ICIs have been reported to be effective in treating various types of cancers. Although this provides great hope for patients, the response rates are low. Thus, studies are being conducted to identify biomarkers that can be used to predict therapeutic effects [15, 16]. Although PD-L1 is used clinically in patients with lung cancer, its effects have not been reproduced in other types of cancers. Recent studies have suggested that tumour mutation burden and microsatellite instability-high (MSI-H) can be used as biomarkers to predict the therapeutic effects. However, they are far from being established as biomarkers for some types of cancers. In recent years, several reports have indicated that the onset of irAEs is associated with the therapeutic effects in lung cancer, malignant melanoma and gastric cancer. However, these reports are based on small cohort studies with a dozen of patients because ICIs are infrequently used. In the present large-scale study involving 280 patients, we evaluated the association between irAEs and therapeutic effects, searched for predictive factors for the onset of irAEs and examined whether irAE profiles differ among cancer types. In this study, the overall incidence of treatment-associated adverse events was 41.1%, which was comparable with the previously reported incidence [5, 8, 9, 12]. The most common adverse events were skin disorders. In particular, a rash accompanied by dry skin and pruritus was frequently observed. However, grade 3 and higher skin disorders were observed in only two patients. In terms of severity, many patients with skin disorders could be treated with moisturising agents, oral anti-histamines and topical steroids. The skin disorders were not associated with eosinophil or lymphocyte counts. The second most common irAE was thyroid disorders. Thyroid disorders appeared in two patterns. In one pattern, the thyroid function was transiently enhanced by acute thyroiditis, followed by hypothyroidism. In the other pattern, hypothyroidism was detected in regular blood tests. Peiro et al. also reported similar findings [17]. Although Toi et al. [18, 19] and Maekura et al. [20] reported that thyroid peroxidase (TPO) antibody and thyroglobulin antibody (TgAb) levels before ICI therapy were predictive factors for the development of hypothyroidism, whereas our study showed no association with TPO antibody levels but suggested an association with TgAb levels (P = 0.05). Meanwhile, a high TSH level before treatment appeared to be a possible predictive factor for the development of hypothyroidism. Interstitial pneumonia occurred in approximately 7.3% of all patients and 3.4% of patients with gastric cancer, and its incidence tended to be even higher in patients with head and neck cancer and lung cancer. This higher incidence rate appeared to be associated with respiratory symptoms and ease of accidental ingestion. Hori et al. [21] also reported that skin disorders and pneumonia accounted for approximately 17.8% of adverse events in patients treated for head and neck cancer, which is consistent with our findings. The observed serious adverse events of grade 3 and higher were pneumonia, encephalitis, liver disorder and skin disorders. All patients with these serious adverse events were hospitalised and treated with steroids. Among them, two patients with pneumonia did not respond to pulse therapy and died. Regarding therapeutic effects, the ORR was significantly higher in the irAE group, and this was reproducible in a larger number of patients with either gastric or lung cancer. In addition, similar results were obtained for OS and PFS. Masuda et al. [12]., who examined patients with gastric cancer, reported that PFS was extended by ICI therapy, which is consistent with our study. Also Masuda et al. [12] reported in this paper, according to the waterfall plot showing tumour regression rates, all patients with a high rate had developed irAEs. Because significant differences were observed all in ORR, PFS and OS, pre-treatment tests themselves that allow the prediction of irAE onset may be possible biomarkers. In the present study, the comparison between patients with and without irAEs showed a significant difference only in LDH levels. By disorder, hypothyroidism was associated with high TSH and TgAb levels. This suggested that, in patients who already have hypothyroidism before ICI therapy, regardless of being symptomatic or asymptomatic, the probability of exacerbation after therapy could be estimated. Interstitial pneumonia was not associated with Krebs von den Lungen-6 (KL-6) levels at all. However, in some patients with pneumonia, KL-6 levels that were elevated after the onset of pneumonia were decreased following the treatment of pneumonitis, which suggested that KL-6 levels might be meaningful for the purpose of evaluating therapeutic effects. Identifying biomarkers for predicting the onset of irAEs is an issue that should be addressed in future studies [22]. Even among patients with irAEs, many of them resumed ICI therapy after treatment of these irAEs. 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.
The present study is a retrospective study, including patients with different treatment backgrounds; thus, it contains several confounding factors, which is a limitation. A larger scale prospective study, in addition to a search for biomarkers for predicting the onset of irAEs, should be conducted in the future.