Elsevier

The Lancet Oncology

Volume 17, Issue 6, June 2016, Pages 822-835
The Lancet Oncology

Articles
Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(16)00099-1Get rights and content

Summary

Background

Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC.

Methods

In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025.

Findings

Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9–48·4) in the MAGE-A3 group and 39·5 months (27·9–50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2–not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7–not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89–1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6–not reached) in those in the MAGE-A3 group and 56·9 months (44·4–not reached) in the placebo group (HR 0·97, 95% CI 0·80–1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]).

Interpretation

Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped.

Funding

GlaxoSmithKline Biologicals SA.

Introduction

Lung cancer is the most frequent cause of cancer death.1 Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Complete surgical resection is recommended in stage I, II, and selected IIIA NSCLC,2 but 5-year overall survival remains less than 50%.3 Adjuvant cisplatin-based chemotherapy is recommended for stage II–IIIA disease, and is estimated to provide a 5–8% benefit in 5-year overall survival.4 Many patients with resected NSCLC have smoking-induced comorbidities, and are unable to tolerate cisplatin-based chemotherapy because of its toxic effects.5 Safer and more effective adjuvant treatments are needed for the treatment of early stage NSCLC.

Research in context

Evidence before this study

We searched PubMed on Dec 1, 2015, using the following terms: “NSCLC AND (vaccine OR immunotherapeutic) AND clinical trials, phase III” without date or language limitations. We identified two studies, one with a whole tumour cell vaccine (belagenpumatucel-L) in advanced non-small-cell lung cancer (NSCLC), and one with a MUC-1 mucoprotein directed liposomal vaccine (L-BLP25, tecemotide) in locally advanced NSCLC in disease control after chemoradiotherapy. Both studies were negative for their primary endpoint.

Added value of this study

Fewer than half of the patients with completely resected NSCLC are cured, the others experience cancer relapse that is often fatal. During the past decades, several adjuvant treatments to improve prognosis of these patients have been studied. Adjuvant radiotherapy was not beneficial. The improvement of outcome by postoperative cisplatin-based chemotherapy was clearly established in meta-analyses of chemotherapy adjuvant trials. Efforts to improve the efficacy ratio of treatment based on biomarkers have failed up to now. By contrast with the major progress brought by molecularly targeted agents for patients with advanced NSCLC over the last years, no further progress in adjuvant chemotherapy for patients with resected NSCLC has been made.

Therapeutic cancer vaccination has the potential to eliminate remaining cancer cells after complete resection, thereby decreasing relapse rates and improving survival. Early signs with the MAGE-A3 immunotherapeutic in a randomised placebo-controlled phase 2 study suggested clinical activity in resected NSCLC. No other clinical studies of adjuvant immunotherapy were available at the time of the design of MAGRIT.

With almost 14 000 surgical patients screened, MAGRIT is the largest therapeutic trial ever done in the adjuvant setting of NSCLC. Unfortunately, the MAGE-A3 immunotherapeutic did not increase survival in patients with resected NSCLC. The study provides important insights into the clinical characteristics, cancer recurrence, and survival in patients with contemporary thoracic surgery and chemotherapy.

Implications of all the available evidence

Up to now, except for adjuvant cisplatin-based chemotherapy, no other strategy could improve the outcome of patients with resected NSCLC. Phase 3 studies done in patients with NSCLC, including MAGRIT, confirm the acceptable clinical safety profile of cancer immunotherapeutics, but did not improve overall survival. These results question whether therapeutic cancer vaccination with the current technology is able to surmount the immunosuppressive environment of lung cancer and have implications for the conduct of future studies assessing cancer immunotherapies in NSCLC. At present, only TG4010, an attenuated vaccinia Ankara virus expressing MUC-1 and interleukin 2, remains in clinical development (NCT01383148).

Antigen-specific immunotherapies are designed to enhance T-cell responses against specifically expressed tumour antigens. MAGE-A3 is a human gene that encodes a tumour-specific antigen (MAGE-A3 protein) expressed in 30–50% of NSCLCs, with higher expression rates in squamous-cell carcinomas (48%) than in non-squamous-cell carcinomas (24%).6 The MAGE-A3 gene is silent in all normal human tissues except in placenta and the testis.7, 8 Testicular expression of MAGE-A3 is restricted to cells unable to present antigens to the immune system. Therefore, MAGE-A3 can be regarded as a strictly tumour-specific antigen.

The MAGE-A3 immunotherapeutic comprises recombinant MAGE-A3 protein given with a proprietary immunostimulant, AS15.9 In the phase 2 proof-of-concept study including stage IB–II NSCLC, the MAGE-A3 immunotherapeutic, using the less powerful immunostimulant AS02B,10 induced a humoral response in all patients, with few grade 3 or higher adverse reactions or treatment-related adverse events.11 After a median follow-up of 38·8 months, 35% of patients receiving the MAGE-A3 immunotherapeutic had recurrent disease versus 43% of those receiving placebo (hazard ratio [HR] for disease-free survival 0·76, 95% CI 0·48–1·21). Although not significant, this HR was similar to the one obtained with adjuvant chemotherapy, and deemed sufficiently promising to assess the clinical efficacy of adjuvant MAGE-A3 immunotherapeutic in patients with resected NSCLC in this international, multicentre, phase 3 study.

Section snippets

Study design and participants

In this randomised, double-blind, placebo-controlled phase 3 trial, we recruited patients aged at least 18 years from 34 countries worldwide who had histologically proven, completely resected stage IB, II, or IIIA NSCLC defined according to the sixth edition of the TNM staging system.12

After signing informed consent for screening, we established MAGE-A3 gene expression with quantitative PCR (qPCR) analysis on the formalin-fixed paraffin-embedded surgical specimen. Details about the MAGE-A3

Results

Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression from 590 centres in 34 countries (Europe, the Americas, and Asia Pacific); 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 (55%) of these patients (from 443 centres) met all eligibility criteria and were randomly assigned; 2272 received at least one study treatment injection (figure 1). The first patient was randomly assigned on Dec 14, 2007, and the last on July

Discussion

Our findings show that the MAGE-A3 immunotherapeutic did not increase disease-free survival or any other clinical outcome measure in the overall population, the no-chemotherapy population, or in subgroups according to tumour characteristics or treatment procedures. Treatment with MAGE-A3 was safe. There were higher rates of mild injection site reactions and influenza-like symptoms than with placebo, but grade 3 and 4 treatment-related symptoms and treatment-related serious adverse events were

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