RESUMO
Background: Immune checkpoint inhibitors (ICIs) with or without chemotherapy represent first-line standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The most appropriate second-line therapy after failing immunochemotherapy remains an open question. Nintedanib, an oral triple angiokinase inhibitor that targets the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and, platelet-derived growth factor receptor, in combination with docetaxel, is approved for treatment of advanced NSCLC (adenocarcinoma histology) following progression on first-line chemotherapy. Methods: VARGADO (NCT02392455) is an ongoing, prospective, non-interventional study investigating the efficacy and safety of nintedanib plus docetaxel following first-line chemotherapy with or without ICIs in patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma histology. This analysis focuses on Cohort C, which enrolled patients who had received prior first line chemotherapy with ICIs. Patients received second-line docetaxel (75 mg/m2) by intravenous infusion on Day 1, plus oral nintedanib (200 mg twice daily) on Days 2-21 of each 21-day cycle during routine clinical care. The primary endpoint is overall survival (OS) rate 1 year after the start of treatment with nintedanib plus docetaxel. Secondary endpoints include progression-free survival (PFS), OS, and disease control rate (DCR). Safety was also assessed. Results: Among 137 patients treated, the median age was 63 years (range, 37-84); 57 patients (41.6%) were female, most patients had Eastern Cooperative Oncology Group performance status of 0 (28.5%) or 1 (43.1%); 118 (86.1%) had stage IV NSCLC and 27 (19.7%) had brain metastases. Most (n=120, 87.6%) patients had received pembrolizumab/pemetrexed/platinum-based chemotherapy as first-line treatment. In 80 patients with available response data, the DCR was 72.5% (complete response: 1.3%; partial response: 36.3%; stable disease: 35.0%). Median progression-free survival was 4.8 months (95% confidence interval: 3.7-6.6). OS data were immature. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were reported in 62 (45.3%), 50 (36.5%), and 40 patients (29.2%), respectively. Conclusions: This analysis indicates that nintedanib plus docetaxel represents an effective second-line treatment option in patients with advanced adenocarcinoma NSCLC following progression on first-line immunochemotherapy. The safety profile was manageable with no unexpected signals.
RESUMO
BACKGROUND/AIMS: Accumulation of T lymphocytes in the gut is a hallmark of inflammatory bowel disease probably caused by insufficient T cell apoptosis. Activated peripheral T cells, or "resting" lamina propria T lymphocytes (LPLs), are highly susceptible to apoptosis induction, e.g., using the mitogenic anti-CD2 monoclonal antibody (mAb) pair T11(2+3). It is, however, unknown how CD2-mediated LPL apoptosis is related to proliferation and whether the whole CD2 molecule is required for apoptosis induction. MATERIALS AND METHODS: Mapping of anti-CD2 mAb was performed using erythrocyte rosetting assays and cross-blocking enzyme-linked immunosorbent assay (ELISA). Lamina propria mononuclear cells (LPMNCs) or phytohemagglutinin (PHA) blasts were stimulated with a panel of 18 anti-CD2 mAbs followed by apoptosis analysis [Annexin V expression on propidium iodide (PI)-negative cells, 4c6-diamidino-2-phenylindole x 2HCl (DAPI) staining]. Proliferation was measured by [(3)H]-thymidine incorporation. For structural analysis, EL4 cells were used which were transfected with human CD2 (wild type (WT), cytoplasmic-deficient, cytoplasmic CD28). Sorting was performed employing standard techniques RESULTS: All three mitogenic anti-CD2 mAb pairs induced apoptosis of LPMNC and PHA blasts. Two out of four submitogenic anti-CD2 mAb, AICD2.M3, and ICRFCD2.3 lead to LPMNC proliferation but no apoptosis. Importantly, apoptosis was also detected in cytoplasmic-deficient CD2 tg or CD2/CD2/CD28 tg EL4 cells. Sorted CD45(high) huCD2 WT EL4 had higher apoptosis rates compared to WT huCD2tg EL4 cells CONCLUSION: LPMNC apoptosis induction via CD2 is always associated with proliferation, although proliferation is not necessarily associated with apoptosis. The cytoplasmic tail of CD2 is not required, and CD45 appears to transmit apoptotic signals entering the T cell via CD2.
