Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.
BACKGROUND
Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC.


METHODS
148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818.


RESULTS
6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event.


CONCLUSIONS
This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated.


BACKGROUND
Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.
Hôpitaux Universitaires, Université de Strasbourg, Strasbourg, France. elisabeth.quoix@chrustrasbourg.fr
Elisabeth
E
Quoix
Rodryg
R
Ramlau
Virginie
V
Westeel
Zsolt
Z
Papai
Anne
A
Madroszyk
Alain
A
Riviere
Piotr
P
Koralewski
Jean-Luc
JL
Breton
Erich
E
Stoelben
Denis
D
Braun
Didier
D
Debieuvre
Hervé
H
Lena
Marc
M
Buyse
Marie-Pierre
MP
Chenard
Bruce
B
Acres
Gisèle
G
Lacoste
Bérangère
B
Bastien
Annette
A
Tavernaro
Nadine
N
Bizouarne
Jean-Yves
JY
Bonnefoy
Jean-Marc
JM
Limacher
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014614:Vaccines, Synthetic; D014616:Vaccinia virus / Q000235:genetics; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D019496:Cancer Vaccines; C508594:IL2 protein, human; D007376:Interleukin-2; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; C518275:TG4010; D014614:Vaccines, Synthetic; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine