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)
Thatcher, Nick ✉; Hirsch, Fred R; Luft, Alexander V; Szczesna, Aleksandra; Ciuleanu, Tudor E; Dediu, Mircea; Ramlau, Rodryg; Galiulin, Rinat K; Bálint, Beatrix [Bálint, Beatrix (pulmonológia, kar...), author]; Losonczy, György [Losonczy, György (Pulmonológia, kli...), author] Department of Pulmonology
(SU / FM / C); Kazarnowicz, Andrzej; Park, Keunchil; Schumann, Christian; Reck, Martin; Depenbrock, Henrik; Nanda, Shivani; Kruljac-Letunic, Anamarija; Kurek, Raffael; Paz-Ares, Luis; Socinski, Mark A; SQUIRE Investigators [Collaborative Organization]; Briggs, Peter [Collaborator]; Broad, Adam [Collaborator]; Clingan, Philip [Collaborator]; Hui, Rina [Collaborator]; Leong, David [Collaborator]; Aigner, Kurt [Collaborator]; Pirker, Robert [Collaborator]; Ulsperger, Ernst [Collaborator]; Bolitschek, Josef [Collaborator]; Bosquee, Leon [Collaborator]; Bustin, Frédérique [Collaborator]; Goeminne, Jean-Charles [Collaborator]; Lambrechts, Marc [Collaborator]; Louis, Renaud [Collaborator]; Santos Borges, Guiliano [Collaborator]; Escoleguy Barrios, Carlos Henrique [Collaborator]; Brust, Leandro [Collaborator]; Cabral, Claudio Francisco [Collaborator]; de Castro, Gilberto [Collaborator]; Faulhaber, Amanda [Collaborator]; Franke, Fábio Andre [Collaborator]; Ramos Lessa, Álvaro Edson [Collaborator]; Rocha Lima, Angelica Porto [Collaborator]; Abrao Miziara, Jose Elias [Collaborator]; de Matos Neto, João Nunes [Collaborator]; Rodrigues Pereira, Jose [Collaborator]; Ahmed, Shahid [Collaborator]; Reiman, Anthony James [Collaborator]; Sehdev, Sandeep [Collaborator]; Samarzija, Miroslav [Collaborator]; Trivanovic, Dragan [Collaborator]; Vrbica, Zarko [Collaborator]; Barlési, Fabrice [Collaborator]; Berard, Henri [Collaborator]; Burki, Franck [Collaborator]; Chouaid, Christos [Collaborator]; Corre, Romain [Collaborator]; Créquit, Perrine [Collaborator]; Dansin, Eric [Collaborator]; Denis, Fabrice [Collaborator]; Gervais, Radj [Collaborator]; Goupil, Francois [Collaborator]; Rebattu, Paul [Collaborator]; Khayat, David [Collaborator]; Moro-Sibilot, Denis [Collaborator]; Le Moulec, Sylvestre [Collaborator]; Lecaer, Hervé [Collaborator]; Perol, Maurice [Collaborator]; Pouessel, Damien [Collaborator]; Robinet, Gilles [Collaborator]; Bargon, Joachim [Collaborator]; Dittrich, Ina [Collaborator]; Eberhardt, Wilfried Ernst Erich [Collaborator]; Eschbach, Corinna [Collaborator]; Fischer, Jürgen R [Collaborator]; Hapke, Gunnar [Collaborator]; Mezger, Jörg [Collaborator]; Müller, Thomas [Collaborator]; Nagel, Sylke [Collaborator]; von Pawel, Joachim [Collaborator]; Reck, Martin [Collaborator]; Schneller, Folker [Collaborator]; Schmittel, Alexander [Collaborator]; Schulz, Christian [Collaborator]; Schumann, Christian [Collaborator]; Serke, Monika [Collaborator]; Stauder, Heribert [Collaborator]; Thomas, Michael [Collaborator]; Wiest, Gunther H [Collaborator]; Wiewrodt, Rainer [Collaborator]; Wilke, Hans Jochen [Collaborator]; Kropf-Sanchem, Cornelia [Collaborator]; Keilholz, Ulrich [Collaborator]; Schütte, Wolfgang [Collaborator]; Georgoulias, Vassilis [Collaborator]; Kalofonos, Haralabos [Collaborator]; Syrigos, Konstantinos [Collaborator]; Zarogoulidis, Konstantinos [Collaborator]; Bálint, Beatrix [Bálint, Beatrix (pulmonológia, kar...), Collaborator]; Király, Zsolt [Collaborator]; Losonczy, György [Losonczy, György (Pulmonológia, kli...), Collaborator] Department
of Pulmonology (SU / FM / C); Pápai-Székely, Zsolt [Collaborator]; Szalai, Zsuzsanna [Collaborator]; Szima, Barna [Collaborator]; Tolnay, Edina [Collaborator]; Vennes, Zsuzsanna [Collaborator]; Morócz, Éva [Collaborator]; Amoroso, Domenico [Collaborator]; Bearz, Alessandra [Collaborator]; Bidoli, Paolo [Collaborator]; Buzzoni, Roberto [Collaborator]; Crino, Lucio [Collaborator]; Gamucci, Teresa [Collaborator]; Siena, Salvatore [Collaborator]; Sobrero, Alberto [Collaborator]; Tiseo, Marcello [Collaborator]; Zilembo, Nicoletta [Collaborator]; Cho, Eun Kyung [Collaborator]; Kim, Hoon Kyo [Collaborator]; Kim, Joo-Hang [Collaborator]; Kim, Sang-We [Collaborator]; Lee, Jong-Seok [Collaborator]; Park, Keunchil [Collaborator]; Song, Eun-Kee [Collaborator]; Yhim, Ho-Young [Collaborator]; Bello, Maximino [Collaborator]; Fajardo, Therese Naracisa Q [Collaborator]; Galicia, Abdiel P [Collaborator]; Juat, Necy S [Collaborator]; Tamayo, Belen [Collaborator]; Uy, Ma Noemi [Collaborator]; Yap, Matthew G [Collaborator]; Karczmarek-Borowska, Bozenna [Collaborator]; Kazarnowicz, Andrzej [Collaborator]; Ramlau, Rodryg [Collaborator]; Sawrycki, Piotr [Collaborator]; Serwatowski, Piotr [Collaborator]; Szafranski, Wojciech [Collaborator]; Szczesna, Aleksandra [Collaborator]; Tomeczko, Janusz [Collaborator]; Bryl, Maciej [Collaborator]; Almodovar, Maria Teresa [Collaborator]; Barata, Fernando [Collaborator]; Soares, Marta [Collaborator]; Teixeira, Encarnação [Collaborator]; Aldea, Ciprian [Collaborator]; Ciuleanu, Tudor Eliade [Collaborator]; Dediu, Mircea [Collaborator]; Gavrilescu, Doinita Vararu [Collaborator]; Lungulescu, Dan [Collaborator]; Patran, Monica [Collaborator]; Taflan, Cristina Lucia [Collaborator]; Volovat, Constantin [Collaborator]; Akopov, Andrey L [Collaborator]; Cheporov, Sergey [Collaborator]; Davidenko, Irina S [Collaborator]; Dobrovolskaya, Natalia [Collaborator]; Galiulin, Rinat K [Collaborator]; Gotovkin, Eugeny A [Collaborator]; Karaseva, Nina A [Collaborator]; Kotiv, Bogdan N [Collaborator]; Lipatov, Oleg [Collaborator]; Luft, Alexander V [Collaborator]; Sherman, Nailya Z [Collaborator]; Solovyev, Vladimir [Collaborator]; Jovanovic, Dragana [Collaborator]; Perin, Branislav [Collaborator]; Petrovic, Marina D [Collaborator]; Rancic, Milan [Collaborator]; de Lima Lopes, Gilberto [Collaborator]; Beniak, Juraj [Collaborator]; Berzinec, Peter [Collaborator]; Kasan, Peter [Collaborator]; Christoffel Botha, Michiel [Collaborator]; Dreosti, Lydia M [Collaborator]; Landers, George Ashley [Collaborator]; Bastus, Roman [Collaborator]; Belda, Cristóbal [Collaborator]; Perez Cedrés, Susana Maria [Collaborator]; Sánchez-Escribano, Ricardo [Collaborator]; Gonzalez Larriba, Jose [Collaborator]; Ales Martinez, Jose E [Collaborator]; Pallares, Cinta [Collaborator]; Palmero, Ramón [Collaborator]; Paz-Ares, Luis Rodriguez [Collaborator]; Ponce, Santiago [Collaborator]; Provencio, Mariano [Collaborator]; Viñolas Segarra, Nuria [Collaborator]; Rubio Viqueira, Belén [Collaborator]; Chang, Gee-Chen [Collaborator]; Hsia, Te-Chun [Collaborator]; Dechaphunkul, Arunee [Collaborator]; Sunpaweravong, Patrapim [Collaborator]; Thongprasert, Sumitra [Collaborator]; Bower, Mark [Collaborator]; Ezhil, Muthuveni [Collaborator]; Geldart, Thomas Richard [Collaborator]; Lord, Hannah Kate [Collaborator]; Maguire, Joseph [Collaborator]; Middleton, Gary [Collaborator]; Nicolson, Marianne [Collaborator]; Price, Allan [Collaborator]; Rankin, Elaine M [Collaborator]; Skailes, Geraldine E [Collaborator]; Summers, Yvonne J [Collaborator]; Taylor, Paul David [Collaborator]; Alexander, Roland R [Collaborator]; Behl, Deepti [Collaborator]; Bradford, Daniel S [Collaborator]; Dakhil, Shaker R [Collaborator]; Dunder, Steven G [Collaborator]; Ghazal, Hassan [Collaborator]; Gordon, Robert A [Collaborator]; Khojasteh, Ali [Collaborator]; Kio, Ebenezer [Collaborator]; Levine, Marshall A [Collaborator]; McClean, John W [Collaborator]; Miller, Vincent A [Collaborator]; Osarogiagbon, Raymond [Collaborator]; Paik, Paul K [Collaborator]; Payne, Jennifer [Collaborator]; Shtivelband, Mikhail I [Collaborator]; Spira, Alexander [Collaborator]
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.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.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.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.Eli Lilly and Company.
