Elsevier

The Lancet Oncology

Volume 16, Issue 3, March 2015, Pages 257-265
The Lancet Oncology

Articles
Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial

https://doi.org/10.1016/S1470-2045(15)70054-9Get rights and content

Summary

Background

Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer.

Methods

We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759.

Findings

Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease.

Interpretation

Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment.

Funding

Bristol-Myers Squibb.

Introduction

During immunosurveillance, the immune system is capable of recognising and destroying tumour cells; however, tumours can escape elimination by the immune system through activation of inhibitory feedback loops or (so-called immunological brakes) that are essential to avoid autoimmune events, and so can create barriers to T-cell activation and tumour rejection.1, 2 The PD-1 pathway is one such inhibitory pathway, and its activation is exploited by several cancer types, including lung cancer. Inhibition of the PD-1 pathway is a novel therapeutic approach for treating cancer.3 Nivolumab, a fully human, IgG4 immune checkpoint inhibitor antibody, binds PD-1 on activated immune cells to disrupt PD-1 interaction with PD-L1 and PD-L2 ligands, thereby attenuating inhibitory signals and augmenting the host antitumour response.3 Nivolumab has anti-cancer activity against several tumour types, including non-small-cell lung cancer.4, 5, 6, 7 In a phase 1 study5, 6, 7 of about 300 patients with advanced solid tumors, nivolumab treatment resulted in 22 (17%) of 129 patients with non-small-cell lung cancer achieving an objective response. Treatment with nivolumab also resulted in overall survival of 42% (95% CI 33–50) at 1 year, 24% (17–33) at 2 years, and 18% (11–25) at 3 years; similar results have been reported for non-squamous and squamous histological subtypes.5, 6, 7

Lung cancer is a major health burden, with more than 1·6 million new cases diagnosed per year and 1·3 million deaths per year.8 Most cases (85%) are non-small-cell lung cancer, consisting of non-squamous (70%) and squamous (30%) histological subtypes, and half of patients present with incurable metastatic disease.9, 10, 11 Prognosis for refractory squamous non-small-cell lung cancer is very poor, with median overall survival of between 4·0–6·5 months, 1-year survival of 6–18%, and 2-year survival of 3%.12, 13, 14

Recent advances in treatment for non-small-cell lung cancer have been restricted to patients with non-squamous disease, with little progress for the squamous subtype. This might be partly caused by the mutational complexity of squamous non-small-cell lung cancer, which limits the activity of the newly developed targeted therapies, and leaves systemic chemotherapy as the mainstay of treatment. Because of the absence of approved or efficacious treatments for patients with refractory squamous non-small-cell lung cancer, best supportive care or clinical trials remain the primary approaches for this population. Accordingly, we did CheckMate 063 to assess the therapeutic activity of nivolumab for patients with advanced, refractory squamous non-small-cell lung cancer.

Section snippets

Study design and participants

This study was an international, phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in four countries: seven in France, three in Germany, three in Italy, and 14 in USA (one site in the USA enrolled patients but never treated them).

We included patients with histologically or cytologically documented stage IIIB or IV squamous non-small-cell lung cancer, and disease measurable by CT or MRI. Patients had to be aged 18 years or older, have an Eastern Cooperative

Results

From Nov 16, 2012, to July 22, 2013, we enrolled 140 patients, of whom 117 (84%) were treated with nivolumab (appendix). 23 enrolled patients were not treated for the following reasons: no longer met study eligibility criteria (n=20), died before treatment (n=2), or lost to follow-up (n=1). Table 1 shows the patients' characteristics. The patient population was highly refractory, with almost two-thirds having previously received three or more systemic treatments. Progressive disease was the

Discussion

Our findings show that nivolumab monotherapy provides clinically meaningful activity and an acceptable safety profile for patients with advanced refractory squamous non-small-cell lung cancer. The prognosis for patients who have progressed after treatment with two or more chemotherapy regimens is very poor. No standard treatments exist for such patients, other than best supportive care or experimental treatment in clinical trials, and new drugs are urgently needed.

To the best of our knowledge,

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