A randomised phase II study of pemetrexed versus pemetrexed + erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer

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Abstract

Introduction

Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed + erlotinib in patients with advanced non-squamous NSCLC.

Methods

NSCLC stage III–IV patients who failed one prior platinum-based chemotherapy regimen, ≥1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤2 were eligible. Patients received pemetrexed 500 mg/m2 with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity.

Results

Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed + erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed + erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed + erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed + erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed + erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in ≥5% of patients) in pemetrexed/pemetrexed + erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%).

Conclusions

Pemetrexed + erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone.

Section snippets

INTRODUCTION

Of the NSCLC patients experiencing disease progression after first-line standard therapy, about 40–50% will receive second-line therapy [1]. However, only limited therapeutic options are available for second-line treatment [2]. The choice of any second-line treatment should represent a rational selection of a drug or drug combination depending on their activity against tumours pretreated with distinct first-line therapies [3].

Currently, three cytotoxic or cytostatic agents are approved for

Study design

This multicentre, randomised, phase II, open-label, parallel trial was designed to evaluate PFS of pemetrexed and pemetrexed plus erlotinib in an overall advanced NSCLC patient population. The study enrolled its first patient in April 2007. Following a label change for Alimta (pemetrexed) in EU and the USA [13], [5] restricting the patient population to non-squamous NSCLC only, the protocol was amended (approved on 1st August 2008) to narrow the patient population to non-squamous NSCLC to bring

Patient disposition

This study was conducted at 24 study centres in five countries (Austria, Germany, Hungary, Spain, and Sweden) from 11th April 2007 to 27th July 2010 (primary analysis cut-off date). One hundred and sixty-five patients with non-squamous NSCLC of the total enrolled patient population (N = 214) were randomly assigned to a treatment arm (Fig. 1); 159 of these patients received at least one dose of study treatment (pemetrexed, n = 83; pemetrexed + erotinib, n = 76). Three patients treated with pemetrexed + 

Discussion

The combination of pemetrexed with erlotinib as second-line treatment in patients with advanced or metastatic non-squamous NSCLC yielded a statistically significant improvement in PFS (HR 0.63; 95% CI: 0.44, 0.90; log-rank P = 0.0047) compared with single-agent pemetrexed. Thus, the primary study objective was met. Although it might be argued that the envisaged difference of one third increase in PFS is somewhat low – especially with regard to actual expectations from novel targeted drugs tested

Role of the funding source

This study was sponsored by Eli Lilly and Company, Indianapolis, IN, USA. Eli Lilly provided the study medication and collaborated with the principal investigator/investigators on study concept, study design, quality control, data analysis and interpretation, statistical analysis and preparation of this report. The investigators had final responsibility for the content of the report and for the decision to submit for publication.

Conflict of interest statement

Professor Dittrich received honoraria from Eli Lilly and Genentech/Roche. The research institutes headed by Professor Dittrich received research grants from Eli Lilly and Roche Austria. Dr. von Pawel is a member of advisory boards of Daiichi Sankyo, Eli Lilly and Pfizer and also received speaker fees. Dr. Hartmann received research support from Eli Lilly. Dr. Behringer is a member of advisory boards of Roche and Eli Lilly. Drs. Papai-Szekely and Vinolas have no relevant financial disclosure.

Acknowledgements

The authors wish to thank all the investigators and patients who participated in this study.

References (23)

  • M. Di Maio et al.

    Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small cell lung cancer

    J Clin Oncol

    (2009)
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