Elsevier

European Journal of Cancer

Volume 51, Issue 16, November 2015, Pages 2321-2329
European Journal of Cancer

A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer

https://doi.org/10.1016/j.ejca.2015.07.035Get rights and content

Abstract

Background

Treatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-β2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment.

Methods

Stage III/IV NSCLC patients who did not progress after platinum-based chemotherapy were randomised 1:1 to receive maintenance belagenpumatucel-L or placebo. Patients were eligible for randomisation between one and four months from the end of induction chemotherapy. The primary endpoint was overall survival.

Results

This phase III trial enrolled 270 patients in the belagenpumatucel-L arm and 262 in the control arm. Belagenpumatucel-L was well tolerated with no serious safety concerns. There was no difference in survival between the arms (median survival 20.3 versus 17.8 months with belagenpumatucel-L versus placebo, respectively; hazard ratio (HR) 0.94, p = 0.594). There were also no differences in progression-free survival (4.3 months versus 4.0 for belagenpumatucel-L vs placebo, respectively; HR 0.99, p = 0.947). A prespecified Cox regression analysis demonstrated that the time elapsed between randomisation and the end of induction chemotherapy had a significant impact on survival (p = 0.002) and that prior radiation was a positive prognostic factor (median survival 28.4 months with belagenpumatucel-L versus 16.0 months with placebo; HR 0.61, p = 0.032).

Conclusions

Although the overall trial did not meet its survival endpoint, improved survival for belagenpumatucel-L is suggested in patients who were randomised within 12 weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted.

Introduction

Lung cancer is the most prevalent cancer in the western world, with approximately 224,000 new cases and 159,000 deaths expected in the United States in 2014 [1], and 187,000 deaths in the European Union [2].

Most patients with advanced non-small cell lung cancer (NSCLC) are initially treated with four to six cycles of platinum-based doublet chemotherapy [3], [4], [5] but five-year survival of stage IIIB/IV patients is less than 10% [6]. Patients without progression following frontline chemotherapy may be placed on maintenance therapy. Patients with non-squamous cell carcinoma who receive maintenance pemetrexed show a moderate survival benefit [7]. Maintenance with erlotinib, a molecule targeting the epidermal growth factor receptor (EGFR), is approved for all NSCLC histologies [8], although it is most frequently used in EGFR mutant adenocarcinoma patients [3].

Immunotherapy trials performed in NSCLC have included whole tumour cell vaccines [9], [10], [11], [12], single tumour-associated peptides such as MUC1, telomerase, epidermal growth factor, WT1 [13], [14], [15], [16], multiple tumour-associated peptides [17] and dendritic cells pulsed with tumour cells [18].

Belagenpumatucel-L is an allogeneic whole tumour cell vaccine comprised of four NSCLC cell lines that were transfected with a human transforming growth factor (TGF)-β2-antisense vector designated pCHEK/HBA2 [9], [10], [19]. Two previous Phase II trials have demonstrated the safety and efficacy of belagenpumatucel-L in patients with NSCLC [9], [10]. We report on the results of a randomised, placebo-controlled Phase III study to investigate the efficacy of belagenpumatucel-L as a maintenance therapy in patients not progressing following frontline platinum-based chemotherapy.

Section snippets

Study design

Patients with advanced NSCLC were randomised to receive maintenance belagenpumatucel-L (2.5 × 107 cells per dose) or placebo in a 1:1 ratio in this international, double blind, intention to treat (ITT) study (NCT00676507).

Inclusion criteria included histologically confirmed diagnosis of stage IIIA (T3N2), IIIB or IV NSCLC [20]. Patients had stable disease or response following up to 6 cycles of a platinum-based frontline chemotherapy regimen, with or without radiation therapy. Patients had to be

Demographics

This international, randomised, double-blind, placebo controlled study enrolled 532 patients in 73 centres in 8 countries between August 2008 and June 2012. The dataset was locked after the second interim analysis.

The belagenpumatucel-L and placebo arms were well balanced for baseline characteristics (Table 1). 220 patients (41.4%) were randomised in North America, 284 patients (53.4%) were randomised in Europe and 28 patients (5.3%) were randomised in India.

Overall survival (OS)

The study was terminated at the

Discussion

This large double-blind randomised study failed to demonstrate a significant increase in survival of belagenpumatucel-L as a maintenance therapy in the overall patient population with stage III/IV NSCLC who had stable disease after frontline therapy.

A prespecified Cox regression analysis suggests the importance of the time elapsed between completion of chemotherapy and randomisation (p = 0.002). Patients randomised within 12 weeks of the completion of frontline chemotherapy had 20.7-month median

Contributors

Concept and design: Giuseppe Giaccone, Ewa Carrier, Steven C. Moses, Daniel L. Shawler, and Habib Fakhrai.

Assembly of data: Steven C. Moses, Daniel L. Shawler, and Habib Fakhrai.

Enrolment of patients: Giuseppe Giaccone. Lyudmila Bazhenova, John Nemunaitis, Erzsébet Juhász, Rodrig Ramlau, Michel M. van den Heuvel, Rohit Lal, Goetz H Kloecker, Keith D. Eaton, Quincy Chu, David J. Dunlop, Minish Jain, and Edward B. Garon.

Data Analysis and interpretation: Giuseppe Giaccone, Lyudmila Bazhenova, John

Conflict of interest statement

S. Moses, D. Shawer, E. Carrier and H. Fakhrai are employees of NovaRx.

Acknowledgements

The trial was sponsored by NovaRx Corporation, San Diego, CA, USA. The trial was supported by SBIR grant R44 CA096025 (HF) and by NovaRx Corporation.

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  • Cited by (0)

    1

    Drs. Giaccone and Bazhenova are co-first authors for this publication.

    2

    Dr. Habib Fakhrai is the sponsor of the trial and inventor of NovaRx technology.

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