Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non–Small-Cell Lung Cancer Who Received Programmed Death 1 Inhibitors

Abstract

Introduction

Pneumonitis is one of the immune-related adverse events of programmed death 1 (PD-1) inhibitors that sometimes cause lethal outcomes. Although some recent reports have described PD-1 inhibitors as more effective in non–small-cell lung cancer (NSCLC) patients with immune-related adverse events than in those without, few data are available on the prognosis of those treated with PD-1 inhibitors who developed immune-related pneumonitis (IRP). Additionally, the robust risk factors of IRP have not been well elucidated.

Patients and Methods

A retrospective review of patients with recurrent or advanced NSCLC who took a PD-1 inhibitor (nivolumab or pembrolizumab monotherapy) between January 2016 and March 2018 was undertaken. Radiologic findings such as unilateral infiltration were also defined as IRP as long as they were deemed relevant to PD-1 inhibitors.

Results

Twenty-seven (16%) of 170 patients developed IRP. Although 22 (81%) of 27 patients with IRP recovered with drug cessation with or without corticosteroid therapy, 8-week landmark analysis showed the overall survival after administration of the PD-1 inhibitor was significantly shorter in patients with IRP than in those without (8.7 vs. 23.0 months, P = .015). Patients with IRP tended to not receive next-line treatment and choose best supportive care after cessation of PD-1 inhibitor therapy. In the multivariate analysis, pembrolizumab (vs. nivolumab) and low serum albumin were independent risk factors for IRP.

Conclusion

Development of IRP was correlated with poor prognosis in patients with NSCLC. Further study is necessary for establishing the best prediction and management strategies for IRP.

Introduction

Programmed cell death 1 (PD-1) inhibitors such as nivolumab and pembrolizumab exhibit significant clinical efficacy in the treatment of non–small-cell lung cancer (NSCLC). They are the standard agents for pretreated NSCLC patients,1, 2, 3 and additionally, pembrolizumab improved survival when combined with platinum-based chemotherapy in the first-line setting.4, 5 Despite such robust evidence for the effectiveness of PD-1 inhibitors, immune-related adverse events (irAEs) frequently prevent patients from taking the treatment continuously. A standard method of management for each irAE has not yet been well established, and information about their predictors or prognoses is limited.

Immune-related pneumonitis (IRP) is one of the relatively rare irAEs first reported in 3 patients with melanoma in 2015.⁶ Subsequently, it was also described in 2 patients with NSCLC in 2016.⁷ Its prevalence has been reported as 2.7% to 5.8% in patients with NSCLC in randomized controlled trials.2, 3 Although it is sometimes associated with death, development of IRP may reflect the extent of immune activity, and PD-1 inhibitors may therefore be more effective in NSCLC patients with IRP compared to those without IRP. To date, whether the development of IRP is an indicator of better antitumor response or outcome remains unclear. Given the fact that clinicians are frequently confronted with difficulty in reducing the dosage of corticosteroid and resuming administration of PD-1 inhibitors in patients with IRP because IRP tends to recur and is sometimes life-threatening, even if IRP can be correlated with a better overall response rate (ORR) and progression-free survival (PFS), difficulties in continuing optimal treatment may shorten survival.

Additionally, the characteristics of patients who are likely to develop IRP have not been well elucidated. Although some clinical parameters such as a combination of more than 2 immunocheckpoint inhibitors8, 9, 10 or a history of radiotherapy10, 11 have been reported to be risk factors of pneumonitis, these results vary from report to report and are not universal.

The aims of this multicenter retrospective study were to evaluate the prognostic impact and risk factors of IRP through a review of the baseline clinical background of patients with recurrent or advanced NSCLC who took PD-1 inhibitors.