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3. Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

Author

Brahmer, Julie, Long, Georgina, Hamid, Omid, Garon, Edward, Herbst, Roy, Andre, Thierry, Armand, Philippe, Bajorin, Dean, Bellmunt, Joaquim, Burtness, Barbara, Choueiri, Toni, Cohen, Ezra, Diaz, Luis, Shitara, Kohei, Kulkarni, Girish, McDermott, David, Shah, Manish, Tabernero, Josep, Vogel, Arndt, Zinzani, Pier, Jafari, Niusha, Bird, Steven, Snyder, Ellen, Gause, Christine, Bracco, Oswaldo, Pietanza, M, Gruber, Todd, and Ribas, Antoni

Subjects
Neoplasms, Pembrolizumab, Programmed cell death 1 receptor, Safety, Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Antibodies, Monoclonal, Humanized, Melanoma
Abstract

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Published
2024

4. Phase Ib/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type RAS Metastatic Colorectal Cancer.

Author

Van Cutsem, Eric, Yaeger, Rona, Delord, Jean-Pierre, Tabernero, Josep, Siu, Lillian, Ducreux, Michel, Siena, Salvatore, Elez, Elena, Kasper, Stefan, Zander, Thomas, Steeghs, Neeltje, Murphy, Danielle, Edwards, Michelle, and Wainberg, Zev

Subjects
RAS mutation, RAS wild type, binimetinib, colorectal cancer, panitumumab, Humans, Panitumumab, Colorectal Neoplasms, Benzimidazoles, Colonic Neoplasms, Rectal Neoplasms, ErbB Receptors, Antineoplastic Combined Chemotherapy Protocols, Proto-Oncogene Proteins p21(ras)
Abstract

INTRODUCTION: Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. METHODS: Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. RESULTS: No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. CONCLUSIONS: The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).

Published
2023

5. 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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6. Cardiotoxicity

Author

González, Nadia Saoudi, primary, Alvarez, Alejandro García, additional, Braña, Irene, additional, Tabernero, Josep, additional, and Oristrell, Gerard, additional

Published
2023
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7. Development of a prognostic model to predict 90-day mortality in hospitalised cancer patients (PROMISE tool): a prospective observational study

Author

Mirallas, Oriol, Martin-Cullell, Berta, Navarro, Víctor, Vega, Kreina Sharela, Recuero-Borau, Jordi, Gómez-Puerto, Diego, López-Valbuena, Daniel, Salva de Torres, Clara, Andurell, Laura, Pedrola, Anna, Berché, Roger, Palmas, Fiorella, Ucha, José María, Villacampa, Guillermo, Rezqallah, Alejandra, Sanz-Beltran, Judit, Bach, Rafael, Bueno, Sergio, Viaplana, Cristina, Molina, Gaspar, Hernando-Calvo, Alberto, Aguilar-Company, Juan, Roca, María, Muñoz-Couselo, Eva, Martínez-Martí, Alex, Alonso, Ada, Eremiev, Simeon, Macarulla, Teresa, Oaknin, Ana, Saura, Cristina, Élez, Elena, Felip, Enriqueta, Peñuelas, Ángeles, Burgos, Rosa, Pardo, Patricia Gómez, Garralda, Elena, Tabernero, Josep, Serradell, Sònia, Servitja, Sònia, Paez, David, Dienstmann, Rodrigo, and Carles, Joan

Published
2024
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9. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis

Author

Cohen, Romain, Raeisi, Morteza, Chibaudel, Benoist, Shi, Qian, Yoshino, Takayuki, Zalcberg, John R., Adams, Richard, Cremolini, Chiara, Van Cutsem, Eric, Heinemann, Volker, Tabernero, Josep, Punt, Cornelis J.A., Arnold, Dirk, Hurwitz, Herbert I., Douillard, Jean-Yves, Venook, Alan P., Saltz, Leonard B., Maughan, Timothy S., Kabbinavar, Fairooz, Bokemeyer, Carsten, Grothey, Axel, Mayer, Robert J., Kaplan, Richard, Tebbutt, Niall C., Randolph Hecht, J., Giantonio, Bruce J., Díaz-Rubio, Eduardo, Sobrero, Alberto F., Peeters, Marc, Koopman, Miriam, Goldberg, Richard M., Andre, Thierry, and de Gramont, Aimery

Published
2024
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10. European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4)

Author

Kroese, Tiuri E., Bronzwaer, Sebastiaan, van Rossum, Peter S.N., Schoppman, Sebastian F., Deseyne, Pieter R.A.J., van Cutsem, Eric, Haustermans, Karin, Nafteux, Philippe, Thomas, Melissa, Obermannova, Radka, Mortensen, Hanna R., Nordsmark, Marianne, Pfeiffer, Per, Elme, Anneli, Adenis, Antoine, Piessen, Guillaume, Bruns, Christiane J., Lordick, Florian, Gockel, Ines, Moehler, Markus, Gani, Cihan, Liakakos, Theodore, Reynolds, John V., Morganti, Alessio G., Rosati, Riccardo, Castoro, Carlo, Cellini, Francesco, D'Ugo, Domenico, Roviello, Franco, Bencivenga, Maria, de Manzoni, Giovanni, van Berge Henegouwen, Mark I., Hulshoff, Maarten C.C.M, van Dieren, Jolanda, Vollebergh, Marieke, van Sandick, Johanna W., Jeene, Paul, Muijs, Christel, Slingerland, Marije, Voncken, Francine E.M., Hartgrink, Henk, Creemers, Geert-Jan, van der Sangen, Maurice J.C., Nieuwenhuijzen, Grard A.P., Berbee, Maaike, Verheij, Marcel, Wijnhoven, Bas, Beerepoot, Laurens V., Mohammad, Nadia Haj, Mook, Stella, Ruurda, Jelle P., Kolodziejczyk, Piotr, Polkowski, Wojciech P., Wyrwicz, Lucjan, Alsina, Maria, Tabernero, Josep, Pera, Manuel, Kanonnikoff, Tania F., Cervantes, Andrés, Nilsson, Magnus, Monig, Stefan, Wagner, Anna D., Guckenberger, Matthias, Griffiths, Ewen A., Smyth, Elizabeth, Hanna, George B., Markar, Sheraz, Chaudry, M. Asif, Hawkins, Maria A., Cheong, Edward, van Laarhoven, Hanneke W.M., and van Hillegersberg, Richard

Published
2024
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11. PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

Author

Zimmer, Kai, Kocher, Florian, Untergasser, Gerold, Kircher, Brigitte, Amann, Arno, Baca, Yasmine, Xiu, Joanne, Korn, W. Micheal, Berger, Martin D., Lenz, Heinz-Josef, Puccini, Alberto, Fontana, Elisa, Shields, Anthony F., Marshall, John L., Hall, Michael, El-Deiry, Wafik S., Hsiehchen, David, Macarulla, Teresa, Tabernero, Josep, Pichler, Renate, Khushman, Moh’d, Manne, Upender, Lou, Emil, Wolf, Dominik, Sokolova, Viktorija, Schnaiter, Simon, Zeimet, Alain G., Gulhati, Pat, Widmann, Gerlig, and Seeber, Andreas

Published
2023
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12. Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

Author

Linares, Jenniffer, Sallent-Aragay, Anna, Badia-Ramentol, Jordi, Recort-Bascuas, Alba, Méndez, Ana, Manero-Rupérez, Noemí, Re, Daniele Lo, Rivas, Elisa I., Guiu, Marc, Zwick, Melissa, Iglesias, Mar, Martinez-Ciarpaglini, Carolina, Tarazona, Noelia, Varese, Monica, Hernando-Momblona, Xavier, Cañellas-Socias, Adrià, Orrillo, Mayra, Garrido, Marta, Saoudi, Nadia, Elez, Elena, Navarro, Pilar, Tabernero, Josep, Gomis, Roger R., Batlle, Eduard, Pisonero, Jorge, Cervantes, Andres, Montagut, Clara, and Calon, Alexandre

Published
2023
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14. Efficacy of immune checkpoint inhibitors for metastatic colorectal cancer with microsatellite instability in second or latter line using synthetic control arms: A non-randomised evaluation

Author

Cohen, Romain, Raeisi, Morteza, Chibaudel, Benoist, Yoshino, Takayuki, Shi, Qian, Zalcberg, John R., Adams, Richard, Cremolini, Chiara, Grothey, Axel, Mayer, Robert J., Van Cutsem, Eric, Tabernero, Josep, Bando, Hideaki, Misumi, Toshihiro, Overman, Michael J., André, Thierry, and de Gramont, Aimery

Published
2024
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15. Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients

Author

Brahmer, Julie R., Long, Georgina V., Hamid, Omid, Garon, Edward B., Herbst, Roy S., Andre, Thierry, Armand, Philippe, Bajorin, Dean, Bellmunt, Joaquim, Burtness, Barbara, Choueiri, Toni K., Cohen, Ezra E.W., Diaz, Luis A., Jr, Shitara, Kohei, Kulkarni, Girish, McDermott, David, Shah, Manish, Tabernero, Josep, Vogel, Arndt, Zinzani, Pier Luigi, Jafari, Niusha, Bird, Steven, Snyder, Ellen, Gause, Christine, Bracco, Oswaldo L., Pietanza, M. Catherine, Gruber, Todd, and Ribas, Antoni

Published
2024
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16. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study

Author

Shitara, Kohei, Rha, Sun Young, Wyrwicz, Lucjan S, Oshima, Takashi, Karaseva, Nina, Osipov, Mikhail, Yasui, Hisateru, Yabusaki, Hiroshi, Afanasyev, Sergey, Park, Young-Kyu, Al-Batran, Salah-Eddin, Yoshikawa, Takaki, Yanez, Patricio, Di Bartolomeo, Maria, Lonardi, Sara, Tabernero, Josep, Van Cutsem, Eric, Janjigian, Yelena Y, Oh, Do-Youn, Xu, Jianming, Fang, Xiao, Shih, Chie-Schin, Bhagia, Pooja, and Bang, Yung-Jue

Published
2024
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17. A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

Author

Tabernero, Josep, Argilés, Guillem, Falcone, Alfredo, Ciardiello, Fortunato, Goldberg, Richard, Bennouna, Jaafar, Argilés, Tabernero, J., Mulet, N., Limón, M.L., Valladares, M., Jiménez, P., Vieitez, J. M<ce:sup loc='post">a</ce:sup>, Grávalos, C., García-Alfonso, P., Santos, C., Páez, D., Tobeña, M., Sastre, J., García Paredes, B., Benavides, M., Aranda, E., Cano, M.T., Loupakis, F., Rguez Garrote, M., Guillén, C., Rivera, Ma F., Safont, J., Hiret, S., Bennouna, J., Pannier, D., Malka, D., Falcone, A., Cremolini, C., Mulet, Nuria, Valladares-Ayerbes, Manuel, Viéitez, José M., Grávalos, Cristina, García-Alfonso, Pilar, Santos, Cristina, Tobeña, María, García-Paredes, Beatriz, Benavides, Manuel, Cano, María T., Loupakis, Fotios, Rodríguez-Garrote, Mercedes, Rivera, Fernando, Goldberg, Richard M., Cremolini, Chiara, Tabernero, Josep M., and Aranda, Enrique

Published
2022
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20. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial

Author

Janjigian, Yelena Y, Kawazoe, Akihito, Bai, Yuxian, Xu, Jianming, Lonardi, Sara, Metges, Jean Phillipe, Yanez, Patricio, Wyrwicz, Lucjan S, Shen, Lin, Ostapenko, Yuriy, Bilici, Mehmet, Chung, Hyun Cheol, Shitara, Kohei, Qin, Shu-Kui, Van Cutsem, Eric, Tabernero, Josep, Li, Kan, Shih, Chie-Schin, Bhagia, Pooja, and Rha, Sun Young

Published
2023
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22. A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials

Author

Hernando-Calvo, Alberto, Vila-Casadesús, Maria, Bareche, Yacine, Gonzalez-Medina, Alberto, Abbas-Aghababazadeh, Farnoosh, Lo Giacco, Deborah, Martin, Agatha, Saavedra, Omar, Brana, Irene, Vieito, Maria, Fasani, Roberta, Stagg, John, Mancuso, Francesco, Haibe-Kains, Benjamin, Han, Ming, Berche, Roger, Pugh, Trevor J., Mirallas, Oriol, Jimenez, Jose, Gonzalez, Nadia Saoudi, Valverde, Claudia, Muñoz-Couselo, Eva, Suarez, Cristina, Diez, Marc, Élez, Elena, Capdevila, Jaume, Oaknin, Ana, Saura, Cristina, Macarulla, Teresa, Galceran, Joan Carles, Felip, Enriqueta, Dienstmann, Rodrigo, Bedard, Philippe L., Nuciforo, Paolo, Seoane, Joan, Tabernero, Josep, Garralda, Elena, and Vivancos, Ana

Published
2023
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24. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype

Author

Cuesta-Borràs, Estefania, Salvans, Cándida, Arqués, Oriol, Chicote, Irene, Ramírez, Lorena, Cabellos, Laia, Martínez-Quintanilla, Jordi, Mur-Espinosa, Alex, García-Álvarez, Alejandro, Hernando, Jorge, Tejedor, Juan Ramón, Mirallas, Oriol, Élez, Elena, Fraga, Mario F., Tabernero, Josep, Nuciforo, Paolo, Capdevila, Jaume, Palmer, Héctor G., and Puig, Isabel

Published
2023
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25. Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study

Author

Carranza, Omar, Greco, Martin Alberto, Coward, Jim, Joshua, Anthony, Karapetis, Christos, Hart, Christopher, Zhang, Alison, Prenen, Hans, Goeminne, Jean-Charles, Machiels, Jean-Pascal, Rottey, Sylvie, Corassa, Marcelo, Molin, Graziela Zibetti Dal, Tiscoski, Katsuki, Jardim, Denis Leonardo Fontes, Mak, Milena, Fu, Wei, Yao, Herui, Huang, Jing, Jiang, Haiping, Qin, Shukui, Chen, Baoshi, Yan, Dong, Yang, Yu, Loriot, Yohann, Le Tourneau, Christophe, Penel, Nicolas, Salas, Sébastien, Blay, Jean-Yves, Brachet, Pierre-Emmanuel, Durando, Xavier, Emambux, Sheik, Ravaud, Alain, Folprecht, Gunnar, Arnold, Dirk, Schuler, Martin, Ahrens, Marit, Golf, Alexander, Haag, Georg Martin, Lordick, Florian, Desuki, Alexander, Cazzaniga, Marina, Ciardiello, Fortunato, Milella, Michele, Koyama, Takafumi, Hirooka, Yoshiki, Okamoto, Wataru, Aogi, Kenjiro, Kuboki, Yasutoshi, Lee, Jungyun, Kim, Sung-Bae, Ahn, Myung-Ju, Chang, Jong Hee, Kim, Yong-Man, Nam, Do-Hyun, Park, Jae-Sung, Lugowska, Iwona, Paz-Ares, Luis, Moreno, Victor, Cervantes, Andres, Calvo, Mariona, Falcon, Alejandro, Gonzalez, Antonio, Tabernero, Josep, Martinez Bueno, Alejandro, García-Corbacho, Javier, Longo, Federico, Yen, Chia-Jui, Chen, Jen-Shi, Hou, Ming-Feng, Chao, Yee, Rau, Kun-Ming, Chiu, Tai-Jan, Feng, Yin-Hsun, Hsu, Chih-Hung, Huang, Wen-Tsung, Lai, Kuan-Ming, Yeh, Su-peng, Palmer, Daniel, Minchom, Anna, Winter, Helen, Welsh, Liam, Plummer, Ruth, Iyer, Gopakumar, Gutierrez, Martin, Bilen, Mehmet, Arrowsmith, Edward, Pant, Shubham, Spigel, David Robert, Zandberg, Dan Paul, Doroshow, Deborah, Lu-Emerson, Christine, Moezi, Mehdi, Paulson, Scott, Reardon, David, Ward, Patrick, Chaves, Jorge, Grigg, Claud, Hussein, Atif, Manda, Sudhir, Monticelli, Michael, Qamar, Rubina, Richey, Stephen L, Tamura, David, Wilks, Sharon, Iyer, Gopa, Witt, Olaf, Doi, Toshihiko, Reardon, David A, Massard, Christophe, Stuyckens, Kim, Crow, Lauren, Najmi, Saltanat, Hammond, Constance, Thomas, Shibu, Santiago-Walker, Ademi, Triantos, Spyros, and Sweiti, Hussein

Published
2023
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26. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study

Author

Dasari, Arvind, Lonardi, Sara, Garcia-Carbonero, Rocio, Elez, Elena, Yoshino, Takayuki, Sobrero, Alberto, Yao, James, García-Alfonso, Pilar, Kocsis, Judit, Cubillo Gracian, Antonio, Sartore-Bianchi, Andrea, Satoh, Taroh, Randrian, Violaine, Tomasek, Jiri, Chong, Geoff, Paulson, Andrew Scott, Masuishi, Toshiki, Jones, Jeremy, Csőszi, Tibor, Cremolini, Chiara, Ghiringhelli, Francois, Shergill, Ardaman, Hochster, Howard S, Krauss, John, Bassam, Ali, Ducreux, Michel, Elme, Anneli, Faugeras, Laurence, Kasper, Stefan, Van Cutsem, Eric, Arnold, Dirk, Nanda, Shivani, Yang, Zhao, Schelman, William R, Kania, Marek, Tabernero, Josep, and Eng, Cathy

Published
2023
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27. BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer

Author

Middleton, Gary, Yang, Yiqun, Campbell, Catarina D, André, Thierry, Atreya, Chloe E, Schellens, Jan HM, Yoshino, Takayuki, Bendell, Johanna C, Hollebecque, Antoine, McRee, Autumn J, Siena, Salvatore, Gordon, Michael S, Tabernero, Josep, Yaeger, Rona, O'Dwyer, Peter J, De Vos, Filip, Van Cutsem, Eric, Millholland, John M, Brase, Jan C, Rangwala, Fatima, Gasal, Eduard, and Corcoran, Ryan B

Subjects
Genetics, Digestive Diseases, Clinical Research, Cancer, Colo-Rectal Cancer, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Colorectal Neoplasms, ErbB Receptors, Gene Expression Regulation, Neoplastic, Humans, Imidazoles, MAP Kinase Kinase 1, Mutation, Oximes, Panitumumab, Prognosis, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Survival Rate, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeThe influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E-mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer.Patients and methodsPaired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS).ResultsConfirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect.ConclusionsBM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.

Published
2020

30. Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial

Author

Bekaii-Saab, Tanios, Okusaka, Takuji, Goldstein, David, Oh, Do-Youn, Ueno, Makoto, Ioka, Tatsuya, Fang, Weijia, Anderson, Eric C., Noel, Marcus S., Reni, Michele, Choi, Hye Jin, Goldberg, Jonathan S., Oh, Sang Cheul, Li, Chung-Pin, Tabernero, Josep, Li, Jian, Foos, Emma, Oh, Cindy, and Van Cutsem, Eric

Published
2023
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31. SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry

Author

Evans, Joanne S, Swallow, Judith, Hanbury, Georgina, Chung, Chris, Patel, Meera, Dettorre, Gino, Belessiotis, Katherine, Saorise, Dolly, Jones, Eleanor, Apthorp, Eleanor, Moss, Charlotte, Russell, Beth, Townsend, Sarah, Jackson, Amanda, Loizidou, Angela, Piccart, Martine, Pommeret, Fanny, Colomba-Blameble, Emeline, Prat, Aleix, Cruz, Claudia A, Reyes, Roxana, Segui, Elia, Marco-Hernández, Javier, Viladot, Margarita, Harbeck, Nadia, Wuerstlein, Rachel, Henze, Franziska, Mahner, Sven, Felip, Eudald, Scotti, Lorenza, Marrari, Andrea, Grosso, Federica, Fusco, Vittorio, Delfanti, Sara, Rossi, Maura, Zambelli, Alberto, Tondini, Carlo, Chiudinelli, Lorenzo, Franchi, Michela, Libertini, Michela, Provenzano, Salvatore, Generali, Daniele, Grisanti, Salvatore, Baggi, Alice, Tovazzi, Valeria, Ficorella, Corrado, Porzio, Giampiero, Saponara, Maristella, Filetti, Marco, Tucci, Marco, Berardi, Rossana, Cantini, Luca, Paoloni, Francesco, Guida, Annalisa, Bracarda, Sergio, Iglesias, Maria, Sanchez de Torre, Ana, Tagliamento, Marco, Cortellini, Alessio, Tabernero, Josep, Mukherjee, Uma, Salazar, Ramon, Sureda, Anna, Maluquer, Clara, Ferrante, Daniela, Bower, Mark, Sharkey, Rachel, Mirallas, Oriol, Plaja, Andrea, Cucurull, Marc, Mesia, Ricard, Dalla Pria, Alessia, Newsom-Davis, Thomas, Van Hemelrijck, Mieke, Sita-Lumsden, Ailsa, Vincenzi, Bruno, Di Fazio, Giuseppina Rita, Tonini, Giuseppe, Pantano, Francesco, Bertuzzi, Alexia, Rossi, Sabrina, Brunet, Joan, Lambertini, Matteo, Pedrazzoli, Paolo, Biello, Federica, D'Avanzo, Francesca, Lee, Alvin J X, Shawe-Taylor, Marianne, Rogers, Lucy, Murphy, Cian, Cooper, Lee, Andaleeb, Ramis, Khalique, Saira, Bawany, Samira, Ahmed, Sarah, Carmona-García, M Carmen, Fort-Culillas, Roser, Liñan, Raquel, Zoratto, Federica, Rizzo, Gianpiero, Perachino, Marta, Doonga, Kris, Gaidano, Gianluca, Bruna, Riccardo, Patriarca, Andrea, Martinez-Vila, Clara, Pérez Criado, Ignacio, Giusti, Raffaele, Mazzoni, Francesca, Antonuzzo, Lorenzo, Santoro, Armando, Parisi, Alessandro, Queirolo, Paola, Aujayeb, Avinash, Rimassa, Lorenza, Diamantis, Nikolaos, Bertulli, Rossella, Fulgenzi, Claudia A M, D'Alessio, Antonio, Ruiz-Camps, Isabel, Saoudi-Gonzalez, Nadia, Garcia Illescas, David, Medina, Irene, Fox, Laura, Gennari, Alessandra, Aguilar-Company, Juan, and Pinato, David J

Published
2023
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32. Napabucasin Plus FOLFIRI in Patients With Previously Treated Metastatic Colorectal Cancer: Results From the Open-Label, Randomized Phase III CanStem303C Study

Author

Shah, Manish A., Yoshino, Takayuki, Tebbutt, Niall C., Grothey, Axel, Tabernero, Josep, Xu, Rui-Hua, Cervantes, Andres, Oh, Sang Cheul, Yamaguchi, Kensei, Fakih, Marwan, Falcone, Alfredo, Wu, Christina, Chiu, Vi K., Tomasek, Jiri, Bendell, Johanna, Fontaine, Marilyn, Hitron, Matthew, Xu, Bo, Taieb, Julien, and Van Cutsem, Eric

Published
2023
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33. RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Author

Elez, Elena, Ros, Javier, Fernández, Jose, Villacampa, Guillermo, Moreno-Cárdenas, Ana Belén, Arenillas, Carlota, Bernatowicz, Kinga, Comas, Raquel, Li, Shanshan, Kodack, David Philip, Fasani, Roberta, Garcia, Ariadna, Gonzalo-Ruiz, Javier, Piris-Gimenez, Alejandro, Nuciforo, Paolo, Kerr, Grainne, Intini, Rossana, Montagna, Aldo, Germani, Marco Maria, Randon, Giovanni, Vivancos, Ana, Smits, Ron, Graus, Diana, Perez-Lopez, Raquel, Cremolini, Chiara, Lonardi, Sara, Pietrantonio, Filippo, Dienstmann, Rodrigo, Tabernero, Josep, and Toledo, Rodrigo A.

Published
2022
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34. Efficacy and safety of erdafitinib in adults with breast cancer and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial.

Author

Carranza, Omar, primary, Schuler, Martin H., additional, Tabernero, Josep, additional, Loriot, Yohann, additional, Arnold, Dirk, additional, Folprecht, Gunnar, additional, Palmer, Daniel, additional, Zibetti Dal Molin, Graziela, additional, Gutierrez, Martin, additional, Prenen, Hans, additional, Lugowska, Iwona A., additional, Cervantes, Andres, additional, Sweiti, Hussein, additional, Hammond, Constance, additional, Najmi, Saltanat, additional, Thomas, Shibu, additional, Triantos, Spyros, additional, Crow, Lauren, additional, and Pant, Shubham, additional

Published
2024
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35. Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): Results from the FRESCO-2 trial.

Author

Stintzing, Sebastian, primary, Tabernero, Josep, additional, Satoh, Taroh, additional, Dasari, Arvind, additional, Lonardi, Sara, additional, Eng, Cathy, additional, Garcia-Carbonero, Rocio, additional, Elez, Elena, additional, Yoshino, Takayuki, additional, Sobrero, Alberto F., additional, Yao, James C., additional, Kasper, Stefan, additional, Arnold, Dirk, additional, Basic, Edin, additional, Granold, Matthias, additional, Petschulies, Marco, additional, Wu, Liwen, additional, Chen, Lucy F., additional, Yang, Zhao, additional, and Van Cutsem, Eric, additional

Published
2024
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36. Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 study.

Author

Fayette, Jerome, primary, Clatot, Florian, additional, Brana, Irene, additional, Saada, Esma, additional, van Herpen, Carla M.L.-, additional, Mazard, Thibault, additional, Perez, Cesar Augusto, additional, Tabernero, Josep, additional, Le Tourneau, Christophe, additional, Hollebecque, Antoine, additional, Arrazubi Arrula, Virginia, additional, Fontana, Elisa, additional, Kato, Shumei, additional, Sacco, Assuntina G., additional, Harandi, Amir, additional, De Boer, J.P., additional, Hellyer, Jessica, additional, Pennella, Eduardo, additional, Joe, Andrew K., additional, and Daste, Amaury, additional

Published
2024
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38. Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study

Author

Evans, Joanne S, Swallow, Judith, Chung, Chris, Patel, Meera, Dettorre, Gino, Ottaviani, Diego, Chowdhury, Amani, Merry, Eve, Chopra, Neha, Lee, Alvin JX, Sng, Christopher CT, Yu, Tamara, Shawe-Taylor, Marianne, Bain, Hamish DC, Wong, Yien Ning Sophia, Galazi, Myria, Benafif, Sarah, Dileo, Palma, Earnshaw, Irina, Patel, Grisma, Wu, Anjui, Soosaipillai, Gehan, Cooper, Lee, Andaleeb, Ramis, Dolly, Saoirse, Apthorp, Eleanor, Srikandarajah, Krishnie, Jones, Eleanor, Van Hemelrijck, Mieke, Moss, Charlotte, Russell, Beth, Chester, John, Loizidou, Angela, Piccart, Martine, Cruz, Claudia A, Reyes, Roxana, Segui, Elia, Marco-Hernández, Javier, Viladot, Margarita, Eremiev, Simeon, Fort-Culillas, Roser, Garcia, Isabel, Liñan, Raquel, Roqué Lloveras, Ariadna, Harbeck, Nadia, Wuerstlein, Rachel, Henze, Franziska, Mahner, Sven, Felip, Eudald, Pous, Anna, D'Avanzo, Francesca, Scotti, Lorenza, Krengli, Marco, Marrari, Andrea, Delfanti, Sara, Maconi, Antonio, Betti, Marta, Tonini, Giuseppe, Di Fazio, Giuseppina Rita, Tondini, Carlo, Chiudinelli, Lorenzo, Franchi, Michela, Libertini, Michela, Bertulli, Rossella, Baggi, Alice, Tovazzi, Valeria, Ficorella, Corrado, Porzio, Giampiero, Saponara, Maristella, Filetti, Marco, Zoratto, Federica, Paoloni, Francesco, Berardi, Rossana, Guida, Annalisa, Bracarda, Sergio, Iglesias, Maria, Sanchez de Torre, Ana, Tagliamento, Marco, Colomba, Emeline, Pommeret, Fanny, Pinato, David J, Aguilar-Company, Juan, Ferrante, Daniela, Hanbury, Georgina, Bower, Mark, Salazar, Ramon, Mirallas, Oriol, Sureda, Anna, Plaja, Andrea, Cucurull, Marc, Mesia, Ricard, Townsend, Sarah, Jackson, Amanda, Dalla Pria, Alessia, Newsom-Davis, Thomas, Handford, Jasmine, Sita-Lumsden, Ailsa, Vincenzi, Bruno, Bertuzzi, Alexia, Brunet, Joan, Lambertini, Matteo, Maluquer, Clara, Pedrazzoli, Paolo, Biello, Federica, Sinclair, Alasdair, Bawany, Samira, Khalique, Saira, Rossi, Sabrina, Rogers, Lucy, Murphy, Cian, Belessiotis, Katherine, Carmona-García, M Carmen, Sharkey, Rachel, García-Illescas, David, Rizzo, Gianpiero, Perachino, Marta, Saoudi-Gonzalez, Nadia, Doonga, Kris, Fox, Laura, Roldán, Elisa, Gaidano, Gianluca, Ruiz-Camps, Isabel, Bruna, Riccardo, Patriarca, Andrea, Martinez-Vila, Clara, Cantini, Luca, Zambelli, Alberto, Giusti, Raffaele, Mazzoni, Francesca, Caliman, Enrico, Santoro, Armando, Grosso, Federica, Parisi, Alessandro, Queirolo, Paola, Aujayeb, Avinash, Rimassa, Lorenza, Prat, Aleix, Tucci, Marco, Grisanti, Salvatore, Mukherjee, Uma, Diamantis, Nikolaos, Fusco, Vittorio, Generali, Daniele, Provenzano, Salvatore, Gennari, Alessandra, Tabernero, Josep, and Cortellini, Alessio

Published
2022
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39. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors

Author

Herpers, Bram, Eppink, Berina, James, Mark I., Cortina, Carme, Cañellas-Socias, Adrià, Boj, Sylvia F., Hernando-Momblona, Xavier, Glodzik, Dominik, Roovers, Rob C., van de Wetering, Marc, Bartelink-Clements, Carina, Zondag-van der Zande, Vanessa, Mateos, Jara García, Yan, Kuan, Salinaro, Lucia, Basmeleh, Abdul, Fatrai, Szabolcs, Maussang, David, Lammerts van Bueren, Jeroen J., Chicote, Irene, Serna, Garazi, Cabellos, Laia, Ramírez, Lorena, Nuciforo, Paolo, Salazar, Ramon, Santos, Cristina, Villanueva, Alberto, Stephan-Otto Attolini, Camille, Sancho, Elena, Palmer, Hector G., Tabernero, Josep, Stratton, Michael R., de Kruif, John, Logtenberg, Ton, Clevers, Hans, Price, Leo S., Vries, Robert G. J., Batlle, Eduard, and Throsby, Mark

Published
2022
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40. Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial

Author

Élez, Elena, Gómez-España, María Auxiliadora, Grávalos, Cristina, García-Alfonso, Pilar, Ortiz-Morales, María José, Losa, Ferrán, Díaz, Inmaculada Alés, Graña, Begoña, Toledano-Fonseca, Marta, Valladares-Ayerbes, Manuel, Polo, Eduardo, Salgado, Mercedes, Martínez de Castro, Eva, Safont, María José, Salud, Antonieta, Ruiz-Casado, Ana, Tabernero, Josep, Riesco, María del Carmen, Rodriguez-Ariza, Antonio, and Aranda, Enrique

Published
2022
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41. STELLAR-303: randomized phase III study of zanzalintinib + atezolizumab in previously treated metastatic colorectal cancer.

Author

Saeed, Anwaar, Tabernero, Josep, Parikh, Aparna, Van den Eynde, Marc, Karthaus, Meinolf, Gerlinger, Marco, Wang, Zhong, Wang, Guan, Smith, Robina, and Hecht, J Randolph

Abstract

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases. Clinical Trial Registration:NCT05425940 (ClinicalTrials.gov) Plain Language Summary Metastatic colorectal cancer (mCRC) is cancer of the colon or rectum that has spread to other parts of the body, most often to the liver, lungs and abdomen. People with mCRC that has worsened after initial treatment have limited options. Zanzalintinib is a novel oral investigational drug that can slow or stop cancer growth. It works by blocking certain proteins that play important roles in the development, growth and spread of cancer. Zanzalintinib may also help improve the effectiveness of another class of cancer drugs called immune checkpoint inhibitors (ICIs), which work by activating the patient's immune system to fight cancer. Here, we describe the design of STELLAR-303, an ongoing study that is comparing the effects of combining zanzalintinib and an ICI drug called atezolizumab with an approved treatment for mCRC called regorafenib. About 900 participants with mCRC will be enrolled in the study worldwide. To be included in the study, participants must have mCRC that worsened after previous therapies and must not have a high level of microsatellite instability, which is a specific feature of some mCRCs. Participants will be randomly given one of the two treatments. The main goal of the study is to evaluate zanzalintinib plus atezolizumab compared with regorafenib by measuring the length of time participants are alive after starting treatment, specifically in patients with mCRC that has not spread to the liver. Additionally, the study will look at the side effects with each treatment. The study is currently seeking participants. Tweetable Abstract STELLAR-303 is a randomized phase III study evaluating the novel TKI zanzalintinib plus the ICI atezolizumab in patients with previously treated non-MSI-H metastatic colorectal cancer. Patient enrollment is ongoing globally. Article highlights Background & rationale Patients with metastatic colorectal cancer (mCRC) have a poor prognosis and limited treatment options following progression on standard of care therapies. Immune checkpoint inhibitors (ICIs) are approved in microsatellite instability-high (MSI-H) and mismatch repair-deficient mCRC. However, efficacy of these treatments is limited in non-MSI-H or proficient mismatch repair (pMMR) disease. Agents targeting the VEGF pathway in combination with ICIs have been evaluated in non-MSI-H mCRC and have demonstrated encouraging clinical activity. Studies have shown that mCRC patients without liver metastases may derive greater benefit from TKI-ICI combinations than those with liver metastases. Zanzalintinib (XL092) is a tyrosine kinase inhibitor that targets MET, VEGFR and the TAM kinases. Inhibition of these kinases may suppress tumor growth and proliferation and promote an immunopermissive tumor microenvironment, which may enhance response to ICIs such as atezolizumab. Zanzalintinib has shown anti-tumor activity alone and in combination with ICIs in the preclinical setting and has demonstrated immunomodulatory effects, increasing pro-inflammatory immune cells and decreasing immunosuppressive cells. STELLAR-303 study design STELLAR-303 (NCT05425940) is a global, open-label, randomized, phase III study. Approximately 874 patients with non-MSI-H mCRC (with and without liver metastases) who have progressed during/after or are intolerant to standard of care therapies will be randomized 1:1 to oral zanzalintinib plus intravenous atezolizumab or to oral regorafenib. Eligibility criteria Eligible patients are aged ≥18 years and have histologically/cytologically confirmed adenocarcinoma of the colon or rectum that is non-MSI-H and pMMR; MSI/MMR status will be documented and determined by tissue-based analysis. A prespecified number of patients with/without liver metastases will be enrolled. Patients must have received standard of care therapy for mCRC and radiographically progressed or be refractory or intolerant to these therapies; progression during treatment or within 4 months of the most recent therapy is required. Patients who received prior zanzalintinib, regorafenib, trifluridine-tipiracil, or PD-L1/PD-1 targeting ICIs are ineligible. End points The primary end point is overall survival (OS) in patients without liver metastases. Secondary end points are OS in all randomized patients (assessed with hierarchical testing); progression-free survival, objective response rate and duration of response per RECIST v1.1 by investigator in patients without liver metastases and in all randomized patients; and safety. Status The study is actively enrolling patients in the USA, Europe and Asia-Pacific regions. Conclusion STELLAR-303 will assess the efficacy and safety of zanzalintinib plus atezolizumab in patients with previously treated non-MSI-H mCRC, a population with unmet need. [ABSTRACT FROM AUTHOR]

Published
2024
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42. The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology

Author

Tamborero, David, Dienstmann, Rodrigo, Rachid, Maan Haj, Boekel, Jorrit, Lopez-Fernandez, Adria, Jonsson, Markus, Razzak, Ali, Braña, Irene, De Petris, Luigi, Yachnin, Jeffrey, Baird, Richard D., Loriot, Yohann, Massard, Christophe, Martin-Romano, Patricia, Opdam, Frans, Schlenk, Richard F., Vernieri, Claudio, Masucci, Michele, Villalobos, Xenia, Chavarria, Elena, Balmaña, Judith, Apolone, Giovanni, Caldas, Carlos, Bergh, Jonas, Ernberg, Ingemar, Fröhling, Stefan, Garralda, Elena, Karlsson, Claes, Tabernero, Josep, Voest, Emile, Rodon, Jordi, and Lehtiö, Janne

Published
2022
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45. Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

Author

Juric, Dejan, Rodon, Jordi, Tabernero, Josep, Janku, Filip, Burris, Howard A, Schellens, Jan HM, Middleton, Mark R, Berlin, Jordan, Schuler, Martin, Gil-Martin, Marta, Rugo, Hope S, Seggewiss-Bernhardt, Ruth, Huang, Alan, Bootle, Douglas, Demanse, David, Blumenstein, Lars, Coughlin, Christina, Quadt, Cornelia, and Baselga, José

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Patient Safety, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, Administration, Oral, Adult, Aged, Aged, 80 and over, Breast Neoplasms, Class I Phosphatidylinositol 3-Kinases, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Middle Aged, Thiazoles, Treatment Outcome, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

Published
2018

46. Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer

Author

Corcoran, Ryan B, André, Thierry, Atreya, Chloe E, Schellens, Jan HM, Yoshino, Takayuki, Bendell, Johanna C, Hollebecque, Antoine, McRee, Autumn J, Siena, Salvatore, Middleton, Gary, Muro, Kei, Gordon, Michael S, Tabernero, Josep, Yaeger, Rona, O'Dwyer, Peter J, Humblet, Yves, De Vos, Filip, Jung, A Scott, Brase, Jan C, Jaeger, Savina, Bettinger, Severine, Mookerjee, Bijoyesh, Rangwala, Fatima, and Van Cutsem, Eric

Subjects
Digestive Diseases, Colo-Rectal Cancer, Cancer, Good Health and Well Being, Antineoplastic Combined Chemotherapy Protocols, Colorectal Neoplasms, Drug Resistance, Neoplasm, ErbB Receptors, Female, Humans, Imidazoles, MAP Kinase Signaling System, Male, Mitogen-Activated Protein Kinase Kinases, Oximes, Panitumumab, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Oncology and Carcinogenesis
Abstract

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018 AACR.See related commentary by Janku, p. 389See related article by Hazar-Rethinam et al., p. 417This article is highlighted in the In This Issue feature, p. 371.

Published
2018

47. A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer

Author

Wainberg, Zev A, Alsina, Maria, Soares, Heloisa P, Braña, Irene, Britten, Carolyn D, Del Conte, Gianluca, Ezeh, Patrick, Houk, Brett, Kern, Kenneth A, Leong, Stephen, Pathan, Nuzhat, Pierce, Kristen J, Siu, Lillian L, Vermette, Jennifer, and Tabernero, Josep

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Clinical Trials and Supportive Activities, Cancer, Digestive Diseases, Rare Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Antineoplastic Agents, Phytogenic, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Camptothecin, Diphenylamine, Female, Humans, Irinotecan, Male, Morpholines, Neoplasms, Phosphoinositide-3 Kinase Inhibitors, TOR Serine-Threonine Kinases, Triazines, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThis phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors.ObjectivesPrimary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.Patients and methodsDose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D.ResultsThe PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations.ConclusionsFurther evaluations of gedatolisib are warranted in patients with advanced solid malignancies.

Published
2017

48. A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer

Author

Reynolds, Kerry Lynn, Bedard, Philippe L, Lee, Se-Hoon, Lin, Chia-Chi, Tabernero, Josep, Alsina, Maria, Cohen, Ezra, Baselga, José, Blumenschein, George, Graham, Donna M, Garrido-Laguna, Ignacio, Juric, Dejan, Sharma, Sunil, Salgia, Ravi, Seroutou, Abdelkader, Tian, Xianbin, Fernandez, Rose, Morozov, Alex, Sheng, Qing, Ramkumar, Thiruvamoor, Zubel, Angela, and Bang, Yung-Jue

Subjects
Breast Cancer, Clinical Research, Clinical Trials and Supportive Activities, Cancer, Rare Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, Adult, Aged, Antineoplastic Agents, Immunological, Bayes Theorem, Breast Neoplasms, Carcinoma, Squamous Cell, Dose-Response Relationship, Drug, Esophageal Neoplasms, Female, Head and Neck Neoplasms, Humans, Male, Maximum Tolerated Dose, Middle Aged, Receptor, ErbB-2, Receptor, ErbB-3, Squamous Cell Carcinoma of Head and Neck, Stomach Neoplasms, Phase I, HER3, HER2, Monoclonal antibody, LJM716, Receptor, erbB-2, Receptor, erbB-3, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundHuman epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.MethodsThis open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling.ResultsPatients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples.ConclusionsLJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.Trial registrationClinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Published
2017

49. Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study

Author

Swallow, Judith, Chung, Chris, Dettorre, Gino, Chopra, Neha, Lee, Alvin JX, Sng, Christopher CT, Wong, Yien Ning Sophia, Galazi, Myria, Benafif, Sarah, Dileo, Palma, Patel, Grisma, Wu, Anjui, Sinclair, Alasdair, Soosaipillai, Gehan, Jones, Eleanor, Diamantis, Nikolaos, Mukherjee, Uma, Jackson, Amanda, Piccart, Martine, Pommeret, Fanny, Colomba, Johann, Colomba-Blameble, Emeline, Prat, Aleix, Cruz, Claudia A, Reyes, Roxana, Segui, Elia, Marco-Hernández, Javier, Tabernero, Josep, Aguilar-Company, Juan, Ruiz-Camps, Isabel, Fox, Laura, Garcia Illescas, David, Mirallas, Oriol, Roldán, Elisa, Carbó, Anna, Garcia, Isabel, Wuerstlein, Rachel, Mesia, Ricard, Maluquer, Clara, D'Avanzo, Francesca, Tonini, Giuseppe, Provenzano, Salvatore, Tovazzi, Valeria, Ficorella, Corrado, Queirolo, Paola, Giusti, Raffaele, Mazzoni, Francesca, Zoratto, Federica, Tucci, Marco, Berardi, Rossana, Guida, Annalisa, Bracarda, Sergio, Iglesias, Maria, Pinato, David J, Bower, Mark, Scotti, Lorenza, Patel, Meera, Colomba, Emeline, Dolly, Saoirse, Loizidou, Angela, Chester, John, Zambelli, Alberto, Dalla Pria, Alessia, Ottaviani, Diego, Chowdhury, Amani, Merry, Eve, Salazar, Ramon, Bertuzzi, Alexia, Brunet, Joan, Lambertini, Matteo, Tagliamento, Marco, Pous, Anna, Sita-Lumsden, Ailsa, Srikandarajah, Krishnie, Seguí, Elia, Generali, Daniele, Grisanti, Salvatore, Pedrazzoli, Paolo, Rizzo, Gianpiero, Libertini, Michela, Moss, Charlotte, Evans, Joanne S, Russell, Beth, Harbeck, Nadia, Vincenzi, Bruno, Biello, Federica, Bertulli, Rossella, Liñan, Raquel, Rossi, Sabrina, Carmona-García, Maria Carmen, Tondini, Carlo, Baggi, Alice, Fotia, Vittoria, Parisi, Alessandro, Porzio, Giampero, Saponara, Maristella, Cruz, Claudia Andrea, García-Illescas, David, Felip, Eudald, Roqué Lloveras, Ariadna, Sharkey, Rachel, Earnshaw, Irina, Ferrante, Daniela, Gaidano, Gianluca, Patriarca, Andrea, Bruna, Riccardo, Sureda, Anna, Martinez-Vila, Clara, Sanchez de Torre, Ana, Cantini, Luca, Filetti, Marco, Rimassa, Lorenza, Chiudinelli, Lorenzo, Franchi, Michela, Krengli, Marco, Santoro, Armando, Van Hemelrijck, Mieke, Newsom-Davis, Thomas, Gennari, Alessandra, and Cortellini, Alessio

Published
2021
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50. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

Author

Qiu, Miao-Zhen, primary, Oh, Do-Youn, additional, Kato, Ken, additional, Arkenau, Tobias, additional, Tabernero, Josep, additional, Correa, Marcia Cruz, additional, Zimina, Anastasia V, additional, Bai, Yuxian, additional, Shi, Jianhua, additional, Lee, Keun-Wook, additional, Wang, Jufeng, additional, Poddubskaya, Elena, additional, Pan, Hongming, additional, Rha, Sun Young, additional, Zhang, Ruixing, additional, Hirano, Hidekazu, additional, Spigel, David, additional, Yamaguchi, Kensei, additional, Chao, Yee, additional, Wyrwicz, Lucjan, additional, Disel, Umut, additional, Cid, Roberto Pazo, additional, Fornaro, Lorenzo, additional, Evesque, Ludovic, additional, Wang, Hongwei, additional, Xu, Yaling, additional, Li, Jiang, additional, Sheng, Tao, additional, Yang, Silu, additional, Li, Liyun, additional, Moehler, Markus, additional, and Xu, Rui-Hua, additional

Published
2024
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