In this study, the overall incidence of all-grade pneumonitis was 11.7%, similar to a previous retrospective Japanese cohort study in patients with NSCLC treated by nivolumab [10–11]. Although there was no significant difference in the univariate analysis, the NSCLC group tended to have a higher incidence of pneumonitis (14.6%) compared with the HNC/GC group (8.7%), which was related to the high trend of complicating pre-existing ILD in the NSCLC group (P=0.047).
The present analysis revealed that pre-existing ILD and male sex were significant independent risk factors for nivolumab-induced pneumonitis in patients with solid tumors. Previous evidence has strongly indicated that pre-existing ILD is a risk factor for chemotherapy-induced pneumonitis, and these reports were particularly prevalent in lung cancer [12–17]. These findings are related to the fact that both lung cancer and ILD are closely associated with cigarette smoking. There is substantial epidemiological evidence that patients with ILD have a high risk of lung cancer [18, 19], whereas it has been reported that 10%–20% of patients were complicated with ILD when lung cancer was diagnosed [13, 20]. We previously reported that pre-existing ILD is a risk factor for anti-PD-1-induced pneumonitis . However, it has not been elucidated whether pre-existing ILD is at risk of pneumonitis when using anti-PD-1 agents for other type of tumors. In previous phase III clinical trials, HNC and GC had a lower incidence of nivolumab-induced pneumonitis compared with NSCLC. While a recent meta-analysis indicated that anti-PD-1-related pneumonitis of all grades develops more frequently in NSCLC and renal cell cancer than in melanoma [21, 22].
In our analysis based on pre-existing ILD on chest CT, NSCLC and HNC/GC showed similar trends in the development of pneumonitis. Interestingly, in patients with no fibrosis, the incidence of nivolumab-induced pneumonitis was approximately 5% in both NSCLC and HNC/GC, similar to results reported in previous large clinical trials. Moreover, in patients with pre-existing ILD, the incidence of nivolumab-induced pneumonitis jumped to approximately 30%. However, most cases of pneumonitis associated with nivolumab are relatively mild and classified as grade 1 to 2. It has been reported that nivolumab-induced pneumonitis responds well to steroid therapy and its mortality rate is low compared with gefitinib-induced pneumonitis, which is characterized by rapid progression and a high mortality rate of around 30% to 40% .
It should be emphasized that increased risk of anti-PD-1-induced pneumonitis is not synonymous with the avoidance of anti-PD-1 treatment. Previous studies have demonstrated that the development of irAEs is associated with clinical benefit of ICIs in melanoma and NSCLC [24–29]. In a recent retrospective cohort study in patients with NSCLC treated with nivolumab (n=613), landmark analyses of PFS at 2 months revealed no significant differences in PFS between patients with or without pneumonitis (7.9 vs. 5.9 months; P=0.872). Moreover, in our previous report, patients with anti-PD-1-induced pneumonitis had relatively favorable survival outcomes . ICI-induced pneumonitis may not lead to poor outcomes, unlike pneumonitis with a cytotoxic chemotherapy or molecularly targeted therapy that has been reported to have a poor prognosis . Therefore, indications for ICI treatment should be judged comprehensively, taking into consideration pre-existing ILD as well as pulmonary function, which affects the severity of pneumonitis.
A history of thoracic radiotherapy would also affect the incidence of chemotherapy-related pneumonitis in patients with NSCLC. Tamiya et al. reported that the incidence of nivolumab-induced pneumonitis was significantly higher in a group with thoracic radiation history than in a group without thoracic radiation history . A higher incidence of nivolumab-induced pneumonitis in patients with thoracic radiation history may be because nivolumab can induce radiation recall pneumonitis. Therefore, our analysis excluded patients with a history of thoracic radiation to prevent bias.
Male sex was also detected as a risk factor for nivolumab-induced pneumonitis. In a retrospective analysis of gefitinib, not only pre-existing ILD but also male sex and a history of smoking were significantly associated with developing gefitinib-induced pneumonitis . On the other hand, our analysis showed that only two out of 55 female patients (3.6%) had pre-existing ILD and these two patients were classified as "inconsistent with UIP." Therefore, to investigate the relationship between pre-existing ILD and nivolumab-induced pneumonitis particularly in females, further validation of another cohort is needed.
There are several limitations in the present study. First, this was a single-site retrospective study that used chart reviews of a relatively small patient cohort. Second, the number of patients with HNC/GC was smaller, since nivolumab was approved earlier for NSCLC than HNC/GC. Third, we excluded patients who previously received thoracic radiation or other ICIs to prevent biases; however, since the standard treatment differs for each cancer type it is possible that the effects of prior treatment could not be completely excluded. Fourth, the patient cohort was across multiple cancer types, which prevented cancer-specific survival analysis.