We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC. Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS. Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up. Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.

Purpose: The aim of this study was to examine whether, after preceding induction chemotherapy, simultaneous chemoradiotherapy is superior to radiotherapy alone. Patients and Methods: Patients with non–small-cell lung cancer in inoperable stage IIIA or IIIB received induction chemotherapy with two cycles of paclitaxel 200 mg/m² and carboplatin area under the curve 6 every 3 weeks. Patients without progression at restaging after induction chemotherapy were randomly assigned to radiotherapy (60 Gy) or chemoradiotherapy (paclitaxel 60 mg/m² weekly). The primary end point was overall survival; secondary end points were time to progression, response, and toxicity. Results: Three hundred three patients entered the study, and 276 completed induction chemotherapy. Two hundred fourteen patients were randomly assigned (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Median follow-up time of all randomly assigned patients was 13.6 months (interquartile range [IQR], 6.4 to 29.0 months), and median follow-up time of the subgroup of censored patients (n = 52) was 37.4 months (IQR, 5.9 to 57.0 months; maximum, 76.1 months). Toxicities during the induction phase were mild. During radiotherapy, overall toxicity rates were not significantly different between the two arms. Median survival times in the radiotherapy group and chemoradiotherapy group were 14.1 months (95% CI, 11.8 to 16.3 months) and 18.7 months (95% CI, 14.1 to 23.3 months; difference not statistically significant, P = .091). Median time to progression significantly favored simultaneous chemoradiotherapy (11.5 months; 95% CI, 8.3 to 14.7 months) versus radiotherapy alone (6.3 months; 95% CI, 5.0 to 7.6 months; P < .001, log-rank test). Conclusion: Induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel is feasible. Response, time to progression, and survival favor chemoradiotherapy compared with radiotherapy alone.

Stage III nonsmall cell lung cancer (NSCLC) comprises about one-third of NSCLC patients and is very heterogeneous with varying and mostly poor prognosis. It is also called “locoregionally or locally advanced disease”. Due to its heterogeneity a general schematic management approach is not appropriate. Usually a combination of local therapy (surgery or radiotherapy, depending on functional, technical and oncological operability) with systemic platinum-based doublet chemotherapy and, recently, followed by immune therapy is used. A more aggressive approach of triple agent chemotherapy or two local therapies (surgery and radiotherapy, except for specific indications) has no benefit for overall survival. Until now tumour stage and the general condition of the patient are the most relevant prognostic factors. Characterising the tumour molecularly and immunologically may lead to a more personalised and effective approach. At the moment, after an exact staging and functional evaluation, an interdisciplinary discussion amongst the tumour board is warranted and offers the best management strategy.

Purpose: Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT). Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Knowledge of differences in the cellular physiology of malignant and non-malignant cells is a prerequisite for the development of cancer treatments that effectively kill cancer without damaging normal cells. Calcium is a ubiquitous signal molecule that is involved in the control of proliferation and apoptosis. We aimed to investigate if the endoplasmic reticulum (ER) Ca2+-homeostasis is different in lung cancer and normal human bronchial epithelial (NHBE) cells.

In vitro cell-based models of lung cancer are frequently employed to study invasion and the mechanisms behind metastasis. However, these models often study only one cell type with two-dimensional (2D) monolayer cell cultures, which do not accurately reflect the complexity of inflammation in vivo. Here, a three-dimensional (3D) cell co-culture collagen gel model was employed, containing human lung adenocarcinoma cells (HCC), human lung fibroblast cells (MRC-5), and macrophages. Cell culture media and cell images were collected, and matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor (VEGF) production was monitored under different cell culture conditions. We found that simulating hypoxia and/or serum starvation conditions induced elevated secretion of VEGF in the 3D co-culture model in vitro, but not MMP-1; the morphology of HCC in the 2D versus the 3D co-culture system was extremely different. MMP-1 and VEGF were secreted at higher levels in mixed cell groups rather than mono-culture groups. Therefore, incorporating lung cancer cells, fibroblasts, and macrophages may better reflect physiological metastasis mechanisms compared to mono-culture systems. Tumour stromal cells, macrophages, and fibroblast cells may promote invasion and metastasis, which also provides a new direction for the design of therapies targeted at destroying the stroma of tumor tissues.