Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO).
BACKGROUND
This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC).


METHODS
Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200.


RESULTS
There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator.


CONCLUSIONS
The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.
NCT00842712.
Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospitals KU Leuven, Leuven, Belgium johan.vansteenkiste@uzleuven.be.
J
J
Vansteenkiste
Multidisciplinary Oncology and Therapeutic Innovations, Aix Marseille University-Assistance Publique Hôpitaux de Marseille, Marseille, France.
F
F
Barlesi
Haematology, Oncology and Stem Cell Transplantation, University Hospital of Freiburg, Freiburg, Germany.
C F
CF
Waller
Département d'Oncologie Médicale, Centre Rene Gauducheau, Saint-Herblain Cedex, France.
J
J
Bennouna
Division of Medical Oncology, Azienda Ospedaliera 'S.G. Moscati', Avellino, Italy.
C
C
Gridelli
Department of Oncology, Hematology, Stem Cell Transplantation and Hemostaseology, University Hospital Aachen, Aachen, Germany.
E
E
Goekkurt
Iridium Cancer Network, Medical Oncology, AZ Klina, Antwerp, Belgium.
D
D
Verhoeven
Mazowieckie Centrum Leczenia Chorób Pluc i Gruźlicy, Otwock, Poland.
A
A
Szczesna
Lungenpraxis Munich, Munich, Germany.
M
M
Feurer
Department of Pneumology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
J
J
Milanowski
Pulmonary Medicine, AZ Maria Middelares, Ghent, Belgium.
P
P
Germonpre
Pneumology, CHU Rennes, Rennes, France.
H
H
Lena
Oncology/Hematology/Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
D
D
Atanackovic
The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Lung and Thoracic Tumours, Warsaw, Poland.
M
M
Krzakowski
Merck KGaA, Darmstadt.
C
C
Hicking
Merck KGaA, Darmstadt.
J
J
Straub
Merck KGaA, Darmstadt.
M
M
Picard
Krankenhaus Martha-Maria Halle-Dölau, Klinik für Innere Medizin II, Halle, Germany.
W
W
Schuette
Cancer Services, Princess Alexandra Hospital, Brisbane, Australia.
K
K
O'Byrne
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D019030:Receptors, Vitronectin / Q000378:metabolism; D012910:Snake Venoms / Q000008:administration & dosage; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D000093542:Gemcitabine
D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; D003841:Deoxycytidine; C422910:Cilengitide; D014747:Vinblastine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin; D000077235:Vinorelbine; D000093542:Gemcitabine
NSCLC; PFS; cilengitide; integrins; phase II; randomized controlled trials