Elsevier

Lung Cancer

Volume 119, May 2018, Pages 14-20
Lung Cancer

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study

https://doi.org/10.1016/j.lungcan.2018.02.017Get rights and content

Highlights

  • Nivolumab efficacy is unknown in patients who are categorized into small subgroups.

  • This was a 15-center retrospective study of NSCLC patients who received nivolumab.

  • A total of 613 NSCLC patients who received nivolumab were included.

  • We showed efficacy data from previously underreported patient populations.

  • We described common frequency of pneumonitis and some of its key characteristics.

Abstract

Introduction

Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials.

Methods

We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016.

Results

Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation – or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002).

Conclusions

Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

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.

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