Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial
Nick Thatcher, Fred R Hirsch, Alexander V Luft, Aleksandra Szczesna, Tudor E Ciuleanu, Mircea Dediu, Rodryg Ramlau, Rinat K Galiulin, Beatrix Bálint, György Losonczy, Andrzej Kazarnowicz, Keunchil Park, Christian Schumann, Martin Reck, Henrik Depenbrock, Shivani Nanda, Anamarija Kruljac-Letunic, Raffael Kurek, Luis Paz-Ares, Mark A Socinski, SQUIRE Investigators, Peter Briggs, Adam Broad, Philip Clingan, Rina Hui, David Leong, Kurt Aigner, Robert Pirker, Ernst Ulsperger, Josef Bolitschek, Leon Bosquee, Frédérique Bustin, Jean-Charles Goeminne, Marc Lambrechts, Renaud Louis, Guiliano Santos Borges, Carlos Henrique Escoleguy Barrios, Leandro Brust, Claudio Francisco Cabral, Gilberto de Castro Jr, Amanda Faulhaber, Fábio Andre Franke, Álvaro Edson Ramos Lessa, Angelica Porto Rocha Lima, Jose Elias Abrao Miziara, João Nunes de Matos Neto, Jose Rodrigues Pereira, Shahid Ahmed, Anthony James Reiman, Sandeep Sehdev, Miroslav Samarzija, Dragan Trivanovic, Zarko Vrbica, Fabrice Barlési, Henri Berard, Franck Burki, Christos Chouaid, Romain Corre, Perrine Créquit, Eric Dansin, Fabrice Denis, Radj Gervais, Francois Goupil, Paul Rebattu, David Khayat, Denis Moro-Sibilot, Sylvestre Le Moulec, Hervé Lecaer, Maurice Perol, Damien Pouessel, Gilles Robinet, Joachim Bargon, Ina Dittrich, Wilfried Ernst Erich Eberhardt, Corinna Eschbach, Jürgen R Fischer, Gunnar Hapke, Jörg Mezger, Thomas Müller, Sylke Nagel, Joachim von Pawel, Martin Reck, Folker Schneller, Alexander Schmittel, Christian Schulz, Christian Schumann, Monika Serke, Heribert Stauder, Michael Thomas, Gunther H Wiest, Rainer Wiewrodt, Hans Jochen Wilke, Cornelia Kropf-Sanchem, Ulrich Keilholz, Wolfgang Schütte, Vassilis Georgoulias, Haralabos Kalofonos, Konstantinos Syrigos, Konstantinos Zarogoulidis, Beatrix Bálint, Zsolt Király, György Losonczy, Zsolt Pápai-Székely, Zsuzsanna Szalai, Barna Szima, Edina Tolnay, Zsuzsanna Vennes, Éva Morócz, Domenico Amoroso, Alessandra Bearz, Paolo Bidoli, Roberto Buzzoni, Lucio Crino, Teresa Gamucci, Salvatore Siena, Alberto Sobrero, Marcello Tiseo, Nicoletta Zilembo, Eun Kyung Cho, Hoon Kyo Kim, Joo-Hang Kim, Sang-We Kim, Jong-Seok Lee, Keunchil Park, Eun-Kee Song, Ho-Young Yhim, Maximino Bello 3rd, Therese Naracisa Q Fajardo, Abdiel P Galicia, Necy S Juat, Belen Tamayo, Ma Noemi Uy, Matthew G Yap, Bozenna Karczmarek-Borowska, Andrzej Kazarnowicz, Rodryg Ramlau, Piotr Sawrycki, Piotr Serwatowski, Wojciech Szafranski, Aleksandra Szczesna, Janusz Tomeczko, Maciej Bryl, Maria Teresa Almodovar, Fernando Barata, Marta Soares, Encarnação Teixeira, Ciprian Aldea, Tudor Eliade Ciuleanu, Mircea Dediu, Doinita Vararu Gavrilescu, Dan Lungulescu, Monica Patran, Cristina Lucia Taflan, Constantin Volovat, Andrey L Akopov, Sergey Cheporov, Irina S Davidenko, Natalia Dobrovolskaya, Rinat K Galiulin, Eugeny A Gotovkin, Nina A Karaseva, Bogdan N Kotiv, Oleg Lipatov, Alexander V Luft, Nailya Z Sherman, Vladimir Solovyev, Dragana Jovanovic, Branislav Perin, Marina D Petrovic, Milan Rancic, Gilberto de Lima Lopes, Juraj Beniak, Peter Berzinec, Peter Kasan, Michiel Christoffel Botha, Lydia M Dreosti, George Ashley Landers, Roman Bastus, Cristóbal Belda, Susana Maria Perez Cedrés, Ricardo Sánchez-Escribano, Jose Gonzalez Larriba, Jose E Ales Martinez, Cinta Pallares, Ramón Palmero, Luis Rodriguez Paz-Ares, Santiago Ponce, Mariano Provencio, Nuria Viñolas Segarra, Belén Rubio Viqueira, Gee-Chen Chang, Te-Chun Hsia, Arunee Dechaphunkul, Patrapim Sunpaweravong, Sumitra Thongprasert, Mark Bower, Muthuveni Ezhil, Thomas Richard Geldart, Hannah Kate Lord, Joseph Maguire, Gary Middleton, Marianne Nicolson, Allan Price, Elaine M Rankin, Geraldine E Skailes, Yvonne J Summers, Paul David Taylor, Roland R Alexander, Deepti Behl, Daniel S Bradford, Shaker R Dakhil, Steven G Dunder, Hassan Ghazal, Robert A Gordon, Ali Khojasteh, Ebenezer Kio, Marshall A Levine, John W McClean, Vincent A Miller, Raymond Osarogiagbon, Paul K Paik, Jennifer Payne, Mikhail I Shtivelband, Alexander Spira, Nick Thatcher, Fred R Hirsch, Alexander V Luft, Aleksandra Szczesna, Tudor E Ciuleanu, Mircea Dediu, Rodryg Ramlau, Rinat K Galiulin, Beatrix Bálint, György Losonczy, Andrzej Kazarnowicz, Keunchil Park, Christian Schumann, Martin Reck, Henrik Depenbrock, Shivani Nanda, Anamarija Kruljac-Letunic, Raffael Kurek, Luis Paz-Ares, Mark A Socinski, SQUIRE Investigators, Peter Briggs, Adam Broad, Philip Clingan, Rina Hui, David Leong, Kurt Aigner, Robert Pirker, Ernst Ulsperger, Josef Bolitschek, Leon Bosquee, Frédérique Bustin, Jean-Charles Goeminne, Marc Lambrechts, Renaud Louis, Guiliano Santos Borges, Carlos Henrique Escoleguy Barrios, Leandro Brust, Claudio Francisco Cabral, Gilberto de Castro Jr, Amanda Faulhaber, Fábio Andre Franke, Álvaro Edson Ramos Lessa, Angelica Porto Rocha Lima, Jose Elias Abrao Miziara, João Nunes de Matos Neto, Jose Rodrigues Pereira, Shahid Ahmed, Anthony James Reiman, Sandeep Sehdev, Miroslav Samarzija, Dragan Trivanovic, Zarko Vrbica, Fabrice Barlési, Henri Berard, Franck Burki, Christos Chouaid, Romain Corre, Perrine Créquit, Eric Dansin, Fabrice Denis, Radj Gervais, Francois Goupil, Paul Rebattu, David Khayat, Denis Moro-Sibilot, Sylvestre Le Moulec, Hervé Lecaer, Maurice Perol, Damien Pouessel, Gilles Robinet, Joachim Bargon, Ina Dittrich, Wilfried Ernst Erich Eberhardt, Corinna Eschbach, Jürgen R Fischer, Gunnar Hapke, Jörg Mezger, Thomas Müller, Sylke Nagel, Joachim von Pawel, Martin Reck, Folker Schneller, Alexander Schmittel, Christian Schulz, Christian Schumann, Monika Serke, Heribert Stauder, Michael Thomas, Gunther H Wiest, Rainer Wiewrodt, Hans Jochen Wilke, Cornelia Kropf-Sanchem, Ulrich Keilholz, Wolfgang Schütte, Vassilis Georgoulias, Haralabos Kalofonos, Konstantinos Syrigos, Konstantinos Zarogoulidis, Beatrix Bálint, Zsolt Király, György Losonczy, Zsolt Pápai-Székely, Zsuzsanna Szalai, Barna Szima, Edina Tolnay, Zsuzsanna Vennes, Éva Morócz, Domenico Amoroso, Alessandra Bearz, Paolo Bidoli, Roberto Buzzoni, Lucio Crino, Teresa Gamucci, Salvatore Siena, Alberto Sobrero, Marcello Tiseo, Nicoletta Zilembo, Eun Kyung Cho, Hoon Kyo Kim, Joo-Hang Kim, Sang-We Kim, Jong-Seok Lee, Keunchil Park, Eun-Kee Song, Ho-Young Yhim, Maximino Bello 3rd, Therese Naracisa Q Fajardo, Abdiel P Galicia, Necy S Juat, Belen Tamayo, Ma Noemi Uy, Matthew G Yap, Bozenna Karczmarek-Borowska, Andrzej Kazarnowicz, Rodryg Ramlau, Piotr Sawrycki, Piotr Serwatowski, Wojciech Szafranski, Aleksandra Szczesna, Janusz Tomeczko, Maciej Bryl, Maria Teresa Almodovar, Fernando Barata, Marta Soares, Encarnação Teixeira, Ciprian Aldea, Tudor Eliade Ciuleanu, Mircea Dediu, Doinita Vararu Gavrilescu, Dan Lungulescu, Monica Patran, Cristina Lucia Taflan, Constantin Volovat, Andrey L Akopov, Sergey Cheporov, Irina S Davidenko, Natalia Dobrovolskaya, Rinat K Galiulin, Eugeny A Gotovkin, Nina A Karaseva, Bogdan N Kotiv, Oleg Lipatov, Alexander V Luft, Nailya Z Sherman, Vladimir Solovyev, Dragana Jovanovic, Branislav Perin, Marina D Petrovic, Milan Rancic, Gilberto de Lima Lopes, Juraj Beniak, Peter Berzinec, Peter Kasan, Michiel Christoffel Botha, Lydia M Dreosti, George Ashley Landers, Roman Bastus, Cristóbal Belda, Susana Maria Perez Cedrés, Ricardo Sánchez-Escribano, Jose Gonzalez Larriba, Jose E Ales Martinez, Cinta Pallares, Ramón Palmero, Luis Rodriguez Paz-Ares, Santiago Ponce, Mariano Provencio, Nuria Viñolas Segarra, Belén Rubio Viqueira, Gee-Chen Chang, Te-Chun Hsia, Arunee Dechaphunkul, Patrapim Sunpaweravong, Sumitra Thongprasert, Mark Bower, Muthuveni Ezhil, Thomas Richard Geldart, Hannah Kate Lord, Joseph Maguire, Gary Middleton, Marianne Nicolson, Allan Price, Elaine M Rankin, Geraldine E Skailes, Yvonne J Summers, Paul David Taylor, Roland R Alexander, Deepti Behl, Daniel S Bradford, Shaker R Dakhil, Steven G Dunder, Hassan Ghazal, Robert A Gordon, Ali Khojasteh, Ebenezer Kio, Marshall A Levine, John W McClean, Vincent A Miller, Raymond Osarogiagbon, Paul K Paik, Jennifer Payne, Mikhail I Shtivelband, Alexander Spira
Abstract
Background: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer.
Methods: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058.
Findings: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations.
Interpretation: Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease.
Funding: Eli Lilly and Company.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Source: PubMed