First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. METHODS: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. FINDINGS: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). INTERPRETATION: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. FUNDING: Bristol Myers Squibb.

Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study.

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). FUNDING: Epizyme.

Evaluation of a National Comprehensive Cancer Network Guidelines-Based Decision Support Tool in Patients With Non-Small Cell Lung Cancer: A Nonrandomized Clinical Trial.

Importance: The association of guideline-based decision support with the quality of care in patients with non-small cell lung cancer (NSCLC) is not known. Objective: To evaluate the association of exposure to the National Comprehensive Cancer Center (NCCN) guidelines with guideline-concordant care and patients' decisional conflict. Design, Setting, and Participants: A nonrandomized clinical trial, conducted at a tertiary care academic institution, enrolled patients from February 23, 2015, to September 28, 2017. Data analysis was conducted from July 19, 2019, to April 22, 2020. A cohort of 76 patients with NSCLC seen at diagnosis or disease progression and a retrospective cohort of 157 patients treated before the trial were included. Adherence to 6 NCCN recommendations were evaluated: (1) smoking cessation counseling, (2) adjuvant chemotherapy for patients with stage IB to IIB NSCLC after surgery, (3) pathologic mediastinal staging in patients with stage III NSCLC before surgery, (4) pathologic mediastinal staging in patients with stage III NSCLC before nonsurgical treatment, (5) definitive chemoradiotherapy for patients with stage III NSCLC not having surgery, and (6) molecular testing for epidermal growth factor receptor and anaplastic lymphoma kinase alterations for patients with stage IV NSCLC. Subgroup analysis was conducted to compare the rates of guideline concordance between the prospective and retrospective cohorts. Secondary end points included decisional conflict and satisfaction. Interventions: An online tool customizing the NCCN guidelines to patients' clinical and pathologic features was used during consultation, facilitated by a trained coordinator. Main Outcomes and Measures: Concordance of practice with 6 NCCN treatment recommendations on NSCLC and patients' decisional conflict. Results: Of the 76 patients with NSCLC, 44 were men (57.9%), median age at diagnosis was 68 years (interquartile range [IQR], 41-87 years), and 59 patients (77.6%) had adenocarcinoma. In the retrospective cohort, 91 of 157 patients (58.0%) were men, median age at diagnosis was 66 years (IQR, 61-65 years), and 105 patients (66.9%) had adenocarcinoma. After the intervention, patients received more smoking cessation counseling (4 of 5 [80.0%] vs 1 of 24 [4.2%], P < .001) and less adjuvant chemotherapy (0 of 7 vs 7 of 11 [63.6%]; P = .012). There was no significant change in mutation testing of non-squamous cell stage IV disease (20 of 20 [100%] vs 48 of 57 [84.2%]; P = .10). There was no significant change in pathologic mediastinal staging or initial chemoradiotherapy for patients with stage III disease. After consultation with the tool, decisional conflict scores improved by a median of 20 points (IQR, 3-34; P < .001). Conclusions and Relevance: The findings of this study suggest that exposure to the NCCN guidelines is associated with increased guideline-concordant care for 2 of 6 preselected recommendations and improvement in decisional conflict. Trial Registration: ClinicalTrials.gov Identifier: NCT03982459.

Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express mesothelin, a tumor-associated antigen highly expressed in MPM. CRS-207 induces antitumor immune responses and increases susceptibility of neoplastic cells to immune-mediated killing. PATIENTS AND METHODS: Patients with unresectable MPM, ECOG 0 or 1, and adequate organ and pulmonary function were enrolled in this multicenter, open-label phase Ib study. They received two priming infusions of 1 × 109 CFU CRS-207, followed by pemetrexed/cisplatin chemotherapy, and CRS-207 booster infusions. Primary objectives were safety and induction of immune response. Secondary/exploratory objectives included tumor response, progression-free survival (PFS), overall survival (OS), immune subset analysis, and gene-expression profiling of tumor. RESULTS: Of 35 evaluable patients, 89% (31/35) had disease control with one complete response (3%), 19 partial responses (54%), and 10 stable disease (29%). The estimated median duration of response was 5.0 months (95% CI, 3.9-11.5). The median PFS and OS were 7.5 (95% CI, 7.0-9.9) and 14.7 (95% CI, 11.2-21.9) months, respectively. Tumor size reduction was observed post-CRS-207 infusion prior to chemotherapy in 11 of 35 (31%) patients. No unexpected treatment-related serious adverse events or deaths were observed. IHC analysis of pre- and post-CRS-207 treatment tumor biopsies revealed possible reinvigoration and proliferation of T cells, increased infiltration of dendritic and natural killer cells, increased CD8:Treg ratio, and a shift from immunosuppressive M2-like to proinflammatory M1-like macrophages following CRS-207 administration. CONCLUSIONS: Combination of CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients.

Incorporation of a Molecular Prognostic Classifier Improves Conventional Non-Small Cell Lung Cancer Staging.

INTRODUCTION: Despite adoption of molecular biomarkers in the management of NSCLC, the recently adopted eighth edition of the TNM staging system utilized only clinicopathologic characteristics and validated improvement in risk stratification of early-stage disease has remained elusive. We therefore evaluated the integration of a clinically validated molecular prognostic classifier into conventional staging. METHODS: A novel staging system, the TNMB (with the B denoting biology) system, which integrates a 14-gene molecular prognostic classifier into the eighth edition of the TNM staging system, was developed by using data from 321 patients with NSCLC at the University of California, San Francisco. The TNMB staging system was subsequently validated in an independent, multicenter cohort of 1373 patients, and its implementation was compared with adoption of the seventh and eighth edition staging systems utilizing metrics of reclassification. RESULTS: Compared with staging according to the eighth edition of the TNM system, the TNMB staging system enhanced the identification of high-risk patients, with a net reclassification improvement of 0.33 (95% confidence interval [CI]: 0.24-0.41). It better predicted differences in survival, with a relative integrated discrimination improvement of 22.1% (95% CI: 8.8%-35.3%), and it improved agreement between observed and predicted survival, with a decrease in the reclassification calibration statistic of from 39 to 21. The seventh and eighth editions failed to change the net reclassification improvement (0.01 [95% CI: -0.04 to 0.03] and 0.03 [95% CI: 0.00 to 0.06], respectively) or relative integrated discrimination improvement (2.1% [95% CI: -5.8 to 9.9] and -2.5% [95% CI: -17.6 to 12.4], respectively); in addition, the eighth edition worsened calibration, with an increase in the reclassification calibration statistic from 23 to 25. CONCLUSIONS: Incorporation of a molecular prognostic classifier significantly improved identification of high-risk patients and survival predictions compared with when conventional staging is used. The TNMB staging system may lead to improved survival of early-stage disease through more effective application of adjuvant therapy.

Distinct attentional function profiles in older adults receiving cancer chemotherapy.

PURPOSE: While attentional function is an extremely important patient outcome for older adults, research on changes in function in this group is extremely limited. The purposes of this study were to: identify subgroups of older patients (i.e., latent growth classes) based on changes in their level of self-reported attentional function; determine which demographic and clinical characteristics were associated with subgroup membership; and determine if these subgroups differed on quality of life (QOL) outcomes. METHODS: Older oncology outpatients (n = 365) who were assessed for changes in attention and working memory using the Attentional Function Index a total of six times over two cycles of chemotherapy (CTX). QOL was assessed using the Medical Outcomes Study-Short Form 12 and the QOL-Patient Version Scale. Latent profile analysis (LPA) was used to identify subgroups of older adults with distinct attentional function profiles. RESULTS: Three distinct attentional functional profiles were identified (i.e., low, moderate, and high attentional function). Compared to the high class, older adults in the low and moderate attentional function classes had lower functional status scores, a worse comorbidity profile and were more likely to be diagnosed with depression. In addition, QOL scores followed an expected pattern (low class < moderate class < high attentional function class). CONCLUSIONS: Three distinct attentional function profiles were identified among a relatively large sample of older adults undergoing CTX. The phenotypic characteristics associated with membership in the low and moderate latent classes can be used by clinicians to identify high risk patients.

Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline.

Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .

Adjuvant Chemotherapy Guided by Molecular Profiling and Improved Outcomes in Early Stage, Non-Small-Cell Lung Cancer.

INTRODUCTION: Many early stage non-small-cell lung cancer (NSCLC) patients who are not considered candidates for adjuvant treatment according to current guidelines do harbor occult metastasis, and have disease recurrence despite complete resection. Although National Comprehensive Cancer Network (NCCN) guidelines suggest clinicopathologic characteristics to identify high-risk patients for adjuvant intervention, molecular profiling more accurately predicts 5-year survival. Early evidence of clinical benefit from application of this molecular-based management strategy, however, has not been reported. PATIENTS AND METHODS: An internationally validated, prognostic, 14-gene quantitative polymerase chain reaction expression assay was used to stratify risk prospectively in 100 consecutive patients with stage IA, IB, and IIA nonsquamous NSCLC. Kaplan-Meyer estimates, log rank analysis, and Cox regression were used to compare disease-free survival (DFS) between high-risk patients who did or did not elect adjuvant chemotherapy. RESULTS: Forty-eight patients (48%) were deemed high-risk according to molecular testing and 36 (36%) met NCCN high-risk criteria; risk designations were discordant in 34 (34%) of all patients. Estimated 5-year DFS was 48.9% among molecular high-risk patients who did not undertake adjuvant chemotherapy, 93.8% among untreated molecular low-risk patients, and 91.7% in molecular high-risk patients who did undergo chemotherapy (P = .004). In contrast, DFS was only 75.2% in untreated NCCN low-risk patients, and 61.9% in untreated NCCN high-risk patients (P = .183). CONCLUSION: This prospective, nonrandomized study provides initial evidence that high-risk designation according to the 14-gene prognostic assay also predicts benefit from adjuvant chemotherapy for very early stage NSCLC, and further supports the superiority of molecular stratification over current NCCN criteria at identifying high-risk patients.

Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies.

Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.

NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016.

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

Intraoperative Radiotherapy in the Management of Locally Recurrent Extremity Soft Tissue Sarcoma.

Purpose. To investigate the efficacy and morbidity of limb-sparing surgery with intraoperative radiotherapy (IORT) for patients with locally recurrent extremity soft tissue sarcoma (ESTS). Methods and Materials. Twenty-six consecutively treated patients were identified in a single institution retrospective analysis of patients with locally recurrent ESTS treated with IORT following salvage limb-sparing resection from May 2000 to July 2011. Fifteen (58%) patients received external beam radiotherapy (EBRT) prior to recurrence (median dose 63 Gy), while 11 (42%) patients received EBRT following IORT (median dose 52 Gy). The Kaplan-Meier product limit method was used to estimate disease control and survival and subsets were compared using a log rank statistic, Cox's regression model was used to determine independent predictors of disease outcome, and toxicity was reported according to CTCAE v4.0 guidelines. Results. With a median duration of follow-up from surgery and IORT of 34.9 months (range: 4 to 139 mos.), 10 patients developed a local recurrence with 4 subsequently undergoing amputation. The 5-year estimate for local control (LC) was 58% (95% CI: 36-75%), for amputation-free was 81% (95% CI: 57-93%), for metastasis-free control (MFC) was 56% (95% CI: 31-75%), for disease-free survival (DFS) was 35% (95% CI: 17-54%), and for overall survival (OS) was 50% (95% CI: 24-71%). Prior EBRT did not appear to influence disease control (LC, p = 0.74; MFC, p = 0.66) or survival (DFS, p = 0.16; OS, p = 0.58). Grade 3 or higher acute and late toxicities were reported for 6 (23%) and 8 (31%) patients, respectively. The frequency of both acute and late grade 3 or higher toxicities occurred equally between patients who received EBRT prior to or after IORT. Conclusions. IORT in combination with oncologic resection of recurrent ESTS yields good rates of local control and limb-salvage with acceptable morbidity. Within the limitations of small subsets, these data suggest that prior EBRT does not significantly influence disease control or toxicity.

Non-Small Cell Lung Cancer, Version 6.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

The impact of a fourteen-gene molecular assay on physician treatment decisions in non-small-cell lung cancer.

BACKGROUND: Five-year survival in early-stage, non-squamous, non-small-cell lung cancer (NSCLC) remains poor compared with other solid tumors, even after complete resection. Post-operative management depends on prognostic staging to identify individuals at highest risk for death, and therefore with the greatest need for further intervention. A 14-gene quantitative RT-PCR test successfully differentiates stage I-III NSCLC patients who are at high-, intermediate-, or low-risk for 5-year mortality. This study assesses the impact of the assay's prognostic information on physician decisions regarding adjuvant chemotherapy. METHODS: We invited 115 physicians who ordered the test to participate in an on-line survey. The primary outcome measure was the proportion of patients with different pre- and post-test chemotherapy recommendations. RESULTS: Fifty-eight physicians (50 %) completed the survey on 120 stage I or II NSCLC patients. Ninety-one patients (76 %) had stage I lung cancer; 27 (23 %), 39 (33 %), and 54 (45 %) patients had low-, intermediate-, and high-risk scores, respectively. Physicians' chemotherapy recommendations were changed post-testing in 37 patients (30.8 %, 95 % CI 22.7-39.9 %). High-risk patients were more likely to have a change in treatment recommendation (44.4 %, 95 % CI 30.9-58.6 %) than low risk patients (3.7 %, 95 % CI 0.1-19.0 %); a substantial number of changes were observed in both stage I (33.0 %, 95 % CI 23.5-43.6 %) and stage II (24.1 %, 95 % CI 10.3-43.5 %). CONCLUSIONS: Our data show that the assay resulted in a significant impact on physician treatment decisions in early-stage NSCLC, and that the nature of treatment changes generally correlated with the test's assessment of risk.

Non-small cell lung cancer, version 1.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

Prognostic molecular assay might improve identification of patients at risk for recurrence in early-stage non-small-cell lung cancer.

INTRODUCTION: Adjuvant chemotherapy improves survival for some patients with NSCLC and is recommended in NCCN guidelines for stage Ib to IIa patients with certain "high-risk" characteristics. An internationally validated, 14-gene expression assay has been shown to better stratify mortality risk in nonsquamous NSCLC than either conventional staging or these high risk clinicopathologic features. PATIENTS AND METHODS: A blinded chart review of 52 patients with prospective molecular risk stratification using the 14-gene test compared recurrence outcomes with a mean follow-up of 15.2 ± 11.7 months of patients with high- or low-risk determined according to either NCCN criteria or the molecular assay. RESULTS: Molecular risk assessment was discordant from NCCN criteria in 14 of 23 patients in stages Ib and IIa (61%). Recurrence was not observed among any of 31 molecular intermediate- or low-risk patients, including 10 NCCN high-risk patients, whereas 2 of 6 recurrences (33%) occurred among NCCN low-risk patients. Recurrences in stages I or IIa were seen in 2 of 18 NCCN high-risk patients (11%; both were stage IIa and both received a high-risk molecular designation), and in 4 of 18 patients (22%) with a high-risk molecular score, including 1 stage Ia and 1 stage Ib patient. CONCLUSION: This small cohort study suggests that a 14-gene prognostic assay more accurately stratifies risk among early-stage NSCLC patients than current NCCN criteria. NCCN guidelines already advocate risk stratification within tumor, node, metastases stages. This molecular assay has clinical utility in better identifying high-risk patients and might improve NCCN adjuvant chemotherapy recommendations.

Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma.

PURPOSE: Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM. EXPERIMENTAL DESIGN: In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety. RESULTS: Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1-6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1-62.3)], median PFS was 6.1 months (95% CI, 5.8-6.4), and median OS was 14.8 months (95% CI, 12.4-18.5) with 29 patients alive at data cut-off. CONCLUSIONS: Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis.

A novel use of foley catheters to prevent injury to the pelvic viscera during stereotactic radiosurgery for undifferentiated pleomorphic sarcoma of the sacrum.

The use of a Foley catheter to protect the small and large bowel from radiation injury during stereotactic radiosurgery to the spine has not previously been described in the surgical literature. Many spine tumors should be treated with stereotactic radiosurgery as opposed to external beam therapy, yet the proximity of visceral organs may preclude adequate target delivery of radiation. We describe the novel use of Foley catheters placed intraoperatively to displace the bowel during stereotactic radiosurgery, allowing for a full radiation dose to be safely delivered to the tumor. The advantages of this technique are the low cost, the ability to place multiple catheters intraoperatively, and the ability to withdraw all the catheters after radiation without the need for reoperation.

A phase II, open-label study of ramucirumab in combination with paclitaxel and carboplatin as first-line therapy in patients with stage IIIB/IV non-small-cell lung cancer.

INTRODUCTION: The objective of this study was to determine whether the addition of ramucirumab to first-line paclitaxel-carboplatin chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) resulted in a 6-month progression-free survival (PFS) rate that compares favorably with the historic rate for bevacizumab combined with paclitaxel-carboplatin in this patient population. METHODS: In this phase II, single-arm, open-label, multicenter study, 40 patients with advanced NSCLC received ramucirumab (10 mg/kg intravenous [IV]) followed by paclitaxel (200 mg/m IV) and carboplatin area under the curve = 6 on day 1 every 21 days as first-line therapy. Therapy continued for up to six cycles. Patients not experiencing withdrawal criteria may have continued ramucirumab monotherapy every 3 weeks. The primary endpoint was PFS at 6 months, with 80% power to detect a 6-month PFS rate of at least 55%. RESULTS: The 6-month PFS rate was 59.0% and the objective response rate was 55.0%. The most common treatment-related adverse events were fatigue, peripheral neuropathy, nausea, epistaxis, and myalgia. Single-nucleotide polymorphism (SNP) rs2981582 on the FGFR-2gene had significant associations with improved overall survival, PFS, and best overall response (p values without multiplicity adjustment were 0.0059, 0.0429, and 0.0392, respectively). CONCLUSION: Ramucirumab in combination with paclitaxel-carboplatin resulted in a 6-month PFS rate and safety profile that compared favorably with the historical control. In addition, no deaths were associated with this treatment. Furthermore, we describe an association of SNP on FGFR-2 gene with survival and response. These findings warrant further clinical investigation in patients with NSCLC.