Original Study
Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

https://doi.org/10.1016/j.cllc.2018.10.002Get rights and content

Abstract

Background

Immune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non–small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC.

Methods

In this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).

Results

Overall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001).

Conclusions

This report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.

Introduction

Lung cancer, including 85% of non–small-cell lung cancer (NSCLC),1 remains the most common cause of cancer-related death.2

New treatment options, such as immune checkpoint inhibitors (ICIs), are approved for the treatment of naive and relapsing advanced NSCLC. ICIs target and inhibit programmed cell death protein 1 on T cells (anti-PD-1) or its ligand (PD-L1) on tumor cells (anti-PD-L1) or on tumor microenvironment cells to enhance anti-tumor immunity.3

Until recently, ICIs have been primarily used for the second-line treatment of advanced NSCLC. To date, 3 drugs have been approved by the United States Food and Drug Administration based on 4 phase III clinical trials demonstrating the superiority of ICIs over standard docetaxel.4, 5, 6 ICIs are now also registered in the first-line setting alone or in combination with chemotherapy as a result of the Keynote024 (phase III trial of pembrolizumab (MK-3475) vs platinum-based chemotherapy as first-line therapy for patients with metastatic non-small cell lung cancer (NSCLC) that expresses programmed cell death ligand 1) and 021G (Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study) trials.5, 7

Releasing the brakes of the host-immune system, ICIs may alter the physiologic homeostasis of immune response, thus leading to the development of immune-related adverse events (IRAEs). A meta-analysis of the phase III Checkmate 017 (Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer), Checkmate 057 (Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer), and Keynote 010 (Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial) studies was performed to assess the type and frequency of these IRAEs.8 Adverse events of any grades based on the National Cancer Institute Common Terminology Criteria for Adverse Events occurred in 69% of patients, and adverse events grade 3 or higher occurred in 7% to 13% of patients.9, 10, 11 The most frequent IRAEs exhibit endocrinopathy (hypothyroidism 4%-8%, hyperthyroidism 0%-5%), skin rashes (5%-11%), and hepatitis (2%-11%). The most severe were pneumonitis (3%-5%), colitis (1%-2%), hypophysitis (2%), and adrenal failure (0%-1%).

The development of new targeted therapies sometimes leads to new adverse events.12, 13 In a totally different context, these adverse events have been assessed as markers of treatment outcomes. This is the case for skin rash and tyrosine kinase inhibitors efficacy,14 and we tried to find an analogy with ICIs and IRAEs.

A first trial published in November 2016 suggested a correlation between IRAEs and efficacy of ICIs in melanomas.15

To date, there is mainly 1 retrospective study with 134 patients16 and 2 prospective studies with 3817 and 43 patients,18 all treated with nivolumab only, suggesting an association between the occurrence of IRAEs and the efficacy of ICIs in NSCLC.

The primary endpoint of this study was to assess the association between IRAEs and overall survival (OS) of patients with advanced NSCLC. Our secondary endpoints were to assess the association between IRAEs (type and severity) and progression-free survival (PFS), as well as the objective response rate (ORR) and disease control rate (DCR).

Section snippets

Patients

In this observational retrospective study, data from all patients older than 18 years of age who were diagnosed with metastatic NSCLC at 2 centers and who received at least 1 cycle of ICI (anti-PD-L1 or anti-PD-1) alone or in combination from April 2, 2013 to February 14, 2017 were analyzed. Patients known to have any previously controlled autoimmune disease were excluded.

Before the data collection, all patients provided signed informed consent allowing the use of data collected during standard

Patient and Disease Characteristics

Overall, 270 patients treated with ICIs were retrieved from our database and analyzed. Patient and disease characteristics are summarized in Table 1. The median age was 61 years (IQR, 32-84 years), and there were more men (65.6%) than women (34.4%). Most patients (88.5%; n = 239) were current or former smokers. The most frequent mutations (34.8%; n = 94) were the KRAS mutations. Regarding the treatments with ICIs, 89.3% (n = 241) of the patients received an anti-PD1 antibody; with 91.4% (n =

Discussion

To the best of our knowledge, this study is the largest case series to assess the association between IRAEs and the efficacy of ICIs. Statistically significant differences were observed in the in OS, PFS, and ORR, in favor of the patients with IRAEs compared with the patients without any IRAEs. Subgroup analyses also showed better OS and PFS for patients with thyroid dysfunction.

The primary limitations of this trial are retrospective design and the low number of centers involved (2 centers).

Disclosure

The authors have stated that they have no conflicts of interest.

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