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This participatory action research (PAR) project describes crossover students’ college and career readiness needs in a major west coast urban school district. The paper provided insights from administrator researchers, participants, facilitator, and recommendations for school counselors, educators, and organizations who are thinking of creating more counseling support and educational opportunities for crossover students. The results include the reflections and recommendations of crossover youths (e.g., encourage us, we are worth the rigor). The discussion includes strategies for supporting the academic, career, emotional, and social needs of crossover students.

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

The aim of this study was to identify the correspondence between the workload demands in training sessions and the game performance from elite basketball players, according to their specific positions. Data were collected from a professional men's basketball team competing in the Spanish Professional League and Euroleague. Players' activity during the training sessions was measured using WIMU PRO® and the game statistics were used as a measure of game performance. Cluster analysis allowed to classify the training workload and the game performance, whereas correspondence analysis allowed to explore their relationship. In essence, there was no correspondence from the higher workloads with the best performances, on the contrary, the small forwards' best performances corresponded to lower training workouts. Despite their importance, the external measures of load need to be complemented with additional (and valid) measures that can be translated to game performance.

Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721

Introduction: ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).Patients and Methods: The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier:NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.Results: Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7-20.0 versus 24.1 months, 95% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%).Conclusions: Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Aim: This pooled safety analysis was conducted to analyze incidence and management of key dacomitinib-associated adverse drug reactions (ADRs). Patients & methods: Patients with EGFR mutation-positive advanced non-small-cell lung cancer who received first-line dacomitinib at the 45 mg/day recommended starting dose were included. ADRs were identified based on reasonable association with EGFR tyrosine kinase inhibitors. Results: Overall, 251/255 patients (98%) experienced ADRs. The most common were diarrhea, rash, stomatitis, nail disorder and dry skin. Dose interruptions and dose reductions were reported in 47 and 52% of patients, respectively. Fewer grade 3 key ADRs were observed following dose reductions. Conclusion: Dacomitinib was generally tolerable. Most reported ADRs were known to be associated with EGFR tyrosine kinase inhibitors and were managed with standard medical management and dose modifications.

Background ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib. Objective This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. Patients and methods In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019). Results After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591–0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420–0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib. Conclusions The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. ClinicalTrials.gov NCT01774721 (registered 24 January 2013). Electronic supplementary material The online version of this article (10.1007/s40265-020-01441-6) contains supplementary material, which is available to authorized users.

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [

INTRODUCTION: In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data. METHODS: Patients with advanced NSCLC with disease progression following ≥2 previous systemic regimens received durvalumab 10 mg/kg every 2 weeks. The primary endpoint was objective response rate among patients with increased PD-L1 expression (defined as ≥25 % or ≥90 % of tumour cells [TCs], cohort-dependent). Secondary endpoints included OS and safety. RESULTS: 444 patients received durvalumab: 111 in Cohort 1 (EGFR+/ALK+), 265 in Cohort 2 (EGFR-/ALK-), and 68 in Cohort 3 (EGFR-/ALK-; TC ≥ 90 %). Median (95 % CI) OS was 13.3 months (6.3-24.5) in patients with EGFR+/ALK+ NSCLC with TC ≥ 25 %, 10.9 months (8.6-13.6) in patients with EGFR-/ALK- NSCLC with TC ≥ 25 %, and 13.2 months (5.9-not reached) in patients with EGFR-/ALK- NSCLC with TC ≥ 90 %. Median (95 % CI) OS was slightly shorter in patients with TC

Introduction: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. Methods: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. Results: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. Conclusions: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs. (C) 2020 Elsevier Ltd. All rights reserved.

Background Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. Methods These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. Results Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. Conclusions Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. Clinical trial registration NCT01403974; NCT01317420.

The introduction of licensed front-line immunotherapies has heralded a new era for the treatment of non-oncogene-addicted, advanced non-small cell lung cancer (NSCLC). Yet as with all evolutions in clinical management, changes in practice can outpace the availability of the clinical evidence needed to inform subsequent therapeutic decision making. At the time of writing, there is limited available evidence on the optimum therapeutic options after progression on immunotherapy. Further research is needed to define mechanisms of immunotherapy resistance in patients with advanced NSCLC, and to understand the implications for subsequent treatment response. Pending the availability of robust clinical data and proven therapeutic options to underpin an optimized therapeutic pathway after progression on immunotherapy, attention must turn to the potential utility of currently licensed agents and any available supporting clinical data in this setting. Within this context we review the mechanistic arguments and supporting evidence for the use of anti-angiogenic agents as a means of targeting immunosuppression within the tumor microenvironment. We consider whether VEGF inhibition may help to normalize the tumor vasculature and to address immunosuppression - reinstating, and potentially enhancing, the effect of subsequent therapies. We also highlight evidence needs and signpost ongoing trials that should enable current clinical opinion in this area to be replaced by robust, evidence-based guidance.

Background Genomic alterations studies in cell-free DNA (cfDNA) have increasing clinical use in oncology. Next-generation sequencing (NGS) technology provides the most complete mutational analysis, but nowadays limited data are available related to the comparison of results reported by different platforms. Here we compare two NGS panels for cfDNA: Oncomine™ Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific), suitable for clinical laboratories, and Guardant360® (GuardantHealth), with more genes targeted but only available in an outsourcing laboratory. Methods Peripheral blood was obtained from 16 advanced cancer patients in which Guardant360® (G360) was requested as part of their clinical assistance. Blood samples were sent to be analyzed with G360 panel, and an additional blood sample was drawn to obtain and analyze cfDNA with Oncomine™ Pan-Cancer (OM) panel in an Ion GeneStudio S5™ System. Results cfDNA analysis globally rendered 101 mutations. Regarding the 55/101 mutations claimed to be included by manufacturers in both panels, 17 mutations were reported only by G360, 10 only by OM and 28 by both. In those coincident cases, there was a high correlation between the variant allele fractions (VAFs) calculated with each panel (r = 0.979, p Conclusions In summary, G360 and OM can produce different mutational profile in the same sample, even in genes included in both panels, which is especially important if these mutations are potentially druggable.

Purpose ARCHER 1050, a randomized, open-label, phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non–small-cell lung cancer (NSCLC) and activating mutations in EGFR, reported significant improvement in progression-free survival with dacomitinib. The mature overall survival (OS) analysis for the intention-to-treat population is presented here. Patients and Methods In this multinational, multicenter study, patients age 18 years or older (≥ 20 years in Japan and Korea) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR (exon 19 deletion or exon 21 L858R) were enrolled and randomly assigned in a 1:1 manner to dacomitinib (n = 227) or gefitinib (n = 225). Random assignment was stratified by race (Japanese, Chinese, other East Asian, or non-Asian) and EGFR mutation type. The final OS analysis was conducted with a data cutoff date of February 17, 2017; at that time 220 deaths (48.7%) were observed. Results During a median follow-up time of 31.3 months, 103 (45.4%) and 117 (52.0%) deaths occurred in the dacomitinib and gefitinib arms, respectively. The estimated hazard ratio for OS was 0.760 (95% CI, 0.582 to 0.993; two-sided P = .044). The median OS was 34.1 months with dacomitinib versus 26.8 months with gefitinib. The OS probabilities at 30 months were 56.2% and 46.3% with dacomitinib and gefitinib, respectively. Preliminary subgroup analyses for OS that are based on baseline characteristics were consistent with the primary OS analysis. Conclusion In patients with advanced NSCLC and EGFR activating mutations, dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) to show significant improvement in OS in a phase III randomized study compared with a standard-of-care TKI. Dacomitinib should be considered one of the standard treatment options for these patients.

Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination’s maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard “3 + 3” design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29–155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013–001750-96. Study GEICAM/2012–12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376

Summary Background Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR -mutation-positive non-small-cell lung cancer (NSCLC). Methods In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. Findings Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3–23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1–16·6) in the dacomitinib group and 9·2 months (9·1–11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47–0·74; p vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). Interpretation Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR -mutation-positive NSCLC and should be considered as a new treatment option for this population. Funding SFJ Pharmaceuticals Group and Pfizer.

This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression-free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.-7.1]; Pem+Cis, 1.5 months [1.3-2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775.

Background Guidelines provide treatment recommendations for advanced non–small-cell lung cancer (NSCLC), but physicians must also consider other factors. We surveyed physicians treating NSCLC to determine their therapy goals, drivers of treatment choice, current prescribing behavior, and therapy expectations. Materials and Methods In 2015, an online survey was conducted of 500 pulmonologists/oncologists treating lung adenocarcinoma in Germany, France, Italy, Spain, and the United Kingdom, comprising screening and therapy decision questions. Results On average, physicians had 14.7 years of experience and treated 79 patients/3 months with stage IIIb/IV NSCLC. In patients with Eastern Cooperative Oncology Group (ECOG) 0-1, "prolonged survival/extending life" was the main therapy goal of physicians for first- (63%) and second-line (40%) patients; improvement in quality of life (QoL) was the main goal of 14% of physicians for second-line patients. For patients with ECOG ≥2, the main goal of second-line therapy was improvement in QoL (26%) or tumor-related symptoms (23%). Most (57%) physicians strongly agreed that they preferred a second-line treatment that extends overall survival (OS) while maintaining QoL; their greatest dissatisfaction with available second-line treatment options was the inability to "stop tumor progression over the long term" (66%). Physicians expected new therapies to become available within 12 months that would provide improvements in progression-free survival (83%) or OS (69%). Conclusion OS is important for second-line treatments in patients with stage IIIb/IV NSCLC, although QoL improvements should not be underestimated. This survey highlights the wait faced by patients and physicians as treatments transition from clinical trials to clinical practice.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:15 issue:2 pages:274-287 ispartof: location:AUSTRIA, Vienna status: published

PURPOSE: Both nintedanib/docetaxel and anti-PD-1/PD-L1 immunotherapies have demonstrated efficacy as second-line treatment of patients with advanced lung adenocarcinoma. This is the first report on the efficacy of the nintedanib/docetaxel combination following first-line platinum-based chemotherapy and subsequent immunotherapy in a real-world setting. METHODS/PATIENTS: From May 2014 to December 2015, 390 patients in 108 Spanish centres enrolled in the nintedanib named patient use program. Inclusion criteria were advanced lung adenocarcinoma with progressive disease following at least one line of platinum-based doublet chemotherapy. The objective was to evaluate the efficacy of the nintedanib/docetaxel combination in patients who also received immunotherapy. RESULTS: Eleven patients met the inclusion criteria; with a median age of 67 years. PD-L1 expression was positive in six patients. Median progression-free survival (PFS) of first-line platinum-based chemotherapy was 3.3 months (95% CI 1.9-4.6). Second-line immunotherapy was pembrolizumab (36.5%), atezolizumab (36.5%) or nivolumab (27%). Median PFS of second-line immunotherapy was 2.3 months (95% CI 0-6.1). The overall response rate (ORR) to second-line immunotherapy was 18% with a disease-control rate (DCR) of 45%. Median PFS of nintedanib/docetaxel was 3.2 months (95% CI 1.9-4.5). Best response was partial response in four patients (36%), stable disease in five patients (46%), and progressive disease in two patients (18%), for an ORR of 36% and a DCR of 82%. CONCLUSION: Our experience suggests an encouraging efficacy of nintedanib/docetaxel in patients with adenocarcinoma NSCLC pretreated with platinum-based doublet chemotherapy and immunotherapy, reinforcing the importance of an optimal therapeutic sequence for managing advanced lung adenocarcinoma.

High incidence and prognostic relevance of thromboembolic disease in patients with ALK-rearranged NSCLCs

School truancy, defined as any intentional unauthorized or illegal absence from school, influences, and is influenced by, multiple academic, health, and social factors. This project sought to describe how truancy-reduction systems are operating in Los Angeles County and identify the highest priority policy and program options to effectively address truancy. The Department of Public Health convened an expert panel and collected data through literature review, key informant interviews, focus groups, and surveys. Results describe the interconnected players that are working to address truancy. Recommendations focus on increasing school-based efforts, identifying innovative ways to address students' and families' physical and mental health needs, enhancing coordination across partners and elevating their commitment, expanding evidence-based programs, and enhancing data collection efforts to better identify additional effective strategies. Other jurisdictions can build off our prioritization framework to describe the current state of their systems and identify promising programs to augment system functioning.

9066 Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator-assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. > = 2), brain metastases (yes vs. no) or CD74-rearrangement ( CD74- ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.

Purpose In the phase III PARAMOUNT trial, pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo (hazard ratio [HR], 0.62; 95% CI, 0.49 to 0.79; P < .001). Here we report final overall survival (OS) and updated safety data. Patients and Methods In all, 939 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) received four cycles of pemetrexed-cisplatin induction therapy; then, 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were randomly assigned (2:1) to maintenance pemetrexed (500 mg/m2 on day 1 of 21-day cycles; n = 359) or placebo (n = 180). Log-rank test compared OS between arms as measured from random assignment (α = .0498). Results The mean number of maintenance cycles was 7.9 (range, one to 44) for pemetrexed and 5.0 (range, one to 38) for placebo. After 397 deaths (pemetrexed, 71%; placebo, 78%) and a median follow-up of 24.3 months for alive patients (95% CI, 23.2 to 25.1 months), pemetrexed therapy resulted in a statistically significant 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64 to 0.96; P = .0195; median OS: pemetrexed, 13.9 months; placebo, 11.0 months). Survival on pemetrexed was consistently improved for all patient subgroups, including induction response: complete/partial responders (n = 234) OS HR, 0.81; 95% CI, 0.59 to 1.11 and stable disease (n = 285) OS HR, 0.76; 95% CI, 0.57 to 1.01). Postdiscontinuation therapy use was similar: pemetrexed, 64%; placebo, 72%. No new safety findings emerged. Drug-related grade 3 to 4 anemia, fatigue, and neutropenia were significantly higher in pemetrexed-treated patients. Conclusion Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo, further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are smoking-related diseases, with the presence of COPD itself increasing the risk for development of LC, probably owing to underlying inflammation. LC is typically detected at late stages of the disease and carries a poor prognosis. There is an unmet need for methods to facilitate the early detection of LC in high-risk subjects such as smokers.The expression of inflammatory proteins in bronchoalveolar lavage fluid (BALF) samples was studied by antibody arrays in a prospective cohort of 60 smokers of more than 30 pack-years divided into four groups (control, patients with LC, patients with COPD, and patients with LC plus COPD). Relevant biomarkers were validated by Western blot. Additional validation with enzyme-linked immunosorbent assay (ELISA) was carried out on two independent controlled cohorts of 139 patients (control, patients with LC, patients with COPD, and patients with LC plus COPD) and 160 patients (control and patients with LC of all histological types).A total of 16 differentially expressed proteins in samples from patients with LC, COPD, and LC plus COPD were identified by antibody arrays and validated by Western blot and ELISA. C-C motif chemokine ligand 1 (CCL-1) and interleukin-11 (IL)-11 were selectively expressed in samples from patients with adenocarcinoma with or without COPD (p0.005). These proteins exhibited a remarkable diagnostic performance for lung adenocarcinoma in an independent cohort of 139 patients. Receiver operating characteristic curves showed that the optimum diagnostic cutoff value for IL-11 was 42 pg/mL (area under the curve = 0.93 [95% confidence interval: 0.896-0.975], sensitivity 90%, specificity 86%), whereas for CCL-1 it was 39.5 pg/mL (0.83 [95% confidence interval: 0.749-0.902], sensitivity 83%, and specificity 74%). Further validation of the ELISA biomarkers at the aforementioned cutoffs was performed in an additional cohort of 160 patients (20 controls, 66 patients with LC, and 74 patients with LC plus COPD). There was a significant correlation between BALF levels of IL-11 and CCL-1 (rIL-11 and CCL-1 are highly specific biomarkers with great accuracy for the diagnosis of lung adenocarcinoma in BALF specimens. Further study of these proteins as markers for the early diagnosis and screening of plasma and other biological materials is warranted.

The European Society for Medical Oncology (ESMO) is one of the leading societies of oncology professionals in the world. Approximately 30% of the 13 000 ESMO members are below the age of 40 and thus meet the society's definition of young oncologists (YOs). ESMO has identified the training and development of YOs as a priority and has therefore established a comprehensive career development programme. This includes a leadership development programme to help identify and develop the future leaders in oncology. Well-trained and highly motivated future generations of multidisciplinary oncologists are essential to ensure the optimal evolution of the field of oncology with the ultimate goal of providing the best possible care to patients with cancer. ESMO's career development portfolio is managed and continuously optimised by several dedicated committees composed of ESMO officers and is directly supervised by the ESMO Executive Board and the ESMO President. It offers unique resources for YOs at all stages of training and includes a broad variety of fellowship opportunities, educational courses, scientific meetings, publications and resources. In this article, we provide an overview of the activities and career development opportunities provided by ESMO to the next generation of oncologists., SCOPUS: re.j, info:eu-repo/semantics/published

IntroductionIn a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non–small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results.MethodsAfter four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m2 plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D).ResultsFrequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p

The fibroblast growth factor (FGF) signaling pathway is implicated as a key driver of tumor progression and growth via the dysregulation of cell proliferation, differentiation, survival, and angiogenesis in multiple tumor types. In addition, it may serve as a mechanism of resistance to antivascular endothelial growth factor targeted therapy. As such this pathway has emerged as a relevant therapeutic target, and several agents that can inhibit or modulate its signaling are in various stages of development. This review will summarize the current clinical status of agents targeting FGF receptors. In addition, strategies to accelerate the clinical development of these targeted agents will be presented.

Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G1 anti–epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patients), infusion-related reactions (77%), and hypomagnesemia (56%). Grades 3 and 4 AEs were rash (grade 3, 25%), infusion-related reaction (grade 3, 7%; grade 4, 1%), paronychia (grade 3, 3%), and hypomagnesemia (grade 3, 1%; grade 4, 1%). RG7160 exposure increased greater than proportionally over the 50- to 400-mg dose range (with greater than proportional decline in clearance) and approximately dose proportionally above 400 mg (where clearance plateaued). A marked reduction in circulating natural killer cells and increased infiltration of immune effector cells into skin rash were seen. Clinical efficacy included one complete response and two partial responses in patients with colorectal cancer (including one with KRAS mutation) and disease stabilization in 27 patients. Conclusion RG7160 had an acceptable safety profile with manageable AEs and demonstrated promising efficacy in this heavily pretreated patient cohort. On the basis of modeling of available PK parameters, the RG7160 dose selected for part two of this study is 1,400 mg on days 1 and 8 followed by 1,400 mg every 2 weeks.