Table 5.

Systemic treatment considerations for patients with ILD and advanced (stage IV) NSCLC, based on refs. [171,172].

Treatment	Indication	Special Considerations in Patients with ILDs
TARGETED THERAPIES
EGFR-TKI (e.g., afatinib, erlotinib, dacomitinib, gefitinib, osimertinib) ALK inhibitors (e.g., alectinib, brigatinib, ceritinib, crizotinib, lorlatinib) ROS1 Inhibitors (e.g., ceritinib, crizotinib, entrectinib) BRAF Kinase Inhibitors (e.g., dabrafenib, vemurafenib)	EGFR Exon 19 deletion or Exon 21 L858R ALK rearrangement ROS1 rearrangement BRAF V600E mutation	High incidence of pneumonitis, particularly in smokers, patients with pre-existing ILD of Asian origin Gefitinib particularly high risk of pneumonitis Combination with anti-VEGF may reduce risk of pneumonitis Very close monitoring required Suggestion for non-administration by the Japanese Thoracic Society with very low strength of the recommendation
IMMUNE CHECKPOINT INHIBITORS
PD-1/PDL-1 Inhibitors (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab) CTLA-4 Inhibitors (e.g., ipilimumab, tremelimumab)	First line for NSCLC as monotherapy (pembrolizumab, atezolizumab, cemiplimab) or in combination with platin-based regiments according to PDL-1 expression Continuation maintenance Second line depending on first line treatment	High incidence of pneumonitis, particularly in smokers with pre-existing ILD Combination with anti-VEGF agents may reduce risk of pneumonitis CTLA-4 inhibitors may be safer compared to PD-1/PDL-1 inhibitors regarding the risk of pneumonitis Very close monitoring required Suggestion for non-administration by the Japanese Thoracic Society; however, this therapy may be a reasonable option in some patients (very low strength of the recommendation)
CHEMOTHERAPY
Carboplatin or cisplatin combination therapy Combination options include: Docetaxel Etoposide Gemcitabine Paclitaxel Pemetrexed	First line for NSCLC in patients with contraindications to ICIs	Cis- and carboplatin considered the safest option for patients with ILDs Docetaxel associated with increased risk of AE-ILD, not recommended Combination with platinum considered safe Gemcitabine associated with increased risk of AE-ILD, not recommended Combination of paclitaxel with platinum one of the safest combinations Pemetrexed associated with increased risk of AE-ILD Suggestion for administration of cytotoxic drugs by the Japanese Thoracic Society; however, this therapy may not be a reasonable option in some patients (low strength of the recommendation)
ANTI-VEGF AGENTS
Bevacizumab Nintedanib Ramucirumab	First line non-squamous Second line for adenocarcinoma in combination with docetaxel Second line NSCLC	Bevacizumab reported to prevent chemotherapy-induced AE-ILD in patients with ILD and NSCLC ORR significantly improved for nintedanib plus chemotherapy vs. chemotherapy in patients with nonsquamous histology. Overall survival improved only in patients with nonsquamous histology and patients with GAP stage I (J-Sonic trial) Nintedanib is approved for IPF, SScl-associated ILD and progressive pulmonary fibrosis Anti-VEGF agents may reduce risk of pneumonitis due to TKIs and ICIs

EGFR: epidermal growth factor receptor; TKI: tyrosine kinase inhibitor; Exon 21 L858R: exon 21 L858 substitution; ALK: anaplastic lymphoma kinase; ROS1: ROS-proto-oncogene 1, receptor tyrosine kinase; BRAF: B-Raf proto-oncogene, serine/threonine kinase; VEGF: vascular endothelial growth factor; PD-1: programmed cell death protein-1; PD-L1: programmed death-ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein-4.