Luis Paz-Ares1, Jörg Mezger2, Tudor E Ciuleanu3, Jürgen R Fischer4, Joachim von Pawel5, Mariano Provencio6, Andrzej Kazarnowicz7, György Losonczy8, Gilberto de Castro9, Aleksandra Szczesna10, Lucio Crino11, Martin Reck12, Rodryg Ramlau13, Ernst Ulsperger14, Christian Schumann15, Jose Elias A Miziara16, Álvaro E Lessa17, Mircea Dediu18, Beatrix Bálint19, Henrik Depenbrock20, Victoria Soldatenkova20, Raffael Kurek20, Fred R Hirsch21, Nick Thatcher22, Mark A Socinski23. 1. Instituto de Biomedicina de Sevilla-IBIS (Hospital Virgen del Rocío/Universidad de Sevilla/CSIC), Sevilla, Spain; Hospital Universitario Doce de Octubre and CNIO Lung Cancer Unit, Madrid, Spain. Electronic address: lpazaresr@seom.org. 2. St Vincentius Kliniken, Karlsruhe, Germany. 3. Institute of Oncology and University of Medicine and Pharmacy, Cluj-Napoca, Romania. 4. Klinik Löwenstein GmbH, Löwenstein, Germany. 5. Asklepios-Fachkliniken Mönchen-Gauting, Gauting, Germany. 6. Hospital Puerta de Hierro, Madrid, Spain. 7. Samodzielny Publiczny Zespól Gruźlicy i Chorób Pluc w Olsztynie, Olsztyn, Poland. 8. Semmelweis Egyetem, Budapest, Hungary. 9. Instituto do Cancer do Estado de Sao Paulo (ICESP), Sao Paulo, Brazil. 10. Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy, Otwock, Poland. 11. Ospedale Santa Maria della Misericordia, Perugia, Italy. 12. LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. 13. Poznan University of Medical Sciences, Wielkopolskie Centrum Pulmonologii i Torakochirurgii, Poznan, Poland. 14. Landesklinikum Horn, NÖ, Austria. 15. Department of Internal Medicine II, University Clinic Ulm, Ulm, Germany; Klinik für Pneumologie, Thoraxonkologie, Schlaf-und Beatmungsmedizin, Kempten-Oberallgäu, Germany. 16. Hospital de Câncer de Barretos, Sao Paulo, Brazil. 17. Hospital Santa Izabel-Santa Casa de Misericordia da Bahia, Nazare, Nazare, Brazil. 18. Institute of Oncology Bucharest, Bucharest, Romania. 19. Csongrád Megye Mellkasi Betegségek Szakkórháza, Deszk, Hungary. 20. Lilly Deutschland GmbH, Bad Homburg, Germany. 21. University of Colorado, Division of Medical Oncology, Aurora, CO, USA. 22. The Christie Hospital, National Health Services Trust, Manchester, UK. 23. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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.
RCT Entities:
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.
Authors: Marissa Mayor; Neng Yang; Daniel Sterman; David R Jones; Prasad S Adusumilli Journal: Eur J Cardiothorac Surg Date: 2015-10-29 Impact factor: 4.191