General Medicine, Immunotherapy, medicine.disease, Neoadjuvant Therapy, Immune checkpoint, Clinical trial, Canakinumab, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, business, medicine.drug
Abstract

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics.Lay abstract A previous study showed that canakinumab reduced the risk of lung cancer in patients with heart disease. Canakinumab blocks an inflammatory protein called IL-1β that is involved in cancer. Anti-cancer drugs used before surgery (‘neo-adjuvant’) can improve the success rate of surgery and may help prevent the cancer from returning. Neo-adjuvant trials help us understand how the drugs work and how they affect cancer. CANOPY-N (NCT03968419) is an ongoing randomized, exploratory, Phase II clinical trial testing canakinumab and pembrolizumab (a different cancer immunotherapy), alone or combined, for patients with early non-small-cell lung cancer. The study will test whether treatment can kill most cancer cells in the surgery sample (‘major pathological response’). It will also investigate other effects on cancer biology, levels of molecules that measure possible clinical benefit (‘biomarkers’) and side effects.

Published
2021
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7. Blood Biomarkers of Response to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Author

Yolanda Lage Alfranca, María Eugenia Olmedo Garcia, Ana Gómez Rueda, Pablo Álvarez Ballesteros, Diana Rosero Rodríguez, and Marisa Torres Velasco

Subjects
General Medicine
Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), either used in monotherapy or in combination with chemotherapy. While some patients achieve durable responses, some will not get benefit from this treatment. Early identification of non- responder patients could avoid unnecessary treatment, potentially serious immune-related adverse events and reduce treatment costs. PD-L1 expression using immunohistochemistry is the only approved biomarker for the selection of patients that can benefit from immunotherapy. However, application of PD-L1 as a biomarker of treatment efficacy shows many deficiencies probably due to the complexity of the tumor microenvironment and the technical limitations of the samples. Thus, there is an urgent need to find other biomarkers, ideally blood biomarkers to help us to identify different subgroups of patients in a minimal invasive way. In this review, we summarize the emerging blood-based markers that could help to predict the response to ICIs in NSCLC.

Published
2022

9. Challenges in Management of Patients With Lung Cancer in Times of COVID-19: An Imaging Perspective

Author

Rosa Mariela Mirambeaux-Villalona, Amparo Benito-Berlinches, Yolanda Lage-Alfranca, Ana María Ayala-Carbonero, Patricia Paredes-Rodríguez, Luis Gorospe, Gemma María Muñoz-Molina, Ana Gómez-Rueda, Paola Arrieta, and María Carmen Vallejo-Ocaña

Subjects
Pulmonary and Respiratory Medicine, Cancer Research, 2019-20 coronavirus outbreak, Lung Neoplasms, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, Diagnosis, Differential, Betacoronavirus, COVID-19 Testing, Antibodies monoclonal, Pandemic, medicine, Humans, Lung cancer, Pandemics, Letter to the Editor, biology, Clinical Laboratory Techniques, SARS-CoV-2, business.industry, Perspective (graphical), Antibodies, Monoclonal, COVID-19, biology.organism_classification, medicine.disease, Virology, Oncology, Coronavirus Infections, business
Published
2020

10. Percutaneous imaging‐guided biopsies in patients with COVID‐19 positive cancer performed at the peak of the COVID‐19 pandemic

Author

Ana María Ayala-Carbonero, Amparo Benito-Berlinches, Rosa Mariela Mirambeaux-Villalona, Andrés González-García, Luis Gorospe, Gemma María Muñoz-Molina, Ana Gómez-Rueda, and Sara Fra-Fernández

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Percutaneous, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, Cancer, General Medicine, medicine.disease, Oncology, Internal medicine, Pandemic, medicine, In patient, Surgery, business
Published
2020
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11. Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping

Author

Enriqueta Felip, Jon Zugazagoitia, I. Faul, Ana Gómez-Rueda, O. Juan-Vidal, Carlos Camps, P. Iranzo, José Miguel Sánchez-Torres, Israel Ramos, Luis Paz-Ares, Eloisa Jantus-Lewintre, Richard B. Lanman, R. Bernabé, Mariano Provencio, Santiago Ponce-Aix, F. Franco, Magda Palka, Dolores Isla, Pilar Garrido, Rosario García-Campelo, Jose Manuel Trigo, J. de Castro, Instituto de Salud Carlos III, and European Commission

Subjects
Male, Lung adenocarcinoma, 0301 basic medicine, Oncology, Lung Neoplasms, Circulating Tumor DNA, 0302 clinical medicine, co-occurring genomic alterations, Genotype, Prospective Studies, Neoplasm Metastasis, Precision Medicine, Stage (cooking), Prospective cohort study, Insufficient tissue, Aged, 80 and over, actionable genomic alterations, Hazard ratio, High-Throughput Nucleotide Sequencing, DNA, Neoplasm, Genomics, insufficient tissue, Hematology, Middle Aged, Actionable genomic alterations, Prognosis, Survival Rate, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, digital next-generation sequencing, Adenocarcinoma of Lung, 03 medical and health sciences, Proto-Oncogene Proteins, Internal medicine, Biomarkers, Tumor, medicine, ROS1, Humans, Lung cancer, Genotyping, Aged, Digital next-generation sequencing, Lung, Genome, Human, business.industry, ctDNA, Co-occurring genomic alterations, lung adenocarcinoma, medicine.disease, 030104 developmental biology, Mutation, business, Follow-Up Studies
Abstract

[Background] Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. [Patients and methods] We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. [Results] Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1–4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1–2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). [Conclusion] Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies., Research grant support was provided by Guardant Health Inc. (grant number C16/12/00442) for plasma-based comprehensive genomic testing. Instituto de Salud Carlos IIICM15/00196; CIBERONCCB16/12/00350;ISCIIIPI1401964PIE15/00076; RTICCR12/0036/0028; CIBERONCC16/12/00442; Regional Development European Funds Guardant Health IncC16/12/00442.

Published
2019
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12. ALK rearranged non–small cell lung carcinoma with EML4-NTRK3 fusion as a possible mechanism of resistance to third-generation ALK inhibitors

Author

Maria Eugenia Olmedo Garcia, Almudena Santón Roldán, Yolanda Lage Alfranca, Elena Corral de la Fuente, Ana Gómez Rueda, Pilar Garrido, Margaret Lario, and Amparo Benito Berlinches

Subjects
medicine.drug_class, medicine.medical_treatment, Entrectinib, ALK fusion, ALK TKI resistance, Targeted therapy, Non-small cell lung cancer, Next generation sequencing, hemic and lymphatic diseases, ROS1, Carcinoma, Medicine, Epidermal growth factor receptor, RC254-282, General Environmental Science, medicine.diagnostic_test, biology, business.industry, General Engineering, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, respiratory tract diseases, ALK inhibitor, NTRK3 fusion, Cancer research, biology.protein, General Earth and Planetary Sciences, business, Tyrosine kinase, Fluorescence in situ hybridization
Abstract

Objectives Neurotrophic tropomyosin receptor kinase (NTRK) fusions might be an off-target resistance mechanism to ALK Tyrosine Kinase Inhibitors (TKIs) in the same way as it has been suggested with activating epidermal growth factor receptor (EGFR) TKIs. Materials and methods DNA and RNA next-generation sequencing (NGS) was performed on the resected brain metastasis of a patient with advanced ALK Rearranged Non–Small Cell Lung Carcinoma (NSCLC) after resistance to several ALK TKIs including third generation ALK inhibitor, for pathological diagnosis and molecular resistance mechanism analysis. Results and conclusion NGS revealed an EML4-NTRK3 fusion that was confirmed by Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH). Despite having two potential targetable fusions, the patient did not respond to entrectinib, a multi-targeted pan-RTK, ROS1 and ALK inhibitor. NGS analysis in blood or tissues samples should be encouraged once resistance develops to TKIs in patients with ALK rearrangements, as actionable fusions, mutations or amplifications might arise as resistance mechanism and some patients could benefit from targeted therapy.

Published
2021
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13. Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance

Author

Dolores Isla, José Miguel Sánchez-Torres, Richard B. Lanman, Iris Faull, Santiago Ponce-Aix, Enriqueta Felip, Pilar Garrido, O. Juan-Vidal, Rosario García-Campelo, Carlos Camps, Inmaculada Ramos, Ana Gómez-Rueda, Eloisa Jantus-Lewintre, Luis Paz-Ares, R. Bernabé, Jon Zugazagoitia, Jose Manuel Trigo, Mariano Provencio, Javier de Castro, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España), European Commission, and Comunidad de Madrid

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Lung Neoplasms, Tyrosine-kinase inhibitor, Circulating Tumor DNA, chemistry.chemical_compound, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Medicine, Osimertinib, Neoplasm Metastasis, Prospective cohort study, Aged, 80 and over, Disease Management, High-Throughput Nucleotide Sequencing, Middle Aged, 030220 oncology & carcinogenesis, Female, medicine.drug, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Cabozantinib, medicine.drug_class, 03 medical and health sciences, Internal medicine, ROS1, Biomarkers, Tumor, Humans, Lung cancer, Protein Kinase Inhibitors, Aged, Neoplasm Staging, Digital next-generation sequencing, TKI resistance, Crizotinib, business.industry, Oncogene-driven NSCLC, Oncogenes, ctDNA, medicine.disease, Lorlatinib, respiratory tract diseases, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Mutation, business
Abstract

[Objectives] Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance., [Materials and methods] We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1-altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay)., [Results] We included 53 patients separated in 3 cohorts: 31 EGFR-mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790M + NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1-rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (n = 9, 17%), or plasma NGS and tissue sequencing (n = 2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790 M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790 M by Guardant360 but were T790M + by tissue and BEAMing digital PCR respectively, and also received osimertinib., [Conclusion] NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting., J. Zugazagoitia was funded by Instituto de Salud Carlos III (Rio Hortega, CM15/00196). E. Jantus-Lewintre and C. Camps were funded by CIBERONC (CB16/12/00350). P Garrido was funded by ISCIII: PIE15/00050, and CIBERONC (C16/12/00442). L. Paz-Ares was funded by ISCIII: PI1401964, PIE15/00076, RTICC (R12/0036/0028), CIBERONC (C16/12/00442), and CAM (B2017/BMP-3884), co-funded by FEDER from Regional Development European Funds (European Union). M: Provencio was funded by ISCIII: PIE 1400/64, PI16/01818 and European Union Funds: H2020-sc1-2016-2017.

Published
2019

14. ED-33ELDERLY PATIENTS WITH GLIOBLASTOMA: SHOULD BE TREATED IN A DIFFERENT WAY?

Author

José Antonio Gutierrez Cerco, Vanessa Pachón Olmos, Luis Ley Urzaiz, Héctor Pian, Ana Gómez Rueda, Marta Del Álamo de Pedro, Alfredo Carrato Mena, Jacobo Muñoz del Toro, and María Ángeles Vaz Salgado

Subjects
Cancer Research, medicine.medical_specialty, Temozolomide, business.industry, Nausea, Neutropenia, medicine.disease, Surgery, law.invention, Regimen, Abstracts, Oncology, Randomized controlled trial, law, Concomitant, Cohort, medicine, Neurology (clinical), Progression-free survival, medicine.symptom, business, medicine.drug
Abstract

BACKGROUND: The management of glioblastoma (GB) in elderly patients is not well established, since until recently they have been excluded from randomized trials and there are concerns about the toxicity. METHODS: The authors retrospectively reviewed 53 patients at a single institution from 2005 to 2013. Patients were 70 years of age and older with histologically confirmed GB. RESULTS: Median age was 75 years (70-88y). Fifty-six percent men, 43% women. Majority had some kind of minor morbidity (89%), mainly arterial hypertension (55%). Complete resection was performed in 52%. Biopsy in 8%. 90% had presurgical KPS >70. Seven (14%) had worse KPS after surgery. 71% received radiotherapy, in 45% 60 Gy and in 26% 30 Gy. Nearly 40% were treated with concomitant and adjuvant temozolomide. The median number of cycles was 4,43 (1-14). 6% had grade 3 or 4 neutropenia or trombocitopenia. 24% had grade 1 asthenia or nausea and vomits. Median overall survival (OS) for the whole cohort was 7,36 m (95% CI 4,8-9,8). Median progression free survival was 5.9 m (3-8.7m). Treatment with temozolomide concomitant and adjuvant (Stupp regimen) was associated with longer OS (11,16 vs 4,1m p = 0.008 ). The median OS was 8,3 m. for those who received radiotherapy and 1,5m for those who did not (p = 0,046). No statistical differences were found between those treated with 60 or 30 Gy (p = 0.143). Nearly 10% was older than 80. Median OS in these patients was 4,2m even though 71% had a complete resection. CONCLUSION: In our experience, in selected patients with newly diagnosed glioblastoma over the age of 70, more intensive treatment was associated with prolonged OS, and results are close to those obtained in younger patients. Nevertheless these are retrospective data, selection bias should be considerer. Further randomized trial should be conducted to investigate this topic.

Published
2014

15. NEURO/MEDICAL ONCOLOGY

Author

Irene Helenowski, Naoya Hashimoto, Jan J. Heimans, Toshiki Yoshimine, Johan A F Koekkoek, Evelyne Emery, José L. Asencio, Andrea Chamczuck, Carly Bridge, Gilbert Faure, Barbara-Ann Millar, Arthur Rosiello, Michela Casanova, John Freymann, Giulio Bertani, Jun-ich Adachi, Christian LaFougere, Julianne Bloom, Paul Vincent Opinaldo, Tobey J. McDonald, Alexander Khandji, Maciej M. Mrugala, Agnieszka Kowalska, Clifford G. Robinson, Josef Pichler, Jayesh Mehta, Lisa M. DeAngelis, Katie Slusarz, Rachel Grossman, Juan Armando Mejía, Sadhana Kannan, In Ah Kim, Pierre Soubeyran, Nabil Ahmed, Matthew J. Matasar, David A. Reardon, Marie-Laure Tanguy, Andrea Pace, Vani Santosh, Tackeun Kim, Adrienne C. Lahti, John E. Donahue, Pavlina Poloskova, Marc H. A. Jansen, Nilanjana Banerji, Margaret Schwartz, Matthias Kirsch, Robert Jeraj, Guus A.M.S. van Dongen, Samuel Singer, Tom J. Snijders, Santosh Kesari, Riccardo Soffetti, Takashi Sasayama, Diana Ly, Kaoru Kurisu, Carsten Friedrich, Shinji Kawabata, Cedric Revil, Michael A. Jacobs, Ryuichi Hirayama, Wan-Soo Yoon, Kathleen Lupica, Christopher Reilly, Takuichiro Hideo, Miguel Gil, Josep Garcia, Ming Zheng, Edward K. Avila, Mairéad G McNamara, Hartmut Uschmann, Jeffrey S. Weinberg, Craig H. Moskowitz, Jörg Hense, Manmeet Ahluwalia, Georg Bjarnason, David Corwin, Shakti Ramkissoon, Jad Alshami, Eric C. Leuthardt, Paul Dilfer, Margaret Patton, Lindsey Heathcock, Cees van Montfort, Rakesh Kumar Gupta, Akihiko Yoshida, Carmine Maria Carapella, Guy K. Mckhann, Marian Hajduch, Meinhard Nevinny-Stickel, Patricia Bruns, Ashish Suri, Hernán Carranza, David A. Gutman, Carlos Yepes, Patrick Y. Wen, T. Cloughesy, Anna Kaltenboeck, Carlos Bartels, Paul D. Brown, Lisa Fichtel, Lorenzo Giammattei, Steven Hamilton, Nobuyuki Takayama, Nan Lin, Jan Drappatz, Roland Eils, Akihiro Tsuboi, Patrick Urban, Minesh P. Mehta, Remy Gressin, Zarnie Lwin, Clarence Eng, Ian F. Dunn, Sin-Soo Jeun, Alva B. Weir, Elisa Trevisan, silviya Meletath, Fumiyuki Yamasaki, Scott N. Hwang, Navya Nambudiri, Timothy F. Cloughesy, Paolo Rampini, Kathryn J. Ruddy, Justin Kirby, Marc C. Huisman, Normand Laperriere, Abajo Guijarro, Alberto González-Aguilar, David M. Peereboom, Antoine F. Carpentier, Steven M. Greenberg, Chikashi Ishioka, Sarah C. Gaffey, Sneha Arya, Guy M. McKhann, Richard Curry, Takashi Watanabe, Keishi Makino, Radek Trojanec, Hideo Takeshima, Joseph F. Megyesi, Jasmina I. Ivanova, Victor Rodriguez Berrocal, Marcel Kool, Eric Burton, Sandra K. Johnston, Hideyuki Arita, Konstantina Karabatsou, Robert C. Rostomily, Sean Grimm, Ralph G. Dacey, Karl Olson, Sonia Gómez, Harry C. Schouten, Christof M. Kramm, Fred H. Hochberg, Darren Hargrave, Kazuhiko Sugiyama, Wilhelm Boogerd, Stefano Tiziani, Christine McCluskey, Albert H. Kim, Tejpal Gupta, Ida Martinelli, Friedrich-Wilhelm Kreth, Lennea Coombs, Keith L. Ligon, J. Manuel Sarmiento, David R. Macdonald, Holly Dickinson, Cristian Massacesi, Basile Wittwer, Jung-Il Lee, Volker Hovestadt, Mark Smolkin, Sampath Somanna, Ingo K. Mellinghoff, Nancy Ann Oberheim Bush, Sanjeev Francis, Roland Goldbrunner, Jai Ho Choi, John Sampson, Roy Allan Dominique Torcuator, Kathleen R. Lamborn, Simon V. Liubinas, Daniel J. Sargent, Christina K. Cramer, Francine Armentano, Heather Leeper, Stefan Rutkowski, Prakash Shetty, Arivazhagan Arimappamagan, Alicia Ortega, Enrique Jiménez, Kazuhiro Tanaka, Kolette D. Fly, Seunggu Han, Nicolas U. Gerber, David Schiff, Antonella Castellano, Isabel Arrillaga-Romany, Robert J. Wechsler-Reya, Sophie Taillibert, Macarena de la Fuente, Wolfgang Wick, Monica Bennett, Francesco Cognetti, John de Groot, Michael Gonzales, Leon D. Ortiz, Yoshiaki Shiokawa, George Sachs, Ivo Tremont, Charles A. Conrad, Michael D. Taylor, Igor J. Barani, Shannon Langmead, Lisa Sturla, Doosik Kong, Rebecca D. Folkerth, Garrett Riggs, Yoon-La Choi, Carole Soussain, Calvin Soh, Peter Canoll, Mariza Daras, Melissa Hoag, James Rigas, Dana Cernea, Liu Diane, Kenji Wakiya, Sandra Silberman, Ivan A. Reveles, Jeffrey S. Wefel, Wenting Wu, Marie Blonski, MA Majaid, Vanessa A. Nestor, Maurits W.C.B. Sanders, Cynthia Harrison, Ruxandra Costa, Andrea Hawkins-Daarud, Mark R. Gilbert, Ruth Katz, Masayuki Kanamori, Tomek Janicki, Aaron C. Spalding, Dong-Sup Chung, Lauren Foresman, Fateme Salehi, Allan H. Friedman, Eric P. Winer, Robert Kwiecien, Joachim Kuehl, Motoo Nagane, Stanislaw Burzynski, Tomokazu Aoki, Gregory N. Fuller, Nina Paleologos, Darell D. Bigner, Max Wintermark, Adam E. Flanders, Eiichi Ishikawa, Subramanian Hariharan, Doreen Pachow, Glen Stevens, Ulrich Schüller, Jennifer Lycette, Jennifer Garst, Jeffery T. Williams, Gordana Vlahovic, Tjeerd J. Postma, Tribhwan Vats, Isabel Arrilaga, Krista Follmer, Henry S. Friedman, Kenneth Schwartz, James Perry, Jonas M. Sheehan, Christian Grommes, Annette M. Molinaro, Seung-Ho Yang, Peter Lichter, Naoki Kagawa, Trish Whitcomb, Monica Loghin, Amanda L. Bergner, Miroslav Vaverka, Jayashree Kalpathy-Cramer, Chitra Sarkar, Thomas Davidson, Nithya Ramnath, Leland Rogers, Roberta Rudà, Steven A. Toms, Martin Gore, Khê Hoang-Xuan, Emmanuel Gyan, Hani Malone, Jun-ichi Adachi, Jennifer Rifenburg, Stefan M. Pfister, Luis Carlos Mayor, Vanja Vaccaro, Hannah E. Goldstein, Karen Fink, Eva Dombi, Timothy Cloughsey, Sabina Eigenbrod, Jiri Ehrmann, Li Li, Pamela R. Jackson, Makoto Ohno, Craig Nolan, Gerald P. Linette, Tatjana Seute, Eric Bouffet, Patricia M. M. B. Soetekouw, David J. Pisapia, Marc Remke, Susan Snodgras, David Tran, Keiichi Kobayashi, Warren P. Mason, Setsu Sakamoto, Chiara Bosa, Gabriele Schackert, Alfred Yung, David Cachia, Toshihiko Kuroiwa, María Ángeles Vaz Salgado, F. Lonnqvist, Francesca Piludu, Alvina Acquaye, Keisuke Ueki, Jung Ho Han, Kathy Newell, Mythili Shastry, Yoon Jae Cho, Marco Riva, Laura M. Fayad, Kristin Diefes, André O. von Bueren, Ina Ly, Beatrix Lutiger, Hiroyoshi Suzuki, Jeanette K. Doorduijn, Eiji Kohmura, Olivier Chinot, Ichiyo Shibahara, Nathalie Jansen, Marta Del Álamo de Pedro, Scott L. Pomeroy, Andreas Zwergal, Terri S. Armstrong, Elmar Kirches, Daniel P. Cahill, Howard A. Fine, Cezary Szczylik, Stéphane Oudard, Gregg C. Shepard, Mark G. Kris, Andrea Milbourne, Dominique Jennings, Marco Locatelli, Dereck Amakye, Takumi Kudo, Simon Bailey, Alessandra Fabi, Taketoshi Maehara, Soumen Khatua, Caroline Houllier, Klaus J. Müller, Jaishri O. Blakeley, Karen Kelly, Jonathon Yun, Thomas Gergel, Diane Liu, Eric T. Wong, Alin Borha, Brian J. Williams, Rakesh Jalali, Birgit Geoerger, Naosuke Nonoguchi, Julie Walker, Jasmin Jo, Manmohan Singh, Mary Noel, Denise Lally-Goss, Tracy T. 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Gregory Cairncross, Ana Gómez Rueda, Augustus Perez, Ho Jun Seol, Frank Saran, Camillo Porta, Grace Elzinga, Michael Cloney, and Charles P. Hart

Subjects
Cancer Research, medicine.medical_specialty, business.industry, 010403 inorganic & nuclear chemistry, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, Abstracts, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Medical physics, Neurology (clinical), business
Published
2013

16. Targeting KRAS in Non-Small Cell Lung Cancer

Author

Elena Corral de la Fuente, Maria Eugenia Olmedo Garcia, Ana Gomez Rueda, Yolanda Lage, and Pilar Garrido

Subjects
targeted therapy, NSCLC, KRAS, immunotherapy, drug resistance, lung cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

Published
2022
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