Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study
Introduction
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers; the majority of cases are already unresectable and metastatic at the time of initial diagnosis [2]. Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors have been shown to exhibit potent activity against metastatic NSCLC, and the PD-1 inhibitor nivolumab is a standard anticancer treatment for previously treated patients with advanced NSCLC [[3], [4], [5], [6]].
To achieve accurate and meaningful results, clinical trials have eligibility criteria that have increasingly become more strict and complex [[7], [8], [9]]. Only limited patients who are in relatively good general condition with no organ failure meet the general eligibility criteria for these trials [10,11]. As a result, the outcomes of clinical trials are not entirely representative of real-world patients. In particular, there is insufficient evidence regarding nivolumab efficacy in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials, such as those with poor performance status (PS) and/or EGFR mutations [[3], [4], [5], [6]].
Additionally, PD-1 axis inhibitors can cause inflammatory side effects that manifest as so-called immune-related adverse events (irAEs) and differ from those attributed to conventional systemic therapy. Clinical trials of PD-1/PD-L1 inhibitors show favorable safety profiles compared to those of conventional cytotoxic agents [[3], [4], [5], [6]]. However, irAEs can be severe in some cases; in fact, pneumonitis appears to be a prominent irAE in real-world settings, and is notable owing to its severe sequelae [[12], [13], [14], [15]]. Previous studies have shown that the rate of adverse events (AEs) in real-world patients is higher than that in clinical trial participants [16,17]. Furthermore, recent studies found a positive association between irAE incidences and nivolumab efficacy [[18], [19], [20]]. Therefore, accumulating a large amount of efficacy and safety data from patients who received PD-1 axis inhibitors in real-world settings would be beneficial for the purposes of validating previous observations.
The aim of this study was to investigate the efficacy and safety of nivolumab in previously treated real-world patients with NSCLC, and to provide guidance for improving therapy with PD-1 axis inhibitors.
Section snippets
Patients
This study was a multicenter, observational, retrospective study of patients with advanced NSCLC (stage IIIB or IV according to the 7th edition TNM classification) who underwent nivolumab therapy at any of 15 centers in Japan. The clinical data for each patient were retrospectively extracted from medical charts and entered into a database.
Patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016 were eligible for this study. Patients who reported never
Patient characteristics
A total of 613 patients who were previously treated for advanced NSCLC were included in the study; patient characteristics are summarized in Table 1. The mean age was 66.9 years, and most patients were men (71%), had a smoking history (78%), had a PS of 0 or 1 (77%), and had adenocarcinoma (67%). EGFR mutations and ALK rearrangements were investigated in 505 (82%) and 420 patients (69%), respectively, and were detected in 95 (19%) and 12 (3%) of these patients, respectively.
Efficacy in all patients
The ORR was 20%; 1%
Discussion
Our study provides a large amount of efficacy and safety data concerning nivolumab for patients who were previously treated for NSCLC in a real-world setting. To our knowledge, this was the first study to demonstrate a positive association between pneumonitis and nivolumab efficacy. Our efficacy and safety data were comparable to those from other clinical trials that assessed nivolumab [3,4,23,24]. Hence, we can predict similar efficacy and safety results in real-world settings.
We identified
Disclosure of funding
This study was not funded by any external source.
Conflict of interest
Dr. Fujimoto, Yoshioka, Kim, and Mio have received lecture fees from Ono Pharmaceutical Co., Ltd. (Osaka, Japan) and Bristol-Myers Squibb K.K. (Tokyo, Japan). Dr. Kim received research funding from Ono Pharmaceutical Co., Ltd. (Osaka, Japan) and Bristol-Myers Squibb K.K. (Tokyo, Japan) for separate studies. All remaining authors have declared no conflicts of interest.
Acknowledgements
The authors would like to thank Keiko Sakuragawa for her administrative assistance. We are also grateful to all investigators in this study.
References (33)
- et al.
Non-small cell lung cancer: epidemiology risk factors, treatment, and survivorship
Mayo Clin. Proc.
(2008) - et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
(2016) - et al.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial
Lancet
(2017) - et al.
Thoracic oncology clinical trial eligibility criteria and requirements continue to increase in number and complexity
J. Thorac. Oncol.
(2017) - et al.
A study in contrasts: eligibility criteria in a twenty-year sample of NSABP and POG clinical trials. National Surgical Adjuvant Breast and Bowel Program. Pediatric Oncology Group
J. Clin. Epidemiol.
(1998) - et al.
Barriers to enrollment in non-small cell lung cancer therapeutic clinical trials
J. Thorac. Oncol.
(2011) - et al.
Interpreting febrile neutropenia rates from randomized, controlled trials for consideration of primary prophylaxis in the real world: a systematic review and meta-analysis
Ann. Oncol.
(2016) - et al.
Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study
J. Thorac. Oncol.
(2017) - et al.
Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
Ann. Oncol.
(2017) - et al.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours
J. Thorac. Oncol.
(2007)
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur. J. Cancer
Checkpoint inhibitors in metastatic egfr-mutated non-small cell lung cancer-a meta-analysis
J. Thorac. Oncol.
Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment
Ann. Oncol.
Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer
Lung Cancer
CA Cancer J. Clin.
Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer
N. Engl. J. Med.
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