Elsevier

The Lancet Oncology

Volume 16, Issue 7, July 2015, Pages 763-774
The Lancet Oncology

Articles
Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00021-2Get rights and content

Summary

Background

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer.

Methods

We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058.

Findings

Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations.

Interpretation

Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease.

Funding

Eli Lilly and Company.

Introduction

Squamous cell carcinomas account for 30% of non-small-cell lung cancers worldwide.1 In addition to histopathological differences, the mutational profiles of squamous and non-squamous non-small-cell lung cancers are distinctive, with both of these aspects potentially affecting treatment selection.2 For patients with squamous non-small-cell lung cancer, although some potentially targetable molecular lesions have been identified in tumours,1, 3 including PIK3CA amplification, FGFR1 amplification, MET amplification, and DDR2 mutation, none of these biomarkers have yet been validated in this setting as predictive for particular targeted therapies, and available first-line regimens have remained essentially unchanged for the past two decades. In general, such regimens comprise a platinum-based doublet of cisplatin or carboplatin combined with gemcitabine, vinorelbine, or a taxane.1, 4 By contrast, for patients with non-squamous non-small-cell lung cancer, the availability of pemetrexed and bevacizumab as components of first-line or maintenance regimens has widened the choice of possible treatments and provided the opportunity to improve overall survival in this patient group.5, 6, 7, 8, 9 Additionally, a few recurring somatic tumour mutations have been described in adenocarcinomas, offering the potential for selective pathway-directed systemic therapy.10, 11, 12 In particular, EGFR mutations and ALK translocations are predictive of outcome in relation to specific targeted drugs,13, 14 but these mutations are very rare in squamous non-small-cell lung cancer.1, 15 Thus, although clear advances have been made in the first-line treatment of non-squamous non-small-cell lung cancer, especially adenocarcinoma, a substantial unmet need persists to improve outcomes for patients with advanced squamous non-small-cell lung cancer. We note in this context the recent US FDA approval of additional second-line options for patients progressing on or after platinum-based chemotherapy: the PD-1 antibody nivolumab for metastatic squamous non-small-cell lung cancer;16 and the human immunoglobulin G1 VEGFR-2 antibody ramucirumab, in combination with docetaxel, for treatment of metastatic non-small-cell lung cancer (including that of squamous histology).17 However, only about half of patients continue to second-line treatment,18 and neither drug is indicated in the first-line setting.

Research in context

Evidence before this study

In the development of the study design and protocol, we did a systematic review of the published scientific literature. We searched PubMed, with no time restrictions; abstracts of major oncology congresses; and trial websites including ClinicalTrials.gov, for English-language preclinical reports and clinical trials assessing chemotherapy in patients with lung cancer, EGFR therapies in these patients, and the combination of these methods. Search terms for clinical trials of molecular targeted therapies included “lung cancer” and “EGFR”. Clinical data in support of this trial included a phase 1 pharmacological study of necitumumab in patients with advanced solid malignancies that showed necitumumab was well tolerated and had anti-tumour activity at therapeutically relevant trough concentrations. On the basis of our review of the literature and discussions with clinicians, researchers, and regulatory bodies, we postulated that combining chemotherapy with an EGFR-targeted therapy might improve treatment efficacy in patients with advanced squamous non-small-cell lung cancer.

Added value of this study

Our study shows a significant reduction in risk of death and an overall acceptable safety profile in patients who received necitumumab plus gemcitabine and cisplatin. The improvement in overall survival in this patient population compared with those who received gemcitabine and cisplatin chemotherapy alone was supported by a corresponding significant improvement in progression-free survival and a high consistency of the effects of the treatments in subgroup analyses. We recorded no evidence for a predictive association between an EGFR H-score of 200 or more and survival for necitumumab plus gemcitabine and cisplatin in this setting.

Implications of all the available evidence

The SQUIRE trial design was appropriate for the first-line treatment of a patient population with squamous non-small-cell lung cancer and can be generalised to clinical practice. The results confirm the benefit of the addition of an EGFR antibody to standard chemotherapy in this setting and represent clinically meaningful progress in the treatment of squamous non-small-cell lung cancer.

Most non-small-cell lung cancer tumours express EGFR protein, the high-level expression of which is more common in squamous than in non-squamous disease.19, 20 In the phase 3 FLEX trial,20 the addition of the chimeric EGFR antibody cetuximab to cisplatin and vinorelbine improved overall survival in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer, unselected (adenocarcinoma, squamous cell carcinoma, and other) by histological subtype (hazard ratio [HR] 0·871 [95% CI 0·762–0·996]; p=0·044). However, the survival benefit was greatest in the subgroup of patients with squamous non-small-cell lung cancer (HR 0·80 [95% CI 0·64–1·00]), but was accompanied by a higher frequency of febrile neutropenia overall.

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR monoclonal antibody that binds to EGFR with high affinity, competing with natural ligands and thereby preventing receptor activation and downstream signalling. In murine non-small-cell lung cancer xenograft models, the addition of necitumumab to gemcitabine and cisplatin—an established chemotherapy regimen for the first-line treatment of advanced squamous non-small-cell lung cancer21, 22—resulted in a substantial increase in anti-tumour activity.23 Our randomised, phase 3 study (SQUamous NSCLC treatment with the Inhibitor of EGF REceptor [SQUIRE]) assessed the efficacy and safety of necitumumab plus gemcitabine and cisplatin as first-line treatment for patients with advanced squamous non-small-cell lung cancer. In parallel, the phase 3 INSPIRE study24 assessed the efficacy and safety of necitumumab plus pemetrexed and cisplatin as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer.

Section snippets

Study design and participants

We did this open-label, multicentre, randomised, phase 3 study at 184 investigative sites in 26 countries (listed in the appendix). The full inclusion and exclusion criteria are provided in the appendix. Briefly, patients aged 18 years or older with histologically or cytologically confirmed stage IV (according to the AJCC Cancer Staging Manual, seventh edition25) squamous non-small-cell lung cancer were eligible for enrolment. Other key inclusion criteria were an Eastern Cooperative Oncology

Results

Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 eligible patients and randomly assigned them to necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Seven patients in each group did not receive study treatment, and therefore the safety population comprised 1079 patients (figure 1). The baseline characteristics of the treatment groups were well balanced (table 1); notably, 605 (55%) of 1093 patients had metastases to more than two organ systems and 96

Discussion

Our findings show that the addition of necitumumab to gemcitabine and cisplatin was associated with a statistically significant improvement in overall survival in patients with advanced squamous non-small-cell lung cancer. This treatment effect was supported by a corresponding statistically significant improvement in progression-free survival. In this broad patient population, which is typical of one seen in clinical practice, outcome improvements were recorded across major subgroups at a

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