ArticlesTecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial
Introduction
Lung cancer is the leading cause of cancer-related death worldwide, causing about 1·4 million deaths each year.1 Non-small-cell lung cancer accounts for 80–85% of lung cancer cases and 30% of patients present with stage III disease.2 Standard treatment for patients with a good performance status and unresectable stage III non-small-cell lung cancer is platinum-based doublet chemotherapy and radiotherapy administered with curative intent. A meta-analysis of concurrent versus sequential chemoradiotherapy showed better outcomes with concurrent therapy, but even with concurrent chemoradiotherapy, 5-year overall survival is just 15%.3
The mucin 1 (MUC1) glycoprotein is overexpressed and abnormally glycosylated in non-small-cell lung cancer and other cancers.4, 5 Cancer-associated MUC1 is involved in abnormal interactions with receptor tyrosine kinases and other cell surface receptors. These abnormal interactions trigger inappropriate activation of intracellular signalling pathways and thus promote the growth, proliferation, and survival of cancer cells.6, 7, 8, 9, 10, 11 Tecemotide (L-BLP25) is a MUC1 antigen-specific immunotherapy capable of inducing a T-cell response to MUC1 in both a preclinical MUC1-transgenic lung cancer mouse model12 and in patients.13, 14, 15 A National Cancer Institute (NCI) project to prioritise cancer antigens ranked MUC1 very highly on the basis of predefined criteria.16 In a randomised phase 2 trial of tecemotide as maintenance therapy versus best supportive care in responding and stable patients with stage IIIB or IV non-small-cell lung cancer, a potential survival benefit with tecemotide in stage IIIB patients was reported.13, 14 A single-arm phase 2 trial of tecemotide after chemoradiotherapy for unresectable stage III non-small-cell lung cancer showed similar survival results.15
On the basis of these promising findings, we initiated the START (Stimulating Targeted Antigenic Response To non-small-cell lung cancer) study to assess the efficacy of tecemotide when compared with placebo as a maintenance therapy in patients with stage III non-small-cell lung cancer who have received chemoradiotherapy.
Section snippets
Study design and participants
START was an international, randomised, double-blind phase 3 trial that recruited patients from 33 countries worldwide. Eligible patients were those aged 18 years or older with histologically or cytologically unresectable stage III non-small-cell lung cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Stage was confirmed and documented by CT, MRI, or PET. We did not require pathological confirmation of mediastinal nodal involvement and we included all
Results
From Feb 22, 2007, until Nov 15, 2011, 1513 patients were enrolled from 264 centres in 33 countries worldwide (figure 1; appendix). The modified intention-to-treat primary analysis population consisted of 1239 patients after exclusion of 274 patients randomly assigned within the 6 months preceding the clinical hold. Only eight (1%) of 1239 patients were lost to follow-up during the treatment phase (figure 1).
At the time of implementation of the clinical hold in March, 2010, 531 patients were
Discussion
The results of the START trial—the largest done, to our knowledge, in the setting of stage III non-small-cell lung cancer (panel)—showed that the primary endpoint of overall survival in patients who received cyclophosphamide and tecemotide after chemoradiotherapy did not differ significantly from those who received saline and placebo after chemoradiotherapy. However, we noted a favourable effect of tecemotide in patients who received concurrent chemoradiotherapy, with a 10·2 month improvement
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