ArticlesNecitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study
Introduction
Non-small-cell lung cancer (NSCLC) is a heterogeneous disease with respect to tumour histology and molecular profile.1, 2 Patients with EGFR wild-type, ALK translocation-negative non-squamous NSCLC (adenocarcinoma, large-cell carcinoma, and other non-squamous histology), and a good performance status, might be offered a wide choice of first-line regimens consisting of a platinum-based doublet of cisplatin or carboplatin combined with pemetrexed, a taxane, gemcitabine, or vinorelbine, with or without bevacizumab.3 The presence in tumours of sensitising mutations of EGFR or ALK translocations—driver lesions predictive of outcome for particular targeted drugs—offers the possibility of specific, pathway-directed systemic therapy for some patients with adenocarcinoma.4, 5, 6 However, tumour EGFR mutation status does not seem to be associated with efficacy of EGFR antibody therapy.7 In the past few years, expansion of first-line treatment options for patients with non-squamous NSCLC has been reflected in improvements in overall survival.
Most advanced NSCLCs express EGFR, and aberrant function of the EGFR pathway seems to be a key factor in the development of some NSCLCs.8 The randomised phase 3 FLEX study showed that addition of the EGFR antibody cetuximab to cisplatin plus vinorelbine significantly improved overall survival (hazard ratio [HR] 0·871 [95% CI 0·762–0·996]; p=0·044), but not progression-free survival (0·943 [0·825–1·077]; p=0·39) in the first-line treatment of patients with EGFR-expressing advanced NSCLC.8 This improvement in overall survival was accompanied by significant adverse effects in the cetuximab group, in particular an increased incidence of febrile neutropenia, an adverse event that was prevalent in the chemotherapy group. Nevertheless, the FLEX study provided a rationale for the testing of other EGFR antibodies in this setting.
Necitumumab is a second-generation recombinant human immunoglobulin G1 (IgG1) EGFR monoclonal antibody that binds EGFR with high affinity, competing with the natural ligands and thereby preventing receptor activation by all known ligands and thus inhibiting downstream signalling.9 For first-line treatment of patients with advanced non-squamous NSCLC, pemetrexed and cisplatin is an established chemotherapy regimen.10, 11 In murine NSCLC xenograft models, addition of necitumumab to pemetrexed and cisplatin resulted in a substantial increase in anti-tumour activity (unpublished data), suggesting that this regimen was appropriate for use in our present study.
We did the INSPIRE study to investigate whether addition of necitumumab to pemetrexed and cisplatin would improve survival in the first-line treatment of patients with advanced non-squamous NSCLC. We postulated that the choice of pemetrexed and cisplatin as the chemotherapy regimen when combined with an EGFR antibody would result in a lower incidence of febrile neutropenia than did the cisplatin and vinorelbine regimen used in the FLEX study. We also expected to minimise the rate of hypersensitivity reactions on the basis of the human constitution of necitumumab. In parallel, the phase 3 SQUIRE study12 assessed the efficacy and safety of necitumumab plus gemcitabine and cisplatin as first-line treatment for patients with advanced squamous NSCLC.
Section snippets
Study design and patients
We did this open-label, randomised, controlled phase 3 study at 103 sites in 20 countries (appendix). Full inclusion and exclusion criteria are in the appendix. Briefly, eligible patients were aged 18 years or older with histologically or cytologically confirmed stage IV (according to the American Joint Committee on Cancer staging system13) non-squamous NSCLC who had not received chemotherapy for the treatment of advanced disease. Other key inclusion criteria included measurable disease as
Results
Study enrolment began on Nov 11, 2009. After a series of meetings between June 14, 2010, and Jan 31, 2011, the independent data monitoring committee recommended that study enrolment be stopped, and necitumumab treatment discontinued in patients who had not completed two cycles of treatment. This recommendation was made based on data of non-fatal and fatal thromboembolic events from the sponsor's serious adverse event database and on the overall number of deaths from all causes shown in the
Discussion
Our findings provide no evidence to show that the addition of necitumumab to pemetrexed and cisplatin as first-line therapy improves overall survival in patients with stage IV non-squamous NSCLC. The statistical power of the study was reduced by its early curtailment. Nevertheless, the HR for death in the final analysis and the consistent absence of benefit in other efficacy endpoints, including progression-free survival and response, suggest that addition of necitumumab to pemetrexed and
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