ArticlesTG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial
Introduction
Non-small-cell lung cancer is the most frequent cause of cancer-related deaths.1 Most tumours have a non-squamous histology, and the proportion of this type of tumours is still growing. Present first-line treatment of advanced stage disease is based on a platinum-based doublet chemotherapy regimen. In patients with EGFR mutations or ALK rearrangements, targeted treatments are the preferred option. The goal of treatment of advanced disease is to improve the duration of survival while quality of life is maintained.2, 3 Immunotherapy has proven its ability to change the course of neoplastic diseases in a substantial manner, with some patients showing durable responses.4 Some cancer immunotherapy products, such as therapeutic vaccines, induce development of a cellular immune response against the tumour, whereas others, such as immune checkpoint blockers, suppress negative regulatory pathways that prevent the antitumoural immune response from being fully active.
TG4010 (Transgene, Illkirch, France) consists of a suspension of a recombinant modified vaccinia Ankara that codes for the MUC1 tumour-associated antigen and interleukin 2.5 The MUC1 protein is overexpressed in lung cancer and many other epithelial tumours to which it offers a selective advantage. In tumours as compared with healthy tissues, the MUC1 protein seems aberrantly glycosylated and this glycosylation is the source of new antigens that make it an immune target. The full-length MUC1 protein expressed by TG4010 in the cytoplasm of modified vaccinia Ankara-infected cells shares epitopes associated with tumoural MUC1 against which it induces a cellular immune response. This immunisation is potentiated by danger signals related to the viral nature of the product and by local co-expression of interleukin 2 at the injection site.
The combination of TG4010 with first-line chemotherapy for advanced stage non-small-cell lung cancer has been tested in two previous randomised studies.6, 7 Findings from these studies have shown that the combination was feasible and safe; the studies met their respective efficacy endpoints, which were progression-free survival at 6 months6 and the proportion of patients achieving a response.7 A biomarker programme associated with the study by Quoix and colleagues6 identified a low baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL), mainly a phenotype of activated natural killer cells, as being predictive of TG4010 activity in combination with chemotherapy. In the previous clinical study by Quoix and colleagues,6 the 75% of patients with the lowest values of TrPAL benefited from addition of TG4010 to chemotherapy, whereas the 25% with the highest values did not. Natural killer cells positively regulate development of an adaptive immune reaction through close interactions with dendritic and effector T cells, up to a specific level of activation. If their level of activation becomes too high, they shift toward an immune-suppressive behaviour and limit development of an adaptive immune response.8 They are reactive to the presence of tumoural cells and viral infections; these two elements are at play in patients with non-small-cell lung cancer repeatedly receiving the live virus TG4010.
The TIME trial is a randomised, controlled, phase 2b/3 trial in previously untreated patients with advanced stage non-small-cell lung cancer, aiming to substantiate the activity of TG4010 in combination with first-line chemotherapy and the clinical usefulness of the TrPAL biomarker. We present here the results of the phase 2b part of the study.
Section snippets
Study design and participants
In the phase 2b part of this randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited patients from 45 centres located in France, Belgium, the UK, Italy, Spain, Hungary, Poland, Israel, and the USA (appendix p 9). Patients were eligible for study inclusion if they had histologically confirmed, stage IV (according to the Union Internationale Contre le Cancer) non-small-cell lung cancer without a known activating EGFR mutation. MUC1 expression, analysed by immunohistochemistry
Results
Between April 10, 2012, and Sept 14, 2014, we enrolled 222 patients (111 [50%] per treatment group; figure 1). As of Dec 15, 2014 (median follow-up 18·2 months [IQR 16·8–23·5] since randomisation), most patients had discontinued the study; 11 (5%) patients had not yet progressed and were still undergoing treatment (eight [7%] in the TG4010 group and three [3%] in the placebo group). 217 (98%) patients received at least one dose of TG4010 or placebo (TG4010 110 [99%]; placebo 107 [96%]).
Baseline
Discussion
In this phase 2b part of the TIME trial, we have shown that addition of TG4010 to first-line chemotherapy in advanced stage non-small-cell lung cancer significantly improves progression-free survival, particularly in patients with a TrPAL value of less than or equal to the ULN on the basis of a Bayesian analysis. In patients with a TrPAL value of greater than the ULN, the Bayesian analysis did not validate the TrPAL biomarker. Similarly, when the lower cutoff values for TrPAL at baseline based
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