Incidence, survival comparison, and novel prognostic evaluation approaches for stage iii-iv pulmonary large cell neuroendocrine carcinoma and small cell lung cancer.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are two types of high-grade neuroendocrine carcinomas of the lung with poor prognosis. LCNEC has not been thoroughly studied due to its rarity, data are also lacking regarding the survival comparison and prognosis analysis of patients with locally advanced or metastatic LCNEC and SCLC. METHODS: Data of patients with LCNEC, SCLC, and other NSCLC who were diagnosed from 1975 to 2019 were extracted from the Surveillance, Epidemiology and End Results (SEER) database to estimate incidence. Those in stage III-IV and being diagnosed from 2010 to 2015 were utilized further to investigate their clinical characteristics and prognosis. Propensity score matching (PSM) analyses at a ratio of 1:2 was used to compare their survival outcomes. Nomograms of LCNEC and SCLC were established with internal validation, and the nomogram of SCLC was externally validated by 349 patients diagnosed in Cancer hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 1, 2012 to December 31, 2018. RESULTS: The incidence of LCNEC has been increasing in recent decades, meanwhile that of SCLC and other types of NSCLC were decreasing. A total of 91,635 lung cancer patients, including 785 with LCNEC, 15,776 with SCLC, and 75,074 with other NSCLC were enrolled for further analysis. The survival of stage III-IV LCNEC resembles that of SCLC, and significantly worse than other types of NSCLC before and after PSM analysis. In pretreatment prognostic analysis, age, T stage, N stage, M stage, bone metastasis, liver metastasis, and brain metastasis were found to be associated with the survival of both LCNEC and SCLC, besides sex, bilaterality, and lung metastasis were additional prognostic factors for SCLC. Two nomograms and convenient online tools respectively for LCNEC and SCLC were established accordingly with favorable predicting accuracy of < 1-year, < 2-year, < 3-year survival probabilities. In external validation of the SCLC nomogram with a Chinese cohort, the AUCs of 1-year, 2-year and 3-year ROC were 0.652, 0.669, and 0.750, respectively. All the results of 1-, 2-, 3- year variable-dependent ROC curves verified the superior prognostic value of our nomograms for LCNEC and SCLC over the traditional T/N/M staging system. CONCLUSIONS: Based on large sample-based cohort, we compared the epidemiological trends and survival outcomes between locally advanced or metastatic LCNEC, SCLC, and other NSCLC. Furthermore, two prognostic evaluation approaches respectively for LCNEC and SCLC might present as practical tools for clinicians to predict the survival outcome of these patients and facilitate risk stratification.

Clinical activity of pembrolizumab with or without chemotherapy in advanced pulmonary large-cell and large-cell neuroendocrine carcinomas: a multicenter retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI)-based combination strategies have improved the survival outcomes in advanced non-small cell lung cancers; however, data regarding their efficacy remains limited for uncommon histological types, including large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC). METHODS: We retrospectively analyzed a total of 60 patients with advanced LCC and LCNEC - 37 treatment-naïve and 23 pre-treated - who received pembrolizumab with or without chemotherapy. Treatment and survival outcomes were analyzed. RESULTS: Of the 37 treatment-naïve patients who received first-line pembrolizumab combined with chemotherapy, the 27 patients with LCC had an overall response rate (ORR) of 44.4% (12/27) and a disease control rate (DCR) of 88.9% (24/27); whereas 10 patients with LCNEC had an ORR of 70% (7/10) and DCR of 90% (9/10). The median progression-free survival (mPFS) was 7.0 months (95% confidence intervals [CI]: 2.2-11.8) and median overall survival (mOS) was 24.0 months (95%CI: 0.0-50.1) for first-line pembrolizumab plus chemotherapy of LCC (n = 27), whereas mPFS was 5.5 months (95%CI: 2.3-8.7) and mOS was 13.0 months (95%CI: 11.0-15.0) for first-line pembrolizumab plus chemotherapy of LCNEC (n = 10). Of the 23 pre-treated patients who received subsequent-line pembrolizumab with or without chemotherapy, mPFS was 2.0 months (95% CI: 0.6-3.4) and mOS was 4.5 months (95% CI: 0.0-9.0) for LCC and mPFS was 3.8 months (95% CI: 0.0-7.6) and mOS was not reached for LCNEC. CONCLUSION: Our study provides real-world clinical evidence of the anti-tumor activity of pembrolizumab plus chemotherapy in advanced LCC and LCNEC, indicating that this regimen could serve as a treatment option, particularly as first-line therapy, for improving the survival outcomes of patients with these rare histological subtypes of lung cancer. TRIAL REGISTRATION: NCT05023837(ESPORTA, 27/08/2021).

Effect of Chemotherapy in Stage II-IV Large-Cell Lung Carcinoma and Construction of Its Predictive Nomograms: A SEER Analysis.

OBJECTIVES: Large-cell lung carcinoma (LCLC) is generally poorly differentiated with a poor prognosis. This study aimed to explore the impact of chemotherapy on the prognosis of patients with stage II-IV LCLC and to construct nomograms to predict overall survival (OS) and cancer-specific survival (CSS). METHODS: Propensity score matching analysis was used to balance the effects of baseline characteristics. The Kaplan-Meier method was used to analyze the prognostic impact of chemotherapy on LCLC patients. Cox regression analysis was used to identify prognostic risk factors, and then nomograms were constructed and validated. RESULTS: Overall, we identified 2,532 patients with LCLC from the Surveillance, Epidemiology, and End Results (SEER) database. The chemotherapy group showed better OS and CSS compared to the non-/unknown chemotherapy group for stage II-IV LCLC patients (p < 0.05). Two nomograms were plotted based on the results of Cox regression analysis. The areas under the curves (AUCs) of 1-, 3-, and 5-year OS were 0.786, 0.824, and 0.837, and the AUCs of CSS were 0.785, 0.821, and 0.836, respectively. The calibration curves showed excellent agreement between the prediction and the actual observation, and the decision curve analysis demonstrated good clinical utility. CONCLUSIONS: Chemotherapy could improve the prognosis among stage II-IV LCLC patients. In addition, the nomograms showed good predictive ability, which could be useful in making clinical decisions.

[A Case of Long-Term Remission with Surgical Therapy and Chemoradiotherapy for a Rapidly Increasing Large Cell Neuroendocrine Carcinoma(LCNEC)].

BACKGROUND: Large cell neuroendocrine carcinoma(LCNEC)is a relatively rare disease classified as a subtype of neuroendocrine tumor. LCNEC has clinical and histological similarities to small cell lung cancer, both of which have a similarly poor prognosis. There are also unclear points regarding treatment. CASE: 43-years-old, male. He had repeated intermittent fever from 1 month before the consultation. Cough appeared 4 days before the consultation, and the family doctor pointed out an abnormal shadow in the right lung field, and the patient was referred. Blood test showed increased CRP 1.34 mg/dL and mild inflammatory response. Chest CT showed an increased tumor with a major axis of 16 cm in the right thoracic cavity compared to 6 months ago. FDG-PET showed accumulation of SUVmax 11.83 in the same area. A CT-guided needle biopsy was performed, and although tumor cell hyperplasia of like a plasma cells was suspected, but most of them were coagulative necrotic images and could not be diagnosed. After hospitalization, fever continued and the general condition became poor, so surgery was performed for the purpose of diagnostic treatment. Preoperatively, Interventional Radiology was used to embolize the tumor-feeding blood vessels. Intrathoracic tumor resection and partial upper and lower lobe resection were performed under thoracotomy. Postoperative histopathological examination revealed that large round to polyhedron tumor cells proliferated in sheet-like or intercellular binding sparsely, and synaptophysin was positive, which was a diagnosis of large cell neuroendocrine cell carcinoma. The general condition improved promptly after the operation, and the patient was discharged 14 days after the operation without any complications. After discharge, 4 courses of adjuvant chemotherapy (CDDP plus CPT-11)were performed. Six months after the operation, the disseminated nodule recurred in the right thoracic cavity. Chemotherapy(CBDCA plus PTX plus BEV)and radiation therapy were performed and the patient was in remission. It has been 5 years since the operation and has not recurred. SUMMARY: We report a case of rapidly increasing LCNEC with long-term remission by surgical treatment and chemoradiotherapy, with some review of the literature.

Platinum Doublet plus Atezolizumab as First-line Treatment in Metastatic Large Cell Neuroendocrine Carcinoma: A Single Institution Experience.

BACKGROUND: Large Cell Neuroendocrine Carcinoma of the Lung (L-LCNEC) is a rare type of neuroendocrine lung cancer that is increasingly diagnosed. However, the optimal management regarding the advanced stage is unclear. The purpose of this article is to present and compare our experience when L-LCNEC is treated as Small Cell Lung Cancer (SCLC). PATIENTS AND METHODS: Overall, eight cases of L-LCNEC were included. We retrospectively reviewed medical files and reports by accessing the Institution's Data of patients diagnosed with L-LCNEC from April 2019 until December 2020 and evaluated their response to the combination of Platinum - Etoposide - Atezolizumab as first-line chemotherapy. RESULTS: The overall observed response rate (ORR) of 75%. The median PFS was 6.85 months. The median response duration was 5.5 months. CONCLUSIONS: Comparing our findings with other retrospective and prospective studies, it seems that the systematic treatment of choice and management in L-LCNEC of the lung should be that of a small cell carcinoma of the lung.

Metformin use and lung cancer survival: a population-based study in Norway.

BACKGROUND: We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. METHODS: The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005-2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. RESULTS: Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62-0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47-0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73-0.95), in patients with SCC (HR = 0.75; 95%CI 0.57-0.98), regional stage LC (HR = 0.74; 95%CI 0.59-0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38-0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. CONCLUSIONS: Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.

Efficacy and Safety of Anti-Programed Death-1 Blockade in Previously Treated Large-Cell Neuroendocrine Carcinoma.

BACKGROUND: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor with an aggressive clinical course. However, there is limited knowledge of its treatment strategy. This retrospective study aimed to assess the efficacy and safety of anti-programed death-1 (PD-1) blockade monotherapy in previously treated advanced LCNEC. METHODS: Eleven patients with previously treated advanced LCNEC who received immune checkpoint inhibitor monotherapy between January 2015 and November 2020 were retrospectively analyzed for efficacy and safety. RESULTS: Of a total of 11 patients (median [range] age, 66 [37-79] years; 8 men [73%] and 3 women [27%]), 8 patients had performance status (PS) 0-1 [73%] and 3 patients had PS 2 [27%]; 9 patients received 1 prior chemotherapy [82%] and 2 patients received 2 prior chemotherapies [18%]. The median follow-up duration was 4.6 months. Although PD-1 blockade was administered at median cycles of 3 (range, 1-12), overall response rate, median progression-free survival, and median overall survival were 9.1%, 2.7 months, and 4.6 months, respectively. Any adverse events were observed in 9 patients (82%), including 1 patient with grade 3 pneumonitis as a serious adverse event. CONCLUSION: Anti-PD-1 blockade monotherapy as a subsequent line for previously treated advanced LCNEC exhibited usefulness and tolerability and was identified as a valid treatment option.

Outcomes of Patients with Pulmonary Large Cell Neuroendocrine Carcinoma in I-IV Stage.

Background and Objectives: Large cell neuroendocrine cancer is characterised by poor prognosis. The standard of treatment is still not established. The aim of this study was to assess the predictive factors of overall survival (OS) and progression-free survival (PFS) of pulmonary large cell neuroendocrine carcinoma (LCNEC) and combined LCNEC. Materials and Methods: All patients had confirmed pathology stage I-IV disease recorded between period 2002-2018. Survival curves were estimated by Kaplan-Meier method. Uni- and multivariable analysis was conducted using Cox-regression analysis. Results: A total of 132 patients with LCNEC and combined LCNEC were included. Half of them had clinical stage IIIB/C-IV. Patients were treated with radical (n = 67, including surgery alone; resection with neo-adjuvant or adjuvant chemotherapy, radiochemotherapy, or adjuvant radiotherapy; patients treated with radiochemotherapy alone), palliative (n = 41) or symptomatic (n = 24) intention. Seventeen patients were treated with resection margin R1 or R2. Non-small cell carcinoma (NSCLC) chemotherapy (platinum-vinorelbine; PN schedule) and small-cell lung carcinoma (SCLC) chemotherapy approaches (platinum/carboplatinum-etoposide; PE/KE schedule) were administered in 20 and in 55 patients, respectively. The median (95% Confidence Interval (CI)) OS and PFS were 17 months (9.0-36.2 months) and 7 months (3.0-15.0 months), respectively. Patients treated with negative resection margin, with lower clinical stage, without lymph node metastasis, and with size of primary tumour ≤4 cm showed significantly better OS and PFS. The main risk factors with an adverse effect on survival were advanced CS and positive resection margin. Conclusions: Patients with LCNEC characterized poor prognosis. Independent prognostic factors influencing PFS were initial clinical stage and resection margin R0 vs. R1-2.

Real world utilization of EGFR TKIs and prognostic factors for survival in NSCLC during 2010-2016 in Sweden: A nationwide observational study.

The purpose of our study was to investigate time trends in treatment pattern and prognostic factors for overall survival (OS) in epidermal growth factor receptor (EGFR) targeting tyrosine kinase inhibitors (TKIs) treated nonsmall cell lung cancer (NSCLC) patients. Utilizing Swedish nationwide registers, we identified all Stage IIIB-IV NSCLC patients treated with EGFR TKIs and followed them from diagnosis (2010-2015) until death or end of observation (2016). Multivariable Cox regression analyses were performed to test associations of patient-, tumor-related factors with OS. Of 9,992 Stage IIIB-IV NSCLC patients, the 1,419 (14%) who initiated EGFR TKI treatment during observation were younger (median age 68 vs. 71 years), less ≥1 comorbidities (34% vs. 46%), more often female (59% vs. 47%), Stage IV (89% vs. 85%) and adenocarcinoma (85% vs. 66%) compared to non-TKI treated patients. After TKI initiation, 7% (n = 100) of the patients switched, 4% (n = 62) rechallenged a TKI treatment, 65% (n = 919) discontinued and 24% (n = 338) had died. A more recent diagnosis demonstrated shorter time to EGFR TKI initiation, prolonged treatment length and longer median OS (15.3 months 2010-2011; 14.4 months 2012-2013; 18.6 months 2014-2015). Prognostic factors for longer OS when treated with EGFR TKIs were younger age, adenocarcinoma, less advanced clinical stage and less comorbid disease. In conclusion, during the observation period, survival improved for EGFR TKI treated NSCLC patients, as did the accessibility for targeted therapies for these patients.

The association of depressive symptoms, personality traits, and sociodemographic factors with health-related quality of life and quality of life in patients with advanced-stage lung cancer: an observational multi-center cohort study.

BACKGROUND: Identification of patient-related factors associated with Health-Related Quality of Life (HRQoL) and Quality of Life (QoL) at the start of treatment may identify patients who are prone to a decrease in HRQoL and/or QoL resulting from chemotherapy. Identification of these factors may offer opportunities to enhance patient care during treatment by adapting communication strategies and directing medical and psychological interventions. The aim was to examine the association of sociodemographic factors, personality traits, and depressive symptoms with HRQoL and QoL in patients with advanced-stage lung cancer at the start of chemotherapy. METHODS: Patients (n = 151) completed the State-Trait Anxiety Inventory (trait anxiety subscale), the Neuroticism-Extraversion-Openness-Five Factor Inventory (NEO-FFI), the Center for Epidemiologic Studies Depression (CES-D), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Simple linear regression analyses were performed to select HRQoL and QoL associated factors (a P ≤ 0.10 was used to prevent non-identification of important factors) followed by multiple linear regression analyses (P ≤ 0.05). RESULTS: In the multiple regression analyses, CES-D score (ß = - 0.63 to - 0.53; P-values < 0.001) was most often associated with the WHOQOL-BREF domains and general facet, whereas CES-D score (ß = - 0.67 to - 0.40; P-values < 0.001) and Eastern Cooperative Oncology Group (ECOG) performance status (ß = - 0.30 to - 0.30; P-values < 0.001) were most often associated with the scales of the EORTC QLQ-C30. Personality traits were not related with HRQoL or QoL except for trait anxiety (Role functioning: ß = 0.30; P = 0.02, Environment: ß = - 0.39; P = 0.007) and conscientiousness (Physical health: ß = 0.20; P-value < 0.04). CONCLUSIONS: Higher scores on depressive symptoms and ECOG performance status were related to lower HRQoL and QoL in patients with advanced-stage non-small cell lung cancer. Supportive care interventions aimed at improvement of depressive symptoms and performance score may facilitate an increase of HRQoL and/or QoL during treatment.

Does progress achieved in the treatment of patients with metastatic non-small-cell lung cancer reach the elderly population? A cohort study from a cancer centre from Eastern Switzerland.

OBJECTIVE: Treatment options for non-small-cell lung cancer (NSCLC) have been evolving. The goal of our study was to evaluate whether novel therapeutics are used in the elderly population and improve outcomes to a similar extent as in young patients. METHODS: We enrolled patients registered in the Cancer Registry of Eastern Switzerland and grouped them into four cohorts: Elderly patients aged ≥70 years diagnosed 2005-2007 and 2015-2016 (elderly cohorts 1,2) were compared to cohorts of patients < 70 years diagnosed during the same time periods (young cohorts 1,2). RESULTS: 499 individuals were analysed. Median cancer-specific survival in the elderly cohorts 1 and 2 was 3.9 months and 6.3 months, respectively, and 8.0 and 12.7 months in the young cohorts 1 and 2. 12-month survival significantly improved over ten years only in younger patients (35.6% and 54.9%), however not in the elderly cohorts (20% vs. 35%). Proportion of patients receiving any line of systemic treatment remained lower in the elderly cohorts (53% vs. 78%). CONCLUSION: Despite the increase in median cancer-specific survival in both cohorts, a significant and clinically meaningful improvement of 12-month cancer-specific survival was only seen in young patients. The adoption of novel treatment approaches is lagging behind in the elderly population.

Patient-derived xenograft models of non-small cell lung cancer for evaluating targeted drug sensitivity and resistance.

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.

Differential efficacy of cisplatin plus pemetrexed between L858R and Del-19 in advanced EGFR-mutant non-squamous non-small cell lung cancer.

BACKGROUND: LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R. METHODS: This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis. RESULTS: Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0-12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6-8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62-0.98) (p = 0.033). CONCLUSION: Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.

The serum-based VeriStrat® test is associated with proinflammatory reactants and clinical outcome in non-small cell lung cancer patients.

BACKGROUND: The VeriStrat test is a serum proteomic signature originally discovered in non-responders to second line gefitinib treatment and subsequently used to predict differential benefit from erlotinib versus chemotherapy in previously treated advanced non-small cell lung cancer (NSCLC). Multiple studies highlight the clinical utility of the VeriStrat test, however, the mechanistic connection between VeriStrat-poor classification and poor prognosis in untreated and previously treated patients is still an active area of research. The aim of this study was to correlate VeriStrat status with other circulating biomarkers in advanced NSCLC patients - each with respect to clinical outcomes. METHODS: Serum samples were prospectively collected from 57 patients receiving salvage chemotherapy and 70 non-EGFR mutated patients receiving erlotinib. Patients were classified as either VeriStrat good or poor based on the VeriStrat test. Luminex immunoassays were used to measure circulating levels of 102 distinct biomarkers implicated in tumor aggressiveness and treatment resistance. A Cox PH model was used to evaluate associations between biomarker levels and clinical outcome, whereas the association of VeriStrat classifications with biomarker levels was assessed via the Mann-Whitney Rank Sum test. RESULTS: VeriStrat was prognostic for outcome within the erlotinib treated patients (HR = 0.29, p < 0.0001) and predictive of differential treatment benefit between erlotinib and chemotherapy ((interaction HR = 0.25; interaction p = 0.0035). A total of 27 biomarkers out of 102 unique analytes were found to be significantly associated with OS (Cox PH p ≤ 0.05), whereas 16 biomarkers were found to be associated with PFS. Thrombospondin-2, C-reactive protein, TNF-receptor I, and placental growth factor were the analytes most highly associated with OS, all with Cox PH p-values ≤0.0001. VeriStrat status was found to be significantly associated with 23 circulating biomarkers (Mann-Whitney Rank Sum p ≤ 0.05), 6 of which had p < 0.001, including C-reactive protein, IL-6, serum amyloid A, CYFRA 21.1, IGF-II, osteopontin, and ferritin. CONCLUSIONS: Strong associations were observed between survival and VeriStrat classifications as well as select circulating biomarkers associated with fibrosis, inflammation, and acute phase reactants as part of this study. The associations between these biomarkers and VeriStrat classification might have therapeutic implications for poor prognosis NSCLC patients, particularly with new immunotherapeutic treatment options.

Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.

BACKGROUND: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS: We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS: Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION: Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING: Stemcentrx Inc.

Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial.

BACKGROUND: Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. PATIENTS AND METHODS: In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. RESULTS: Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. CONCLUSION: Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. REGISTERED CLINICAL TRIAL NUMBERS: EudraCT number 2010-022273-34, NCT01317615.

Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer).

BACKGROUND: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. RESULTS: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. CONCLUSION: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. CLINICAL TRIAL NUMBER: Japan Pharmaceutical Information Center, JapicCTI-101155.

Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter?

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003-2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as "NSCLC-t", comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; "NSCLC-pt", with pemetrexed treatment only; and "SCLC-t", consisting of etoposide chemotherapy.A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n=20) and SCLC-t in 38% (n=48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0-9.9) months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0-6.9) months (hazard ratio 2.51, 95% CI 1.39-4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0-8.5) months (hazard ratio 1.66, 95% CI 1.08-2.56; p=0.020).In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC-pt and SCLC-t chemotherapy.

Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001.

BACKGROUND: This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). METHODS: Patients received four cycles of S-1 (80 mg/m2/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m2/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was ≥50%. RESULTS: Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%. CONCLUSIONS: We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC. CLINICAL REGISTRATION NUMBER: UMIN000005041.

[Precision medical treatment of non-adenocarcinoma NSCLC patients with EGFR mutation].

EGFR tyrosine kinase inhibitors (TKIs) treatment has been established as standard therapy for EGFR-mutated adenocarcinomas. In the studies which published prospective randomized trials comparing EGFR TKIs with chemotherapy, a very low percentage of EGFR-mutated non-adenocarcinomas was enrolled in clinical trials. The efficacy of TKIs treatment for EGFR-mutated non-adenocarcinomas and their relationship with clinicopathological characteristics remain debatable. The results of retrospective studies show that the frequency of EGFR mutation is lower in non-adenocarcinoma than that of adenocarcinoma and efficacy of TKIs treatment for non-adenocarcinoma is inferior to adenocarcinoma. Smoking status is significantly associated with the efficacy of TKIs treatment for EGFR-mutated non-adenocarcinomas. The EGFR mutation rate and efficacy of TKIs treatment in adenosquamous cell carcinoma are higher than those of squamous cell carcinoma or large cell lung carcinoma. It may be concluded that the incidence of EGFR mutations in patients with non-adenocarcinoma NSCLC from mainland China is not very low and it is reasonable that EGFR TKIs could be an option for the treatment of EGFR-mutated non-adenocarcinoma NSCLC, especially for patients with adenosquamous histology and non-smokers. It is necessary to conduct a large-sample prospective study to understand the clinicopathological characteristics of non-adenocarcinomas and to evaluate the efficacy of EGFR TKI treatment or/and chemotherapy for EGFR-mutated non-adenocarcinoma NSCLC.