As for the first-line treatment of advanced NSCLC with comorbid IP, there have been six prospective trials reported so far, all of which were single-arm studies (Table 2
). Two single-arm phase II studies of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) have been reported 
. The incidence of acute exacerbation of pre-existing IP was low (4.3–5.6%), and the efficacy was also favorable, with a response rate of 51–56%, median progression-free survival (PFS) of 5.3–6.2 months, and median OS of 15.4 months in both studies. Both trials included a relatively large number of patients (94 and 36 patients, respectively), and these results suggest that this regimen is the current standard of care for untreated NSCLC patients with comorbid IP. The results of two prospective trials have also been reported for carboplatin plus weekly paclitaxel combination therapy 
. The incidence of acute exacerbation induced by this combination therapy ranged from 5.6% to 12.1%. The response rate was 61–70%, with a median progression-free survival of 5.3–6.3 months and a median survival of 10.6–19.8 months, making it a potential treatment option. Furthermore, two prospective trials of carboplatin plus S-1 were conducted in 21 and 33 patients respectively, with an acute exacerbation incidence of 6.1–9.5%, response rate of 33.0–33.3%, median PFS of 4.0–4.8 months, and median OS of 10.4–12.8 months. With these results, carboplatin plus S-1 therapy is another option for first-line treatment 
. The concomitant use of bevacizumab is unlikely to change the risk of triggering the development of acute exacerbations and may be considered in cases where it can be administered 
. Nintedanib is a multi-kinase inhibitor of platelet-derived growth factor receptor (PDGFR) alpha-beta, fibroblast growth factor receptor (FGFR) 1–3, and vascular endothelial growth factor receptor (VEGFR). Nintedanib is a widely approved and recognized antifibrotic agent for IPF and progressive fibrosing interstitial lung disease in many countries around the world. Nintedanib is expected to be effective not only in slowing down the decline of FVC but also in preventing acute exacerbations. In the INPULSIS study, a randomized phase III trial of IPF, there were significantly fewer adjudicated confirmed/suspected acute exacerbations in the nintedanib group than in the placebo group (1.9% and 4.7%, p
= 0.010) 
. In addition, nintedanib is also approved in Europe as a second or subsequent therapy for advanced NSCLC in combination with docetaxel, and is expected to enhance the antitumor effect as an antiangiogenic agent. In Japan, the world’s first randomized phase III trial of carboplatin plus nab-paclitaxel with or without nintedanib in advanced NSCLC with comorbid IPF (J-SONIC trial) was conducted, and is currently under follow-up 
In recent years, monotherapy with anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, atezolizumab) or in combination with platinum doublet has become the standard of care for advanced NSCLC patients with PS 0–1, without IP. However, several studies indicated that pre-existing IP increases the risk of ICI-induced pneumonitis 
, and the package insert of various ICIs states that they should be administered with caution in patients with comorbid IP. Therefore, at this time, ICIs should not be used as first-line therapy for patients with IP.
For NSCLC with driver gene mutations/translocations, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase, the BRAF and ROS1 genes, first-line therapy with tyrosine kinase inhibitors (TKIs) targeting the respective gene mutations/translocations is usually recommended. However, when gefitinib-induced pneumonitis appeared with high frequency in Japan and became a social problem, pre-existing IP was identified as an independent risk factor for gefitinib-induced pneumonitis 
. Since then, special precautions have been required when administering molecular-targeted drugs to driver oncogene-positive NSCLC with comorbid IP. However, since it has been reported that only 0.4% of lung adenocarcinoma patients with EGFR mutations have pre-existing IP 
, there may be few situations in which we actually wonder whether we should administer TKI or not. There are no data on the incidence of pre-existing IP in patients with driver mutations/translocations other than EGFR, or on which types of IP are associated with a higher risk of acute exacerbation induced by TKI, so further study is needed.