Necitumumab 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

doi:10.1016/S1470-2045(15)70046-X

The Lancet Oncology

Volume 16, Issue 3, March 2015, Pages 328-337

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https://doi.org/10.1016/S1470-2045(15)70046-X Get rights and content

Summary

Background

Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC).

Methods

We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m² and pemetrexed 500 mg/m² on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111.

Findings

Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84–1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group.

Interpretation

Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.

Funding

Eli Lilly and Company.

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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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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Ann Oncol

Ann Oncol

J Thorac Oncol

Lancet

Health Policy

Lancet Oncol

Lancet Oncol

Lung Cancer

Ann Oncol

Ann Oncol

Ann Oncol

J Thorac Oncol

J Thorac Oncol

New pathologic classification of lung cancer: relevance for clinical practice and clinical trials

J Clin Oncol

Molecular biology of lung cancer

J Thorac Dis

Management and future directions in non-small cell lung cancer with known activating mutations

Am Soc Clin Oncol Educ Book

Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer

Ann Oncol

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

Expert Opin Biol Ther

Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer

Oncologist

Articles
Necitumumab 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