Elsevier

The Lancet Oncology

Volume 20, Issue 10, October 2019, Pages 1395-1408
The Lancet Oncology

Articles
Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis

https://doi.org/10.1016/S1470-2045(19)30407-3Get rights and content

Summary

Background

Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival.

Methods

We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab.

Findings

Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals.

Interpretation

Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage.

Funding

Bristol-Myers Squibb.

Introduction

Lung cancer, which is the most common type of cancer worldwide,1 has historically been associated with poor outcomes. In the USA, the proportion of patients with metastatic lung cancer alive at 5 years after diagnosis between 2008–15 was estimated to be about 5%.2 The advent of immunotherapy as a second-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) in 2014 was an important milestone in the improvement of outcomes for these patients. Based on data from multiple randomised controlled trials,3, 4, 5, 6 single-agent immunotherapy with antibodies directed against PD-1 or PD-L1 has become the standard of care for patients with metastatic NSCLC who progressed during or after treatment with platinum chemotherapy and had not previously received immunotherapy.7 CheckMate 003,8 a dose-escalation study of the anti-PD-1 antibody nivolumab in patients with solid tumours, has the longest reported follow-up for survival in patients with NSCLC who were treated with immunotherapy after disease progression on other therapies. The estimated proportion of patients alive at 5 years after the start of nivolumab treatment was 16% in this patient population.8 Results of the phase 3 CheckMate 017 and 057 studies3, 4 showed that nivolumab significantly prolonged overall survival versus docetaxel in patients with previously treated advanced squamous and non-squamous NSCLC, respectively, with an unprecedented 17% of patients treated with nivolumab alive at 3 years versus 8% for docetaxel.9, 10

In CheckMate 017 and 057,3, 4 the proportion of patients with an objective response was improved with nivolumab versus docetaxel, and median duration of response increased by almost three times.9 Furthermore, subgroup analyses suggested that the overall survival benefit associated with nivolumab versus docetaxel was greatest among patients who achieved an objective response.9

Research in context

Evidence before this study

We searched the scientific literature for long-term survival outcomes with approved PD-1 and PD-L1 inhibitors in the treatment of previously treated advanced NSCLC. We used the search terms “atezolizumab” AND “nivolumab” AND “pembrolizumab” AND “non-small cell lung cancer” AND “overall survival” AND “previously treated” to search for publications in PubMed from Jan 24, 2014 to Jan 22, 2019, and for congress abstracts presented in 2018 at annual congresses of the American Association of Cancer Research, the American Society of Clinical Oncology, the European Society for Medical Oncology, and the World Conference on Lung Cancer. Our search results showed that monotherapy with PD-1 or PD-L1 inhibitor antibodies in randomised controlled trials improves survival compared with docetaxel in patients with advanced NSCLC previously treated with chemotherapy. Key benefits of these immunotherapies are the durability of responses and the improved long-term survival compared with docetaxel. In addition, greater maximum reduction in tumour target lesions (depth of response) has been associated with longer progression-free survival and overall survival. However, the effect of response status on long-term survival has not been evaluated in detail or in a large patient population to provide more robust analyses.

Added value of this study

Our analyses of 4-year survival outcomes in pooled populations from four studies, including two randomised studies comparing nivolumab and docetaxel, represent, to our knowledge, the longest follow-up to date for immunotherapy in a large population of patients with previously treated advanced NSCLC. The results show a continued long-term survival advantage with nivolumab versus docetaxel up to and beyond 4 years. Six-month landmark analyses of overall survival by response category show that patients with a response (at 6 months) had the greatest post-landmark survival benefit. Additionally, stable disease at the landmark provided a survival benefit versus progressive disease. A survival benefit of response was maintained even after loss of response. In nivolumab-treated patients with disease progression, those who had a previous complete or partial response had the longest overall survival post-progression. A smaller post-progression survival benefit was noted in patients with disease progression after initial achievement of stable disease.

Implications of all the available evidence

Although it has been known for some time that nivolumab is associated with much longer duration of response than docetaxel in patients with previously treated advanced NSCLC, to our knowledge, the current analyses show for the first time that an objective response to nivolumab is associated with an exceptionally durable survival benefit, with the median not reached at 4 years from the time of response. Part of this sustained benefit is attributable to extended survival even after disease progression. Corresponding survival benefits with docetaxel were substantially smaller. Overall, the results show that responses to nivolumab compared with docetaxel are more durable and have a more sustained effect on survival, even after loss of response.

The long-term and durable overall survival provided by immunotherapy was first shown with ipilimumab in a large population of patients with melanoma using a pooled analysis from 12 studies with up to 10 years of follow-up.11 Herein, to determine if nivolumab provides similar durable benefit for patients with lung cancer, we assessed duration of response, overall survival, and progression-free survival in a large population of patients with previously treated advanced NSCLC with a minimum follow-up of 4 years. We pooled patients treated with nivolumab from four studies: CheckMate 017,3 057,4 063,12 and 003.8, 13

Section snippets

Study design and data collection

We analysed long-term outcomes in patients with previously treated advanced NSCLC from pooled populations of four nivolumab studies with a minimum follow-up of 4 years: CheckMate 017,3 057,4 063,12 and 003.8, 13 Study designs, eligibility criteria, and primary outcomes for these studies have been reported previously,3, 4, 12, 13 and additional details are provided in the appendix (p 4). To analyse survival and safety outcomes with nivolumab only, we pooled data from all nivolumab-treated

Results

Across all four studies, 664 patients were treated with nivolumab, including 129 in CheckMate 003, 117 in CheckMate 063, 131 in CheckMate 017, and 287 in CheckMate 057. Analysis populations are summarised in the appendix (pp 5–6). Baseline characteristics for the pooled study populations are shown in table 1. Most patients treated with nivolumab (572 [86%] of 664) received 3 mg/kg every 2 weeks; 33 (5%) patients received 1 mg/kg every 2 weeks and 59 (9%) patients received 10 mg/kg every 2 weeks

Discussion

Our survival analyses are based on a minimum follow-up of 4 years, which is—to our knowledge—the longest follow-up to date for an anti-PD-1 or anti-PD-L1 therapy in a large population of patients with previously treated advanced NSCLC. Across all four studies, nivolumab showed long-term survival benefit, with estimated 4-year overall survival of 14% overall, 11% in patients with less than 1% PD-L1 expression, and 19% in patients with at least 1% PD-L1 expression. The proportions of patients

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