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Purpose Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Patients and Methods Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Results Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

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Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.

Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.

Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

This study demonstrated that COPD patients produce greater quantities of MMP-12 than controls, which may be a critical step in the pathogenesis of COPD and emphysema.

17. Herder GJ, van Tinterent TH, Golding RP et al. Clinical prediction Background: The optimal treatment of large-cell neuroendocrine carcinoma (LCNEC) of the lung remains unclear.Here, our primary objective was to assess the efficacy of cisplatin-etoposide doublet chemotherapy in advanced LCNEC. Accuracy of the pathological diagnosis and treatment toxicity were assessed as secondary objectives.Patients and methods: Prospective, multicentre, single-arm, phase II study with a centralised review of treatmentresponse and pathological data. Patients had untreated performance status (PS) 0/1 stage IV/IIIB LCNEC and received cisplatin (80 mg/m22 d1) and etoposide (100 mg/m22 d1-3) every 21 days. Results: Eighteen centres included 42 patients (mean age, 59 ± 9 years; 69% men; median of four cycles/patient). At least one grade-3/4 toxicity occurred in 59% of patients (neutropaenia, thrombocytopaenia, and anaemia in 32%, 17%, and 12%, respectively). The median progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% confidence interval, CI, 3.1-6.6) and 7.7 months (95% CI, 6.0-9.6), respectively. The centralised pathologist review reclassified 11 of 40 (27.5%) patients: 9 as small-cell lung cancer, 1 as undifferentiated non-small-cell lung cancer, and 1 as atypical carcinoid. Survival data were not significantly changed by excluding the reclassified patients. Conclusions:The pathological diagnosis of LCNEC is difficult. The outcomes of advanced LCNEC treated with cisplatin-etoposide doublets are poor, similar to those of patients with advanced small-cell lung carcinoma (SCLC). Key words: carcinoma, clinical trial phase II, large cell neuroendocrine tumours, small-cell lung cancer introduction Large-cell neuroendocrine carcinoma (LCNEC) of the lung accounts for no more than 1% of all lung cancers. The typical histological features, first described in 1991 [1, 2], include large cells with abundant cytoplasm, a high mitotic rate, extensive necrosis, and a neuroendocrine growth pattern. The World Health Organisation currently classifies LCNEC as a distinct subtype of pulmonary large-cell carcinoma [3] and, therefore, as a subtype of non-small-cell lung carcinoma (NSCLC). However, LCNEC lacks the specific histologic features of NSCLC such as glandular or squamous differentiation, but instead displays evidence of neuroendocrine differentiation reminiscent of small-cell lung carcinoma (SCLC), although the malignant cells in SCLC are smaller, with scant cytoplasm, and invade the tissues in sheets. LCNECLCNEC shares genetic alterations with SCLC [4]. The higher mitotic rates and more extensive necrosis seen in LCNEC and SCLC are in contrast to the lower-grade neuroendocrine tumours, i.e. typical and atypical carcinoids. LCNEC and SCLC also share clinical characteristics including a preponderance of males and smokers and an aggressive clinical course [5][6][7][8][9]. The clinical outcome of LCNEC patients is poor, with overall 5-year survival rates ranging from 15% to 57%. Studies have demonstrated signifi...