Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial.
BACKGROUND
An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer.


METHODS
From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m(2), intravenously, every 21 days, or docetaxel 75 mg/m(2), intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690.


RESULTS
142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8-10·9) in the chemotherapy group and 7·7 months (5·9-10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08-2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77-1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group.


CONCLUSIONS
Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib.


BACKGROUND
Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy. Electronic address: vanesa.gregorc@hsr.it.
Vanesa
V
Gregorc
Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Orbassano, Turin, Italy.
Silvia
S
Novello
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Chiara
C
Lazzari
Division of Medical Oncology, Department of Medical Oncology, Azienda Ospedaliera Treviglio, Treviglio, Italy.
Sandro
S
Barni
Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, Istituto di Ricovero e Cura a Carattere Scientifico, Rionero in Vulture, Italy.
Michele
M
Aieta
Oncology Unit, Villa Scassi Hospital, Azienda Sanitaria Locale 3, Genoa, Italy.
Manlio
M
Mencoboni
Lung Cancer Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Francesco
F
Grossi
Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy.
Tommaso
T
De Pas
Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy; 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome, Italy.
Filippo
F
de Marinis
Department of Medical Oncology, National Cancer Institute of Aviano, Aviano, Italy.
Alessandra
A
Bearz
Department of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.
Irene
I
Floriani
Department of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.
Valter
V
Torri
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Alessandra
A
Bulotta
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Angela
A
Cattaneo
Biodesix, Boulder, CO, USA.
Julia
J
Grigorieva
Biodesix, Boulder, CO, USA.
Maxim
M
Tsypin
Biodesix, Boulder, CO, USA.
Joanna
J
Roder
Università Vita-Salute San Raffaele, School of Medicine, Department of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Claudio
C
Doglioni
Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Orbassano, Turin, Italy.
Matteo Giaj
MG
Levra
Division of Medical Oncology, Department of Medical Oncology, Azienda Ospedaliera Treviglio, Treviglio, Italy.
Fausto
F
Petrelli
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Silvia
S
Foti
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Mariagrazia
M
Viganò
Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Angela
A
Bachi
Biodesix, Boulder, CO, USA.
Heinrich
H
Roder
D014408:Biomarkers, Tumor; D001798:Blood Proteins / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D040901:Proteomics; D011799:Quinazolines / Q000627:therapeutic use*
D014408:Biomarkers, Tumor; D001798:Blood Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors