Abstract
BackgroundImmune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted.MethodsThis study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival.ResultsTwo hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonitis. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P = 0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P < 0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs (P < 0.01, p < 0.01). Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy.ConclusionAlthough the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.
Highlights
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types
Nivolumab was administrated as the first line in 8 patients of malignant melanoma and 1 patient of renal cancer combined with nivolumab + ipilimumab
In the present large-scale study involving 280 patients, we evaluated the association between Immune-related adverse event (irAE) and therapeutic effects, searched for predictive factors for the onset of irAEs and examined whether irAE profiles differ among cancer types
Summary
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. The anti-programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab are immune checkpoint inhibitors (ICIs) that activate the anti-tumour cytotoxic activity of T cells by inhibiting the binding of the PD-1 receptor and programmed cell death protein ligand 1 (PD-L1) They are currently used for the treatment of a wide range of cancers [1]. The overall response rate is low [2, 3], PD-1 and PD-L1 signaling disruption by ICIs regenerates T-cell-mediated anti tumor immunity, producing durable anticancer effects in a subset of patients Their associated adverse events are unique and are termed as immune-related adverse events (irAEs), which are different from the events observed in patients treated with conventional anti-tumour agents. In the present study that involved a larger number of patients treated with anti-PD-1 antibodies for a wide range of cancers, we retrospectively investigated irAEs and therapeutic effects and determined whether the onset of irAEs could be predicted
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