Elsevier

The Lancet Oncology

Volume 17, Issue 2, February 2016, Pages 212-223
The Lancet Oncology

Articles
TG4010 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

https://doi.org/10.1016/S1470-2045(15)00483-0Get rights and content

Summary

Background

MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting.

Methods

In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 108 plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148.

Findings

Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4–6·7) in the TG4010 group and 5·1 months (4·2–5·9) in the placebo group (HR 0·74 [95% CI 0·55–0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54–1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42–1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1–2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events).

Interpretation

TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part.

Funding

Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO.

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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