Background: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune‐related adverse events (irAEs) remain poorly understood, especially in a real‐world setting.Methods: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD‐L1) monotherapy, anticytotoxic T‐lymphocyte antigen‐4 monotherapy, or combination therapy.Results: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28–87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3–5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0–1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD‐L1 expression (≥1%) and who received first‐line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001).Conclusions: The incidence rate of irAEs was 26.9% in a real‐world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Background For lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn-BM), when and how to apply radiotherapy (RT) during first-line tyrosine kinase inhibitor (TKI) treatment remains debatable. Methods From a real-world multicenter database, EGFR-mutant patients with syn-BM diagnosed between 2010–2020 and treated with first-line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression-free survival (mIC-PFS), median overall survival (mOS), and their risk factors were estimated. Results There were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC-PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC-PFS in patients ≤60-year-old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first-generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC-PFS and mOS. mIC-PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3–4 (HR = 10.47, p < 0.001), BM number>3 (HR = 2.19, p = 0.002), and third-generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second-line therapy. Conclusions Upfront brain RT based on first-line EGFR-TKI might improve IC-PFS but not OS in EGFR-mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity.

Background: Clinical significance of various subtypes of epidermal growth factor receptor (EGFR) exon 19 deletion (ex19del) mutation in non‐small cell lung cancer (NSCLC) remains unclear.Methods: We analyzed EGFR ex19del subtypes in NSCLC patients receiving first‐line tyrosine kinase inhibitor (TKI) therapy at our center (January 2018–June 2022) and correlated them with median progression‐free survival (mPFS) and median overall survival (mOS).Results: We identified 17 different EGFR ex19del variants in 101 patients. Between the classic (E746_A750del, 64.4%) and nonclassic groups (the rest variants), no significant difference was observed in mPFS (13.5 vs. 19.3 months, p = 0.18) or mOS (44.1 vs. 77.0 months, p = 0.06). mPFS showed no significant difference between ex19del subgroups classified based on the presence of insertion (ex19delins), starting position or length of deletion. However, patients with ex19delins starting at E746 showed longer mPFS than the others (29.7 vs. 12.5 months, p = 0.04), and patients with ex19del of 15 nucleotides had shorter mOS than the others (44.1 vs. 77.0 months, p = 0.03). In multivariate analysis, ex19delins independently predicted a better PFS (HR = 0.311, p = 0.03); however, 15 nucleotide deletion was no longer associated with OS (HR = 0.181, p = 0.11). Secondary T790M mutation incidence was significantly higher in the ex19del subgroup starting at E746 than the others (64.7% vs. 30.8%, p = 0.04).Conclusions: Our study revealed potential differences in TKI efficacy, resistance mechanism, and prognosis of various EGFR ex19del subtypes in NSCLC, underscoring the need for precise selection of first‐line therapy.

Objective: to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors. Methods: randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science from 1 January 2019 to 31 May 2021. Adverse events data were extracted from clinical trials website or original article by two authors separately. Meta-analysis was used to determine risk ratio (RR) and 95% confidence interval (95% CI) of adverse events in PD-1/PD-L1 inhibitors groups compared to that of control groups. Subgroup analyses were also performed. Results: a total of 5,807 studies were initially identified and after exclusion, 41 studies were included in meta-analysis. All the trials were international multicenter, randomized, phase II/III clinical trials, with the median follow-up of 27.5 months on average. Analysis of all grade adverse events showed that PD-1/PD-L1 inhibitors treatment significantly increased the risk of immune-related adverse events, including pruritus (RR: 2.34, 95% CI: 1.85–2.96), rash (RR: 1.53, 95% CI: 1.25–1.87), ALT elevation (RR 1.54, 95% CI 1.23–1.92), AST elevation (AST: RR 1.49, 95% CI 1.20–1.85), hepatitis (RR: 3.54, 95% CI: 1.96–6.38) and hypothyroid (RR: 5.29, 95% CI: 4.00–6.99) compared with that of control group. Besides that, PD-1/PD-L1 inhibitors were associated with higher risk of adverse events related to respiratory system including cough (RR: 1.33, 95% CI: 1.21–1.48), dyspnea (RR:1.23, 95% CI: 1.12–1.35) and chest pain (RR: 1.26, 95% CI: 1.07–1.47) compared with that of control groups in our meta-analysis and the dyspnea was taken high risk both in all grade and grade 3 or higher (RR: 1.55, 95% CI: 1.13–2.12). The risk of arthralgia was increased with PD-1/PD-L1 inhibitors (RR: 1.27, 95% CI: 1.10–1.47). Although the risk of myalgia was similar with PD-1/PD-L1 inhibitors and control groups, under subgroup analysis, PD-1/PD-L1 inhibitors decreased the risk of myalgia (RR: 0.56, 95% CI: 0.45–0.70) compared with that of chemotherapy. Conclusions: our results provide clear evidence that the risk of treatment-related adverse events in PD-1 or PD-L1 varies widely in different system. In particular, when using PD-1/PD-L1 inhibitors for oncology treatment, besides the common immune-related adverse events like pruritus, rash, hepatitis, and hypothyroid, the respiratory disorders and musculoskeletal disorders, such as cough, dyspnea, arthralgia, and myalgia, should also be taken into consideration.

Background: The clinical implications of different EML4‐ALK fusion variants remain poorly elucidated in the era of second‐generation ALK inhibitors.Methods: This was a retrospective cohort study, wherein patients diagnosed with locally advanced or metastatic non‐small cell lung cancer harboring EML4‐ALK fusion were stratified into two cohorts based on their first‐line treatment: Cohort 1 received alectinib, while Cohort 2 received crizotinib. Statistical analysis was employed to investigate the impact of different EML4‐ALK variants and TP53 status on the efficacy of first‐line ALK‐TKIs.Results: Finally, 49 patients were enrolled in cohort 1 and 53 patients in cohort 2. In cohort 1, patients with long EML4‐ALK fusion variants exhibited prolonged PFS (NR vs. 34.0 m, p = 0.004, HR = 0.30, 95% CI: 0.12–0.74) and an elevated 5‐year OS rate (93.3% vs. 68.4%, p = 0.020, HR = 0.12, 95% CI: 0.02–0.62) compared to those with short variants. The median PFS was not reached in TP53‐wt group and 47.0 m in TP53‐mut group (p = 0.087, HR = 0.44, 95% CI: 0.17–1.17). The TP53‐wt group exhibited a superior 5‐year OS rate (100% vs. 77.8%, p = 0.030) compared to TP53‐mut group. In cohort 2, the median PFS was 14.0 m in long variant group and 12.9 m in short variant group (p = 0.094, HR = 0.65, 95% CI: 0.37–1.13); the median OS was not reached in long variant group and 69.2 m in short variant group (p = 0.254, HR:0.62, 95% CI: 0.27–1.42). However, the efficacy of first‐line crizotinib did not appear to be influenced by the TP53 status.Conclusions: EML4‐ALK short variants and TP53 mutations are both adverse factors for first‐line alectinib efficacy, but they have little effect on first‐line crizotinib.