Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study
Luis Paz-Ares, Jörg Mezger, Tudor E Ciuleanu, Jürgen R Fischer, Joachim von Pawel, Mariano Provencio, Andrzej Kazarnowicz, György Losonczy, Gilberto de Castro Jr, Aleksandra Szczesna, Lucio Crino, Martin Reck, Rodryg Ramlau, Ernst Ulsperger, Christian Schumann, Jose Elias A Miziara, Álvaro E Lessa, Mircea Dediu, Beatrix Bálint, Henrik Depenbrock, Victoria Soldatenkova, Raffael Kurek, Fred R Hirsch, Nick Thatcher, Mark A Socinski, INSPIRE investigators, Peter Briggs, Matthew J Links, Louise M Nott, Ulrike Benold, Robert Pirker, Ernst Ulsperger, Alois Lang, Leon Bosquée, Renaud Louis, Jean C Goeminne, Marc Lambrechts, Jose Elias A Miziara, Carlos H Barrios, Álvaro E Lessa, Aline A Porto Rocha Lima, Amanda Faulhaber, Gilberto de Castro Jr, Fábio A Franke, Adilson A Faccio, João N de Matos Neto, Giuliano Borges, Claudio Francisco Cabral, Leandro Brust, David I Small, Dragan Trivanovic, Radj Gervais, Christos Chouaid, Perrine Crequit, Michael Thomas, Jörg Mezger, Folker Schneller, Martin Reck, Joachim von Pawel, Christian Schulz, Hans Jochen Wilke, Corinna Eschbach, Gunther Wiest, Monika Serke, Sylke Nagel, Alexander Schmittel, Ulrich Keilholz, Thomas Müller, Berthold Fischer, Martin Sebastian, Christian Schumann, Joachim Bargon, Jürgen R Fischer, Ina Dittrich, Rainer Wiewrodt, Vassilis Georgoulias, Haralabos Kalofonos, Konstantinos Syrigos, Beatrix Bálint, Zsolt Pápai-Székely, Zsuzsanna Szalai, Barna Szima, Edina Tolnay, Éva Morócz, Zsuzsanna Vennes, György Losonczy, Roberto Buzzoni, Nicoletta Zilembo, Alberto Sobrero, Marcello Tiseo, Lucio Crino, Alessandra Bearz, Domenico Amoroso, Teresa Gamucci, Rodryg Ramlau, Wojciech Szafranski, Piotr Serwatowski, Aleksandra Szczesna, Janusz Tomeczko, Andrzej Kazarnowicz, Encarnação Teixeira, Fernando Barata, Constantin Volovat, Tudor E Ciuleanu, Ciprian Aldea, Dan Lungulescu, Mircea Dediu, Cristina L Taflan, Monica Patran, Sergey Cheporov, Rinat K Galiulin, Eugeny A Gotovkin, Nina A Karaseva, Oleg Lipatov, Bogdan N Kotiv, Andrey L Akopov, Nailya Z Sherman, Peter Berzinec, Peter Kasan, Lydia M Dreosti, Michiel C Botha, Luis Paz-Ares, Mariano Provencio, Ramón Palmero, Santiago Ponce, Belen Rubio-Viqueira, Cristóbal Belda Iniesta, Roman Bastus, Pablo Rodriguez Martinez, Margarita Majem, Tom R Geldart, Marianne Nicolson, Geraldine E Skailes, Michael Snee, Gary Middleton, Muthuveni Ezhil, Allan Price, Luis Paz-Ares, Jörg Mezger, Tudor E Ciuleanu, Jürgen R Fischer, Joachim von Pawel, Mariano Provencio, Andrzej Kazarnowicz, György Losonczy, Gilberto de Castro Jr, Aleksandra Szczesna, Lucio Crino, Martin Reck, Rodryg Ramlau, Ernst Ulsperger, Christian Schumann, Jose Elias A Miziara, Álvaro E Lessa, Mircea Dediu, Beatrix Bálint, Henrik Depenbrock, Victoria Soldatenkova, Raffael Kurek, Fred R Hirsch, Nick Thatcher, Mark A Socinski, INSPIRE investigators, Peter Briggs, Matthew J Links, Louise M Nott, Ulrike Benold, Robert Pirker, Ernst Ulsperger, Alois Lang, Leon Bosquée, Renaud Louis, Jean C Goeminne, Marc Lambrechts, Jose Elias A Miziara, Carlos H Barrios, Álvaro E Lessa, Aline A Porto Rocha Lima, Amanda Faulhaber, Gilberto de Castro Jr, Fábio A Franke, Adilson A Faccio, João N de Matos Neto, Giuliano Borges, Claudio Francisco Cabral, Leandro Brust, David I Small, Dragan Trivanovic, Radj Gervais, Christos Chouaid, Perrine Crequit, Michael Thomas, Jörg Mezger, Folker Schneller, Martin Reck, Joachim von Pawel, Christian Schulz, Hans Jochen Wilke, Corinna Eschbach, Gunther Wiest, Monika Serke, Sylke Nagel, Alexander Schmittel, Ulrich Keilholz, Thomas Müller, Berthold Fischer, Martin Sebastian, Christian Schumann, Joachim Bargon, Jürgen R Fischer, Ina Dittrich, Rainer Wiewrodt, Vassilis Georgoulias, Haralabos Kalofonos, Konstantinos Syrigos, Beatrix Bálint, Zsolt Pápai-Székely, Zsuzsanna Szalai, Barna Szima, Edina Tolnay, Éva Morócz, Zsuzsanna Vennes, György Losonczy, Roberto Buzzoni, Nicoletta Zilembo, Alberto Sobrero, Marcello Tiseo, Lucio Crino, Alessandra Bearz, Domenico Amoroso, Teresa Gamucci, Rodryg Ramlau, Wojciech Szafranski, Piotr Serwatowski, Aleksandra Szczesna, Janusz Tomeczko, Andrzej Kazarnowicz, Encarnação Teixeira, Fernando Barata, Constantin Volovat, Tudor E Ciuleanu, Ciprian Aldea, Dan Lungulescu, Mircea Dediu, Cristina L Taflan, Monica Patran, Sergey Cheporov, Rinat K Galiulin, Eugeny A Gotovkin, Nina A Karaseva, Oleg Lipatov, Bogdan N Kotiv, Andrey L Akopov, Nailya Z Sherman, Peter Berzinec, Peter Kasan, Lydia M Dreosti, Michiel C Botha, Luis Paz-Ares, Mariano Provencio, Ramón Palmero, Santiago Ponce, Belen Rubio-Viqueira, Cristóbal Belda Iniesta, Roman Bastus, Pablo Rodriguez Martinez, Margarita Majem, Tom R Geldart, Marianne Nicolson, Geraldine E Skailes, Michael Snee, Gary Middleton, Muthuveni Ezhil, Allan Price
Abstract
Background: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC).
Methods: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111.
Findings: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group.
Interpretation: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.
Funding: Eli Lilly and Company.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Source: PubMed