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The role of immune-related adverse event (irAE) occurrence, as a surrogate predictor of the clinical efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic nonesmall-cell lung-cancer with a programmed death-ligand 1 expression of ‡ 50%. A total of 1010 patients were evaluated, and after a 6-week landmark selection, 877 patients were included. We confirmed the irAE profile of first-line, single-agent pembrolizumab, in a large, real-life cohort of patients with nonesmall-cell lung-cancer with programmed death-ligand 1 expression of ‡ 50%. The occurrence of irAEs might be considered a surrogate of clinical activity and improved outcomes also in this setting. Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic nonesmall-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ! 50%. Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ! 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes. Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P ¼ .0025), leading to discontinuation irAEs (P ¼ .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P ¼ .0001), endocrine irAEs (P ¼ .0227), pulmonary irAEs (P ¼ .0479), and rheumatologic irAEs (P ¼ .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P ¼ .0005), cutaneous irAEs (P ¼ .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P ¼ .0391), and rheumatologic irAEs (P ¼ .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P ¼ .0003), cutaneous irAEs (P ¼ .0002), endocrine irAEs (P ¼ .0001), and rheumatologic irAEs (P ¼ .0214) were significantly related to overall survival. Conclusions: This study confirms the feasibility and the safety of first-line, singleagent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ! 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.

Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3–7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients.

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