Second-line chemotherapy regimens following front-line CBDCA plus nab-PTX for patients with NSCLC who have preexisting ILD has not been evaluated in clinical trials; therefore, the effectiveness of such treatments in this patient population has remained unknown to date. To our knowledge, ours is the first study to evaluate the safety and efficacy of second-line chemotherapy in this population.
A randomized phase III trial of pemetrexed versus docetaxel in patients with NSCLC previously treated with chemotherapy revealed overall response rates of 9.1% and 8.8%, respectively, with a median PFS of 2.9 months in each arm [19]. Another phase III trial of S-1 versus docetaxel in East Asian patients with NSCLC previously treated with platinum-based chemotherapy demonstrated a response rate and PFS of 8.3% and 2.89 months in the S-1 arm, respectively, and of 9.9% and 2.86 months in the docetaxel arm, respectively [20]. Accordingly, our study showed that second-line chemotherapy with docetaxel, pemetrexed, and S-1 in patients with NSCLC and preexisting ILD who had undergone front-line CBDCA plus nab-PTX was as effective as it was in patients previously treated for advanced NSCLC who did not have ILD.
AE-ILD occurred in 29.2% of our patients, indicating a high frequency of this adverse event caused by second-line chemotherapy; this was consistent with findings in previous studies [4, 5, 21] (Table 5). Data from previous studies and ours suggest that AE-ILD should be monitored in patients with NSCLC undergoing second-line chemotherapy if they have preexisting ILD. Previous studies indicated that the incidence of AE-ILD was significantly higher in patients with the usual interstitial pneumonia (UIP) pattern than in those without during first-line chemotherapy [22, 23]. While our study showed that the frequency of AE-ILD was higher in patients with a UIP or probable UIP pattern than it was in those with other patterns, there was no significant difference (P = 0.36). Meanwhile, we showed that the incidence of AE-ILD was significantly higher in patients with squamous cell histology than in those with other histological types, and was significantly lower in patients who received S-1 than in those treated with other regimens. To our knowledge, this is the first study to identify risk factors for second-line chemotherapy-related AE-ILD.
Table 5
Summary of existing reports on the incidence of acute exacerbation of interstitial lung disease (including a present study).
| n | Acute exacerbation of interstitial lung disease |
Kenmotsu et al. [5] | 57 | 17 (29.9%) |
Kenmotsu et al. [7] | 49 | 19 (38.8%) |
Fujita et al. [22] | 4 | 2 (50%) |
Present study | 24 | 7 (29.2%) |
Although S-1 and 5-fluorouracil (5-FU) have been widely used for the treatment of various cancers in Japan and other Asian countries (including gastrointestinal, breast, and pancreatic cancers) [24–27], there are only a few reported cases of S-1- and 5-FU-induced ILD [28–31]. This suggests that S-1, a prodrug of 5-FU, rarely causes ILD. With respect to lung cancer, a Japanese prospective study found that S-1 plus CBDCA treatment is safe and effective for patients with NSCLC who have ILD [32]. Thus, S-1 monotherapy may be a reasonable choice as a second-line chemotherapy regimen for this patient population based on the low incidence of AE-ILD.
Although immune checkpoint-blocking agents such as the programmed cell death 1 (PD-1) inhibitors nivolumab and pembrolizumab were shown to be beneficial for patients with NSCLC in 2 phase III trials, the incidence of drug-induced ILD is higher in patients treated with these agents than in those treated with cytotoxic drugs (5% in the nivolumab group vs. 0% in the docetaxel group and 5.8% in the pembrolizumab group vs. 0.7% in the platinum-based chemotherapy group) [22, 23]. A previous study found that the incidences of severe nivolumab-related pneumonitis were 19% and 5% in patients with and without ILD, respectively [24]. The incidence of pneumonitis when using atezolizumab, an established antibody targeting the PD-1 ligand in patients with recurrent NSCLC [33], was reported to be lower than that when using other PD-1 antibodies or cytotoxic agents [34]. Therefore, atezolizumab may be a safer second-line therapy option from among the various immune checkpoint inhibitors that are available. However, a Japanese phase II study evaluating atezolizumab for previously treated patients with NSCLC and ILD showed that the incidences of pneumonitis were 29.4% for all grades, 23.5% for grades ≥ 3, and 5.9% for grade 5 [35]; this indicated that patients with NSCLC and ILD have an increased risk of immune checkpoint inhibitor-induced pneumonitis. Hence, the safety of these agents in such patients is unclear, and additional safety data are warranted from a clinical trial comprising a larger and more carefully selected cohort of patients.
In our study, PPS and 2nd line PFS were significantly associated with 1st line OS. Previously, Imai et al. reported that the PPS after failure of first-line chemotherapy has a greater effect on OS as calculated from the start of first-line chemotherapy in patients with lung cancer [36, 37]. Given that our findings suggest that second or further-line treatment improves the OS of patients with NSCLC whether or not they have coexisting ILD, such treatment ought to be considered for those with ILD despite the apparent risk of AE-ILD.
Our study had several limitations. The results obtained cannot be considered definitive owing to the study's retrospective, single-center design and relatively small sample size. Moreover, the diagnosis of ILD was based on CT findings and not histological analysis, as was the diagnosis of ILD exacerbation. However, the American Thoracic Society/European Respiratory Society Consensus Statement offers criteria for the clinical diagnosis of idiopathic pulmonary fibrosis via CT [38], and high-resolution CT scanning reportedly has sensitivities of 43–78% and specificities of 90–97% for the diagnosis of ILD [39–43]. Therefore, we consider it appropriate to diagnose the subtype of ILD and any exacerbation of this condition using clinical and radiological findings in clinical practice.
In conclusion, second-line chemotherapy significantly improves the OS of patients with NSCLC who have coexisting ILD. Given these findings, second-line chemotherapy ought to be considered for this patient population.