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• This study evaluated the long-term benefits of atezolizumab in NSCLC in China. • Clinically meaningful benefits and no new safety concerns were observed. • Gene mutations that were enriched in atezolizumab responders were identified. • Patient subgroups with higher rates of atezolizumab-related SAEs were identified. To evaluate the long-term safety and efficacy of atezolizumab monotherapy in Chinese patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC). In this open-label, single-arm, multicenter study, patients received atezolizumab 1200 mg intravenously on Day 1 of each 21-day cycle. The primary endpoint was incidence of atezolizumab-related serious adverse events (SAEs). Secondary endpoints included other safety and efficacy measures. Patients with available tumor tissue and blood samples underwent biomarker analyses. Patients with available tumor biopsies underwent exome sequencing. The safety and evaluable populations included 101 and 97 patients, respectively. Exome sequencing data were available for 31 patients. Median follow-up time was 27.43 months. Atezolizumab-related SAEs and immune-related adverse events occurred in 25.7% and 47.5% of the safety population, respectively, and in the following subgroups: central nervous system metastases (n = 14), 35.7% and 35.7%; squamous NSCLC (n = 39), 33.3% and 53.8%. The 24-month overall survival rate was 37.4%. Median overall survival and progression-free survival by RECIST v1.1 were 15.31 and 2.86 months, respectively; objective response rate was 16.5% in the evaluable population. PRRC2C (odds ratio: 12.780, P = 0.014) and ZMYND8 (odds ratio: 19.963, P = 0.016) gene mutations were significantly enriched in atezolizumab responders vs non-responders. Patients with CD8+ TILs > 10% vs ≤ 10% were significantly more likely to be atezolizumab responders. No new safety concerns were raised, and clinically meaningful benefits of atezolizumab monotherapy were shown. The results of the biomarker analyses may guide future therapeutic strategies. [ABSTRACT FROM AUTHOR]

• Third-generation EGFR-TKIs show significant benefits in EGFR-mutated NSCLC and LM. • High-dose third-generation EGFR-TKIs are effective treatments regardless of prior EGFR-TKI exposure. • High-dose third-generation EGFR-TKIs and intrathecal chemotherapy are independent predictors of OS. Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. The median follow-up period was 28.7 months (range 0.6–40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0–15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure. [ABSTRACT FROM AUTHOR]

• The tumor immune microenvironment in uncommon EGFR -mutated NSCLC was determined. • Uncommon EGFR -mutant tumors had a high frequency of PD-L1 and CD8 dual positivity. • Uncommon EGFR -mutated NSCLC had preliminary therapeutic sensitivity to PD-1 blockade. The efficacy of immunotherapy in epidermal growth factor receptor (EGFR) -activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations. Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population. Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P < 0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03–7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR -mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors. High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup. [ABSTRACT FROM AUTHOR]

Highlights • DS-GPA and Lung-molGPA could predict outcomes of NSCLC patients with brain metastases. • Lung-molGPA demonstrated discriminatory capability in patients with gene variations. • A modified Lung-molGPA index was developed. Abstract Objectives The Lung-molGPA index is based on the original diagnosis-specific graded prognostic assessment (DS-GPA) and incorporates recently reported gene alteration data, predicting the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic values of both DS-GPA and Lung-molGPA remain undetermined, especially for patients with different molecular types. Materials and Methods A total of 1184 NSCLC patients with BM were analyzed for clinical factors and outcomes at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA was newly developed for NSCLC patients with gene variations. Results NSCLC patients in the present study had a median survival time of 14.0 months from BM diagnosis. Both the DS-GPA and Lung-molGPA models could effectively predict the outcomes of NSCLC patients with BM (P < 0.001), and the Lung-molGPA model appeared to deliver more accurate predictions. Furthermore, Lung-molGPA scores demonstrated discriminatory capability in patients with gene variations (P < 0.001), and no significant difference was reached in wild-type patients (P = 0.133). Regarding oncogene-positive NSCLC patients with BM, a modified Lung-molGPA index was established based on the prognostic factors with a C-index of 0.73 (95% CI: 0.68-0.80) to accurately calculate survival probability (P < 0.001). Conclusions In the era of precision medicine, Lung-molGPA accurately predicted the prognosis of NSCLC patients with mutant genotypes and BM, although it did not perform well in wild-type patients. Thus, it is worthwhile to explore the prognostic model for patients with positive driving genes. [ABSTRACT FROM AUTHOR]