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BACKGROUND Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to EGFR-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC, and randomized to up-front RT vs. no RT; we now report the pre-specified interim analysis at 68% accrual. METHODS Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly-diagnosed, treatment-naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs. RT (25–40 Gy in 5 fractions depending on tumor size/location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention-to-treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. RESULTS A total of 133 patients (n = 65 TKI only, n = 68 TKI+RT) were enrolled (2016–2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs. 20.2 months (p < .001), and the median OS was 17.4 months vs. 25.5 months (p < .001) for TKI only vs TKI+RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3–4 pneumonitis in the TKI+RT arm. Based on the efficacy results of this pre-specified interim analysis, the ethics committee recommended premature cessation of this trial. CONCLUSIONS As compared to a first-line TKI alone, addition of up-front local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

The 2019 coronavirus disease (COVID-19) outbreak caused by the SARS-CoV-2 virus is an ongoing global health emergency. However, the virus’ pathogenesis remains unclear, and there is no cure for the disease. We investigated the dynamic changes of blood immune response in patients with COVID-19 at different stages by using 5’ gene expression, T cell receptor (TCR), and B cell receptors (BCR) V(D)J transcriptome analysis at a single-cell resolution. We obtained single-cell mRNA sequencing (scRNA-seq) data of 341,420 peripheral blood mononuclear cells (PBMCs) and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies. In addition, we used three control samples. We found expansion of dendritic cells (DCs), CD14+ monocytes, and megakaryocytes progenitor cells (MP)/platelets and a reduction of naïve CD4+ T lymphocytes in patients with COVID-19, along with a significant decrease of CD8+ T lymphocytes, and natural killer cells (NKs) in patients in critical condition. The type I interferon (IFN-I), mitogen-activated protein kinase (MAPK), and ferroptosis pathways were activated while the disease was active, and recovered gradually after patient conditions improved. Consistent with this finding, the mRNA level of IFN-I signal-induced gene IFI27 was significantly increased in patients with COVID-19 compared with that of the controls in a validation cohort that included 38 patients and 35 controls. The concentration of interferon-α (IFN-α) in the serum of patients with COVID-19 increased significantly compared with that of the controls in an additional cohort of 215 patients with COVID-19 and 106 controls, further suggesting the important role of the IFN-I pathway in the immune response of COVID-19. TCR and BCR sequences analyses indicated that patients with COVID-19 developed specific immune responses against SARS-CoV-2 antigens. Our study reveals a dynamic landscape of human blood immune responses to SARS-CoV-2 infection, providing clues for therapeutic potentials in treating COVID-19.

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