bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of adjuvant chemotherapy in non-metastatic node positive bronchial neuroendocrine tumors (BNET).
Authors: Westin Gustavo Figueiredo Marcondes , Alsidawi Samer , Leventakos Konstantinos , Halfdanarson Thorvardur Ragnar , Molina Julian R.
Published: September 2018

8533

Background: BNET are a rare and frequently indolent group of neoplasms. Lobectomy is frequently done for patients with non-metastatic disease, and the role of adjuvant chemotherapy for patients with node positive disease (N+) is debated. Methods: Utilizing the National Cancer Database from 2004-2012 we identified 1682 patients with N+ non-metastatic BNET. All patients underwent primary resection, had pathologically confirmed diagnosis, complete follow up data, and were alive > 30 days following surgery. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used to compare 2 groups of patients that differed based on receiving or not adjuvant chemotherapy. Subgroup analyses were performed based on histologic subtypes. Cox proportional hazards was performed to control for age, sex, race, grade, surgical margins, type of surgery, year of diagnosis, Charlson/Deyo Score, insurance, facility type, and location. Results: 651 patients with typical carcinoid (CT), 239 atypical carcinoid (ACT), 426 large cell neuroendocrine carcinoma (LCNEC), and 366 neuroendocrine carcinoma (NEC) were analyzed. The cohort median age was 61, and the female:male ratio was 1.8 for CT, ACT and NEC, and 1 for LCNEC 90% of patients were White and there were no significant differences amongst histologic subtypes. 6% of patients with CT received ADJ-CT, compared to 40% ACT, 42% NEC, and 70% LCNEC. In a multivariate analysis, only increasing age was associated with worse prognosis across all histologic subtypes, and non-academic facility for CT, and male sex for NEC. ADJ-CT was not associated with OS benefit for patients with ACT (HR 1.1; 95% CI 0.68-1.78; p:0.6), was associated with inferior OS in CT (HR: 3.8 (95% CI 1.9-7.0; p = 0.004) and NEC (HR: 2.15; 95% CI 1.5-3.0; p < 0.001), and may provide benefit for LCNEC (HR: 0.67; 95% CI 0.5-0.9; p = 0.009). Conclusions: Adjuvant chemotherapy was not associated with survival benefit for patients with node positive and non-metastatic BNET except for LCNEC, and may be harmful for patients with CT and NEC.
A nomogram for predicting post-operative cancer specific survival in AJCC 8th edition stage I NSCLC patients.
Authors: Liang Wenhua , Zeng Yuan , He Jianxing
Published: September 2018

8540

Background: The AJCC 8th edition staging system has moved 4-5 cm 7th edition stage Ib NSCLC to current stage IIa, thus theoretically all current stage I patients are not considered candidates for adjuvant therapy (ad-Tx). This study was to develop a clinical nomogram for predicting cancer specific survival (CSS) of the current stage I resected NSCLC to identify those with higher risk for cancer-related deaths and potentially benefiting from ad-Tx. Methods: NSCLC cases between 1998 and 2013 was extracted from the SEER database and were randomly divided into training (n = 23,496) and validation (n = 7,915) cohorts. We identified and integrated the recurrence-associated factors to build a nomogram. The model was subjected to bootstrap internal validation and independent validation. The predictive accuracy and discriminative ability were illustrated by calibration plots and concordance index (C-index). We determined the cut-off for high-risk group by matching the nomogram-predicted 5-year CSS with that of the current 4-5 cm stage IIa cases. Results: In multivariate analysis, independent factors for CSS were examined lymph node count ( < 16 vs. > = 16), tumor size, resection scope (lobectomy/segmentectomy/wedge resection), differentiation grade, histology (squamous vs. non-squamous vs. former BAC with majority being AIS/MIA) and visceral pleural invasion, which were then integrated into the model (sex and age were not included due to lack of direction to ad-Tx selection). The calibration curves showed excellent agreement between nomogram prediction and actual observation. The C-index of the nomogram was higher than that of staging system (Ia1, Ia2, Ia3, Ib) (training set, 0.60 vs. 0.56, P < 0.01; validation set, 0.60 vs. 0.57, P < 0.01). Specifically, 21.5% stage Ib patients (8.8% of all stage I) were categorized into high risk group (score > 29.5) and had inferior CSS compared with 4-5 cm stage IIa patients. Conclusions: We established a nomogram that can individually predict CSS for 8th edition stage I NSCLC. By this model, we identified a subset of patients with relatively high risk for recurrence. Further study to determine the impact of postoperative ad-Tx on these high risk patients is undergoing.
Short- and long-term outcomes of early stage non-small cell lung cancer (NSCLC) surgery.
Authors: Kelley Michael J. , Harpole David , Williams Christina D.
Published: September 2018

8544

Background: The goal of this study was to determine patient factors associated with short- vs long-term survival after surgery for stage I/II NSCLC and assess the distribution of causes of death over time. Methods: Using the VA Central Cancer Registry, we identified patients diagnosed 2001-2005 with stage I/II NSCLC who had surgery and survived 30 days after resection. We used multivariate logistic regression models to determine the impact of patient characteristics on 1 year (1Y), 5 year (5Y), and 10 year (10Y) mortality. We compared causes of death at 1Y versus 5Y after diagnosis. Results: The analysis included 4,693 patients. Among these patients, the 1Y, 5Y, and 10Y overall survival (OS) rates were 87%, 45%, and 22%, respectively. 50% of patients alive at 5 year survived to 10 years. For each survival time period, highest survival rates were among patients who were younger (≤65), had stage I disease, had lobectomy, and had fewer comorbidities (all p < 0.0001). Significant differences in 1Y and 10Y OS were noted for histology, with highest 1Y OS among adenocarcinoma (88%) and squamous cell (87%) and highest 10Y OS among large cell (28%) and adenocarcinoma (25%). Racial differences were only observed in 10Y OS (whites 22%, blacks 26%, p = 0.01). In multivariate analyses, age > 65, stage II disease, surgery other than lobectomy, and ≥3 comorbidities were associated with increased likelihood of 1Y, 5Y, and 10Y mortality. Large cell and other histology were the only additional significant predictors of 1Y mortality [OR: 1.94 (1.33-2.84) and OR:1.36 (1.05-1.77), respectively], and squamous cell histology was a significant predictor of 10Y mortality [OR: 1.19 (1.02-1.40)] relative to adenocarcinoma. Among patients who died within 1 year of diagnosis (n = 616), the primary causes of death were lung cancer (63%), cardiovascular disease (10%), other cancer (8%), respiratory disease (3%), and other causes (15). The contribution of these causes of 5Y mortality (n = 2602) were 60%, 11%, 10%, 4%, and 12%, respectively. Conclusions: Half of patients alive at 5Y after resection of stage I/II NSCLC were alive at 10Y. 10Y survival is associated with younger age, earlier stage, non-squamous histology, lobectomy, and fewer comorbidities, but not race.
Effect of FAK inhibitor defactinib on tumor immune changes and tumor reductions in a phase II window of opportunity study in malignant pleural mesothelioma (MPM).
Authors: Bueno Raphael , Gill Ritu R. , Lizotte Patrick H. , Sprott Kam , Jackman David Michael , Barlow Julianne , Sharma Sristi , Yeap Beow Y. , Chirieac Lucian R. , Lebenthal Abraham , Cavanaugh Megan , Rode Amanda J , Kirschmeier Paul , Kwiatkowski David J. , Wong Kwok-Kin , Richards William G. , Weaver David T.
Published: September 2018

8555

Background: Defactinib is an oral Focal Adhesion Kinase (FAK) inhibitor with preclinical activity in MPM. We assessed responses to defactinib treatment prior to planned surgical resection in naive patients with MPM. Methods: Three cohorts of 10 participants each received defactinib 400mg BID for 12, 35 and 21 days. Pre- and post-treatment blood, tumor biopsies and imaging were obtained for biomarker, immune cell and tumor response (modified RECIST, Tumor volume and SUV max) assessment. Toxicity was monitored for 30 days post treatment. Results: Between 12/2013 and 12/2017, 31 participants were registered at our center; 1 withdrew prior to intervention. Among 30 treated, 24 (80%) were male; median age 70 (47-83) years; surgery was EPP 7%, complete pleurectomy decortication (PD) 10%, extended PD 60%, partial PD 10%, unresectable 13%; MPM subtype was epithelioid 67%, biphasic 17%, sarcomatoid 17%. Expected complications of FAK inhibition, diagnostic/staging/operative procedures occurred in 83% (grade 1, 30%; grade 2, 43%; grade 3, 10%). Unexpected adverse events occurred in 77% (grade 1, 63%; grade 2, 20%; grade 3, 17% [wound-infection, prolonged QT interval, and hyperglycemia in 3% each; increased INR in 7%]; grade 5, 7% [due to progressive disease in 3%, intraoperative anaphylactoid reaction unrelated to the drug in 3%]). Objective partial response was observed in 13%, stable disease in 67%, progression in 17%. Tumor volume decreased 3-72% in 47% patients and increased 1-82% in 53%. SUV max decreased 3-69% in 50% and increased 1-61% in 50%. Biological correlates of treatment included target inhibition (75% pFAK reduction); tumor immune microenvironment changes: increased naïve (CD45RA+PD-1+CD69+) CD4 and CD8 T cells, reduced myeloid and Treg immuno-suppressive cells, reduced exhausted T cells (PD-1+CD69+), reduced peripheral MDSCs; and histological subtype change (pleomorphic or biphasic to epithelioid) in 13% of cases. Conclusions: Brief preoperative defactinib exposure was well tolerated, did not alter resectability or mortality compared to prior series, and showed evidence of therapeutic and immunomodulatory effects. Clinical trial information: NCT02004028.
Optimal thoracic radiation dose in limited stage small cell lung cancer.
Authors: Behera Madhusmita , Zhang Xinyan , Jiang Renjian , Pillai Rathi Narayana , Patel Pretesh R , Pakkala Suchita , Steuer Conor Ernst , Saba Nabil F. , Owonikoko Taofeek Kunle , Belani Chandra , Khuri Fadlo Raja , Curran Walter J , Ramalingam Suresh S. , Higgins Kristin Ann
Published: September 2018

8562

Background: Several studies have demonstrated improved overall survival in limited stage small cell lung cancer (LS-SCLC) patients (pts) with the addition of thoracic radiation therapy (RT) to chemotherapy. However, the optimal dose of thoracic RT when given daily, which is the most common practice pattern in the US, is yet to be firmly established. We analyzed outcomes associated with once-daily low dose (LD) RT relative to once-daily high dose (HD) RT for LS-SCLC in the National Cancer Data Base (NCDB). Methods: The NCDB was queried to capture pts with LS-SCLC treated with thoracic RT from 2004-2013. The cohort of pts that received 60 Gy (LD) was compared with the cohort that received RT ≥70 Gy (HD). The univariate (UV) association of overall survival (OS) was assessed using Cox proportional hazards models and log-rank tests. A multivariable (MV) Cox proportional hazard model and Kaplan-Meier (KM) analyses were performed to compare the LD vs. HD cohorts. Propensity score matching method was also implemented to reduce treatment selection bias. All analyses were performed using SAS Version 9.4. Results: A total of 5,159 pts (LD-3441; HD- 1718) were included in the analysis. Pt characteristics (LD/HD): median age 65/64 yrs; males 44/46%; whites 89/88%, academic centers 28/31%, Charlson-Deyo comorbidity score 0- 61%/64%; government insured 61/57%. 96% of pts in LD and 95% in HD cohorts had received chemotherapy. On MV analysis, no differences were found in OS between HD and LD RT(HR 0.98, p = 0.5), which was confirmed by KM analysis with 5-yr survival of 21% in LD vs 21.5% in HD (p = 0.8). On MV analysis of OS stratified by comorbidity score, LD was associated with significantly better survival compared to HD in pts with a comorbidity score of 1 and above (HR 0.87, p = 0.02). The LD group also had a better 5-yr survival than HD group in pts with higher comorbidity score (19% vs 14%, p = 0.01). No difference in survival was noted between the two cohorts for pts with no recorded comorbidities (HR 1.03, p = 0.6). Conclusions: In LS SCLC pts, survival was similar in pts who received daily RT of 60 Gy compared to those that received 70 Gy and above. In pts with worse performance status, those who received LD RT of 60 Gy had better survival.
Disparities in the management of stage I small cell lung carcinoma (SCLC): A National Cancer Database (NCDB) analysis.
Authors: Ahmed Zaheer , Grover Punita , Kujtan Lara , Kennedy Kevin F , Toor Muhammad Omer , Davis J Russell , Subramanian Janakiraman
Published: September 2018

8563

Background: Effective treatment of stage I SCLC requires both surgical resection and chemotherapy. We analyzed the National Cancer Database (NCDB) for the treatment patterns and disparities in the management of stage I SCLC. Methods: We identified patients with clinical stage I SCLC from the NCDB. Median and 5-year survival were calculated using Kaplan Meier analysis. Multivariable logistic regression model was used to determine the factors that can predict surgical resection. Results: We identified 4,849 patients with clinical stage I SCLC diagnosed between 2004 and 2012. We divided them into 4 treatment groups; surgical resection with chemotherapy (n = 774, 15.9%), surgical resection without chemotherapy (n = 423, 8.7%), non-surgical treatment (n = 2,978, 61.4%) and no treatment (n = 674, 13.9%). 5-year survival for each group was 47%, 36%, 22% and 11% respectively, ( p-value < 0.001). Among patients who underwent surgical resection, lobectomy (67.1%) was the most common procedure followed by sub-lobar resection (28.8%) and pneumonectomy (2.8%) with 5-year survival of 48%, 34% and 33% respectively, ( p-value < 0.001). Multivariate analysis identified that elderly (age ≥ 70) patients, African-Americans, patients with low income and Medicaid are less likely to undergo surgery, ( p-value < 0.001). Patients receiving treatment at academic cancer centers, right sided tumors and Charlson score ≥ 1 are more likely to receive surgery, ( p-value < 0.001). Conclusions: Despite better outcomes only 25% of patients undergo surgery for stage I SCLC. Over the years there has been only a modest increase in the proportion of patients undergoing resection. We have identified significant disparities in the treatment of patients with stage I SCLC. Our data clearly show the need to educate physicians on appropriate delivery of care for patients with stage I SCLC.
Trastuzumab and paclitaxel in patients (pts) with EGFR mutated non-small-cell lung cancer (NSCLC) that express HER2 after progression on EGFR TKI treatment.
Authors: De Langen Joop , Kuiper Justine Leonie , Thunnissen Erik , Hashemi Sayed MS , Monkhorst Kim , Smit Egbert F.
Published: September 2018

9042

Background: HER2 expression as well as amplification has been well recognized in tumor biopsies of pts with an EGFR mutation who developed EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumor responses. Methods: Single arm open label phase II study to study the safety and efficacy of paclitaxel-trastuzumab treatment in pts with a sensitizing EGFR mutation who show tumor membrane HER2 expression in a tumor biopsy (immunohistochemistry (IHC) ≥1) after progression on EGFR TKI treatment. Paclitaxel (60 mg/m2) and trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) were dosed weekly until disease progression or unacceptable toxicity. Primary end-point was tumor response according to RECIST. Sample size of 20 pts was calculated to evaluate the primary objective of ≥30% objective response rate. The study was deemed positive when ≥7 pts would show a partial or complete response. Results: 21 pts were enrolled from 08-2012 to 02-2017. 7 pts were exon 21 L858R positive and 14 exon 19 del. Last TKI was erlotinib (n = 6), gefitinib (n = 4), rociletinib (n = 3) or osimertinib (n = 8). Median HER2 IHC was 2+ (range 1-3). 17 pts were evaluable for response assessment, while 4 pts are awaiting their first response scan. The primary end-point was met with 7/17 pts (41%) showing a partial response. 2 pts showed stable disease, 7 progressive disease and 1 pt had clinical progression before CT response evaluation. Median duration of response was 9 (range 6-18) months with one ongoing responder. 3 pts experienced grade ≥3 toxicity, including fatigue, neuropathy and neutropenia. Upon progression on study treatment, all responding pts were rebiopsied. 4/6 samples were negative for HER2 (IHC), suggesting that the combination effectively targeted HER2 positive tumor cells. Conclusions: The study met its primary end-point. Paclitaxel-trastuzumab induces durable objective tumor responses in EGFR TKI pretreated pts with an activating EGFR mutation and HER2 bypass track activation. The treatment was well tolerated. Post-progression tumor biopsies showed absence of HER2 staining in the majority of pts, suggesting effective HER2 targeting. Clinical trial information: NCT02226757.
Phase 2 trial of chemotherapy followed by consolidative radiation therapy for initial treatment of oligometastatic NSCLC.
Authors: Ahmed Tamjeed , Urbanic James John , Hughes Ryan , D'Agostino Ralph , Lally Brian , Ruiz Jimmy , Chan Michael D , Gandhi Payal , Dothard Andy , Rusthoven Kyle , Bonomi Marcelo Raul , Blackstock A. William , Petty William J.
Published: September 2018

9047

Background: Unselected patients with stage 4 lung cancer who receive front line platinum based chemotherapy and maintenance chemotherapy have demonstrated a PFS less than 6 months with very few patients alive at 5 years. Patients with a small number of metastatic lesions may have a different biology, and aggressive local treatment of oligometastases is an active area of investigation. Methods: Patients were required to have stable disease or response after 3-6 cycles of platinum based chemotherapy and PS 0-2. Oligometastatic disease was defined as a maximum number of 5 metastatic lesions for all disease sites including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Results: 29 patients were enrolled between 10/2010 and 10/2015. 3 patients were excluded from analysis due to concerns regarding eligibility/treatment response. Despite closing early due to slow accrual, the study met its primary endpoint for success which was PFS greater than 6 months. The median PFS (95% CI) was 11.0 months (7.4-15.9 months) and the median OS was 22.2 months (13.3-45.7 months). The 1-year, 3-year, and 5-year OS were 73%, 35%, and 29%. Conclusions: Patients with oligometastatic NSCLC who received platinum based chemotherapy followed by oligometastatic consolidative radiation without maintenance chemotherapy demonstrated prolonged disease control and overall survival. Clinical trial information: nct01185639.
A phase II study of palbociclib (P) for previously treated cell cycle gene alteration positive patients (pts) with stage IV squamous cell lung cancer (SCC): Lung-MAP sub-study SWOG S1400C.
Authors: Edelman Martin J. , Redman Mary Weber , Albain Kathy S. , McGary Eric C. , Rafique Norman , Petro Daniel P. , Waqar Saiama Naheed , Miao Jieling , Griffin Katie , Papadimitrakopoulou Vassiliki , Kelly Karen , Gandara David R. , Herbst Roy S.
Published: September 2018

9056

Background: S1400 is a master platform trial designed to assess targeted therapies in SCC. Study C evaluated the response rate (RR) to P, a CDK 4/6 inhibitor, in pts with cell cycle gene abnormalities. Methods: Pts with SCC, PS 0-2, normal organ function, who had progressed after at least one prior platinum-based chemotherapy for any NSCLC indication were eligible. Tumor specimens were required and evaluated for gene alterations (Foundation Medicine, Foundation One NGS assay). Pts with CDK 4 or CCND1/2/ 3 amplifications were eligible. The study was originally designed as a phase II/III trial comparing P to docetaxel (D), but was modified to a 2-stage phase II trial with primary endpoint of response rate. If > 3 responses (R) of the first 20 pts were seen the study would continue to 40 pts, with 10 R for the 40 pts considered a positive study. Results: 89 pts (14% of pts screened) were assigned to S1400C, 53 pts enrolled (including 17 to D). One pt assigned to D re-registered to P. Frequency of cell cycle gene alterations for the enrolled pts: CCND1 amplification (n = 44, 83%); CCND2 amplification (n = 7, 13%); CCND3 amplification (n = 5, 9%); and CDK4 amplification (n = 3, 6%). (Note: some pts with multiple alterations.) Of the 37pts enrolled to P: 5 were ineligible (4 inadequate baseline labs, 1 did not progress on prior therapy). 1 not determinable for response. For the 32 eligible pts the median age was 67 (53-81), 21M/11F. Response: 2 PR (6% RR, 95% CI: 2%, 20%), 12 SD (38%, 95% CI: 21%, 54%) for a disease control rate (DCR) of 44% (95% CI: 27%, 61%). Median PFS was 1.7 mo (95% CI 1.6-2.9 mo). Of the 2 PR, one has progressed (duration of response, DOR, 7.7 mo), one still responding (DOR, 4 mo). Both responders had CCND1 amplification. 32 pts have been assessed for adverse events (AE). 4 experienced Grade 4 AE including lymphopenia (3), and thrombocytopenia (1). 13 others experienced Grade 3 treatment-related AE. Conclusions: 1. P failed to demonstrate the pre-specified RR to justify advancement to phase III. 2. P was well tolerated in this population. 3. Further analysis of those who derived benefit (e.g. response or prolonged SD) is underway. Clinical trial information: NCT02785939.
ABOUND.70+: Safety and efficacy of nab-paclitaxel/carboplatin (nab-P/C) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Langer Corey J. , Anderson Eric C. , Jotte Robert M. , Goldman Jonathan Wade , Haggstrom Daniel Ernest , Socoteanu Matei Paul , Smith David A. , Dakhil Christopher , Konduri Kartik , Kim Edward S. , Ong Teng Jin , Sanford Alexandra , Amiri Katayoun , Weiss Jared
Published: September 2018

9059

Background: Treatment (tx) of elderly pts with NSCLC is challenging. nab-P/C demonstrated efficacy in a subset of pts with NSCLC ≥ 70 y in a phase III trial. ABOUND.70+ was designed to determine whether a 1-week break can further improve tolerability of nab-P/C in pts ≥ 70 y with NSCLC. Safety and efficacy were evaluated and are reported. Methods: Pts ≥ 70 y with tx-naive locally advanced/metastatic NSCLC were randomized (1:1) nab-P 100 mg/m2 d 1, 8, 15 + C AUC 6 d 1 q3w (Arm A) or the same nab-P/C dose q3w followed by a 1-week break (Arm B). Primary endpoint: percentage of pts with either grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression AEs. Key secondary endpoints: PFS, ORR, OS, for which statistical analyses do not control for type I error ( Pvalues unadjusted). Results: At interim evaluation, the primary endpoint was similar across arms, resulting in early closure of enrollment. In Arms A and B, 71 and 72 pts were randomized; median age was 76 and 75 y, majority of pts were male (57.7% vs 55.6%) and had ECOG PS 1 (70.4% vs 72.2%). There were no differences in histology across tx arms. See table for primary endpoint data. Median number of tx cycles for Arms A and B was 4.0 and 5.5, median cumulative nab-P dose was 875.0 and 1287.5 mg/m2, and median weekly dose intensity was 62.0 and 54.1 mg/m2. nab-P dose modifications (Arms A and B): ≥ 1 dose reduction in 64.7% and 58.6%, ≥ 1 dose delay in 58.8% and 48.6%, and ≥ 1 missed dose in 80.9% and 72.9%, respectively. Median PFS (Arms A and B) 3.9 vs 7.0 mo (HR 0.49; 95% CI, 0.30 - 0.79; P = 0.003), confirmed ORR 23.9% vs 40.3% ( P = 0.037), and median OS 15.2 vs 16.2 mo (HR 0.76; 95% CI, 0.46 - 1.26; P= 0.292). Conclusions: Incidence of grade ≥ 2 PN or grade ≥ 3 myelosuppression AEs was similar between the 2 nab-P/C schedules in pts ≥ 70 y with advanced NSCLC. There appears to be a signal of improvement in PFS and ORR observed in Arm B, potentially due to increased tx exposure. NCT02151149 Clinical trial information: NCT02151149. [Table: see text]
Patient-reported outcomes and quality of life in ALTA: The randomized phase 2 study of brigatinib (BRG) in advanced ALK+ non–small cell lung cancer (NSCLC).
Authors: Langer Corey J. , Huang Hui , Huang Joice , Kerstein David , Reichmann William , Speck Rebecca M , Lenderking William R
Published: September 2018

9066

Background: The ALTA trial (NCT02094573), an open-label, phase 2, randomized, multicenter, international study, evaluated the efficacy and safety of BRG (arm A: 90 mg qd and arm B: 180 mg qd with 7-day lead-in at 90 mg) in patients (pts) with advanced anaplastic lymphoma kinase–positive (ALK+) NSCLC whose disease had progressed on prior therapy with crizotinib (CRZ). The objective of this analysis was to describe pt-reported outcomes (PROs) in the ALTA study. Methods: PROs were collected using the EORTC QLQ-C30 at baseline and on the first day of each cycle. Multivariable mixed effects models were constructed to estimate adjusted mean changes from baseline in QLQ-C30 scores. Cumulative distribution function (CDF) plots of EORTC QLQ-C30 change scores from baseline to Cycle 5 were generated to evaluate a clinically meaningful threshold of individual pt change, which was determined through anchor- and distribution-based methods. Results: Among 222 randomized pts, 208 (94%) completed the questionnaire at baseline and at least 1 on-treatment PRO follow-up. In multivariable analyses, there were no statistically significant differences in Global Health Status (GHS)/QOL between arms over time when adjusted for baseline score, ECOG status, and presence of liver or bone metastases. At Cycle 5, CDF plots indicated that 80% of all pts experienced an increase or no change in GHS/QOL scores; 50% of all pts experienced a clinically meaningful improvement. At Cycle 5, 80% of all pts reported a reduction or no change in pain score, and 90% of all pts reported a reduction or no change in dyspnea score. Approximately 30% of pts had clinically meaningful reductions in these symptoms. Less than 15% and < 5% of all pts reported clinically meaningful worsening of nausea/vomiting and diarrhea scores, respectively, at Cycle 5. Conclusions: Treatment with BRG for CRZ-refractory ALK+ NSCLC resulted in improved GHS/QOL scores and reduction in pain and dyspnea scores, while rates for nausea/vomiting and diarrhea were minimally worse. These pt-level benefits support BRG as a promising treatment option. Clinical trial information: NCT02094573.
Nivolumab (nivo) + nab-paclitaxel (nab-P) + carboplatin (C) in patients (pts) with non-small cell lung cancer (NSCLC): Interim results from a multicenter phase I study.
Authors: Waterhouse David Michael , Goldman Jonathan Wade , George Ben , O'Dwyer Peter J. , Ye Moncy , Chen Tianlei , Trunova Nataliya , Kelly Karen
Published: September 2018

9095

Background: Despite success of single-agent immune checkpoint inhibitors, an unmet therapeutic need remains in pts with NSCLC. Chemotherapy and immunotherapy may have synergistic antitumor activity, but safety and efficacy need to be established. Here, we present interim results for pts with NSCLC (Arm C) from the phase I safety trial of nivo + nab-P in pancreatic cancer (± gemcitabine), NSCLC (+ C), and metastatic breast cancer. Methods: Part 1 evaluated potential dose-limiting toxicities (DLTs) before Part 2 expansion. Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m2d 1, 8, 15 + C AUC 6 d 1 + nivo 5 mg/kg d 15 of each 21-d cycle; in cycles 5+, nivo was continued as maintenance monotherapy. Primary endpoints: number of pts with DLTs (Part 1) and percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1 and 2). DLT-evaluable pts included those who received ≥ 2 complete nivo cycles and remained on study for 14 d after the last nivo dose in cycle 2, received ≥ 1 nivo dose and discontinued due to DLT before completing 2 nivo cycles, or experienced equivocal DLT after ≥ 1 nivo dose. Secondary endpoints included safety, PFS, OS, DCR, ORR, and DOR. Results: All pts (n = 22) received nab-P/C; results for nivo-treated pts (n = 20) are presented. Of the nivo-treated pts, the median age was 66 y (55% ≥ 65 y), 75% were female, 80% were white, and 70% had ECOG PS 1. More pts had adenocarcinoma (50%) than squamous cell carcinoma (35%; 10% other, 5% data pending). No DLTs reported (5 DLT-evaluable pts). Most common grade 3/4 TEAEs were neutropenia (45%) and anemia (35%). No grade 3/4 immune-related colitis or pneumonitis reported. Best ORR (RECIST v1.1) was 50% (1 CR [unconfirmed, 5%] and 9 PRs [45%]; 6 pts had SD [30%]; 4 pts had PD [20%]). Best ORR by histology: squamous, 71%; nonsquamous, 54%. Median PFS was 10.5 months (squamous, 10.5 months; nonsquamous, not evaluable). Conclusions: Results demonstrated safety of the nivo + nab-P/C combination in NSCLC with no unexpected safety signals. Preliminary efficacy results are promising. (NCT02309177) Clinical trial information: NCT02309177.
REGN2810: A fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC)—Initial safety and efficacy from expansion cohorts (ECs) of phase I study.
Authors: Papadopoulos Kyriakos P. , Owonikoko Taofeek Kunle , Johnson Melissa Lynne , Brana Irene , Gil-Martin Marta , Perez Raymond P. , Moreno Victor , Salama April K. , Calvo Emiliano , Yee Nelson S. , Safran Howard , González-Martín Antonio , Aljumaily Raid , Mahadevan Daruka , Mohan Kosalai Kal , Qin Rui , Stankevich Elizabeth , Lowy Israel , Fury Matthew G. , Homsi Jade
Published: September 2018

9503

Background: There is no established standard of care for unresectable locally advanced or metastatic CSCC. UV-induced DNA damage causes hypermutation in most CSCCs. Therefore, these tumors may be responsive to PD-1 checkpoint blockade. In the dose escalation portion of the phase 1 study of REGN2810, a durable (19 + months) radiologic complete response was observed in a patient (pt) with metastatic CSCC (ASCO 2015, #3024). Methods: ECs enrolled pts with distantly metastatic (EC 7) and locally advanced (EC 8) CSCC. All patients received 3 mg/kg REGN2810 by intravenous infusion over 30 minutes every 2 weeks for up to 48 weeks. Research biopsies were performed at baseline and Day 29 (and at progression, if possible). Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate (ORR). Data cutoff date was 31 Jan 2017. Results: 26 pts were enrolled (10 in EC 7 and 16 in EC 8): median age, 72.5 y (range, 56-88y); median PS 1 (range, 0 – 1); 21M:5F; median number of prior systemic therapy regimens, 1 (range, 0 – 2). Median exposure to REGN2810 was 7 doses (range, 1-22). The most common treatment-related adverse event of any grade was fatigue (19.2%). Each of the following ≥ Grade 3 related AEs occurred once: AST elevation, ALT elevation, arthralgia, and rash. ORR (PR + CR, including unconfirmed) and disease control rate (ORR+SD) were 52% (12/23; 4uPR, 5 PR, 2CR, 1 uCR) and 70% (16/23, including 4SD), respectively. Three patients are not yet evaluable. Median PFS and OS have not been reached, and only one patient has experienced PD during REGN2810 treatment after initial response. Correlative studies are in process, including PD-L1 status and whole exome tumor DNA sequencing. Conclusions: REGN2810 is well tolerated and produces antitumor activity in patients with advanced CSCC. A pivotal trial of REGN2810 for patients with advanced CSCC is enrolling patients (NCT02760498). Clinical trial information: NCT02383212.
COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant (mut) melanoma brain metastases (MBM).
Authors: Davies Michael A. , Robert Caroline , Long Georgina V. , Grob Jean Jacques , Flaherty Keith T. , Arance Ana , Chiarion-Sileni Vanna , Thomas Luc , Lesimple Thierry , Mortier Laurent , Moschos Stergios J. , Hogg David , Marquez Rodas Ivan , Del Vecchio Michele , Lebbe Celeste , Meyer Nicolas , Zhang Ying , Huang Yingjie , Mookerjee Bijoyesh , Saiag Philippe
Published: September 2018

9506

Background: CNS metastases are common and associated with very poor prognosis in pts with metastatic melanoma (MM). In the phase II BREAK-MB trial, D had clinical activity in BRAF V600–mut MBM. D + T has shown superiority over D alone in pts with BRAF V600–mut mm without MBM; however, efficacy of this regimen on MBM has not been characterized. Here, we report results from a phase II trial of D + T in BRAFV600–mut MBM (COMBI-MB; NCT02039947). Methods: This open-label, phase II study evaluated D 150 mg BID + T 2 mg QD in 4 MBM cohorts: (A) BRAFV600E, asymptomatic MBM, no prior local treatment (Tx); (B) BRAFV600E, asymptomatic MBM, prior local Tx; (C) BRAFV600D/K/R, asymptomatic MBM, with or without prior local Tx; and (D) BRAFV600D/E/K/R, symptomatic MBM, with or without prior local Tx. The primary objective was intracranial response rate (IRR) in cohort A (null hypothesis, IRR ≤ 35%). Secondary endpoints included IRR in cohorts B, C, and D; extracranial (ERR) and overall (ORR) response rates; intracranial (IDCR), extracranial (EDCR), and overall (ODCR) disease control rates; duration of IR, ER, and OR; PFS; OS; and safety. Results: 125 pts were enrolled (A, n = 76; B, n = 16; C, n = 16; D, n = 17). In cohort A, median age was 52, 53% were male, and 37% had LDH > ULN. At data cutoff (28 Nov 2016; median f/u, 9.0 mo), in cohort A, investigator-assessed IRR was 58% (IDCR, 78%), ERR was 55% (EDCR, 80%), and ORR was 58% (ODCR, 80%). Median duration of IR, ER, and OR was 6.5 mo (95% CI, 4.9-10.3), 10.2 mo (95% CI, 6.5-13.0), and 6.5 mo (95% CI, 4.9-10.3), respectively. Median PFS was 5.6 mo (95% CI, 5.3-7.4). Independent review supported these results. 6-mo OS was 79%; with 31 pts (41%) still in f/u, preliminary median OS was 10.8 mo (95% CI, 8.7-19.6). Efficacy in cohorts B, C, and D will be reported. AEs across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior D + T studies; 10% of pts (8% in cohort A) discontinued due to AEs. Conclusions: In this first report of a phase II trial evaluating a BRAF and MEK inhibitor combination in BRAFV600–mut MBM, the primary endpoint was met. Promising IRR and IDCR were seen with D + T, but responses appear less durable than reported for mm without MBMs. No unexpected safety issues were observed. Clinical trial information: NCT02039947.
Metagenomic shotgun sequencing to identify specific human gut microbes associated with immune checkpoint therapy efficacy in melanoma patients.
Authors: Frankel Arthur E. , Froehlich Thomas W. , Kim Jiwoong , Coughlin Laura A. , Xie Yang , Frenkel Eugene P. , Koh Andrew Y.
Published: September 2018

9516

Background: Immune checkpoint inhibitor therapy, ICT, achieves durable remissions in 30-50% of patients (pts) with metastatic melanoma (Larkin et al. NEJM 2015). It is still unclear what host factors modulate response to ICT. Preclinical mouse studies with B16 melanoma demonstrated that ICT response was dependent on the presence of specific commensal gut bacteria (Vetizou et al. Science 2015; Sivan et al. Science2015). These specific gut bacteria induced the maturation of dendritic cells (DCs) and T-cells needed for effective ICT. We sought to determine whether specific gut microbiota are associated with improved response to ICT in melanoma patients. Methods: 37 melanoma pts treated with ICT (nivolumab plus ipilimumab or pembrolizumab alone) at UTSW Medical Center were enrolled. Fecal samples were collected prior to ICT. Genomic DNA was extracted, and metagenomic shotgun sequencing (MSS) performed on an Illumina HiSeq 2500 PE-100. Taxonomic (MetaPhlAn) and functional (HUMAnN) analysis was performed on MSS data. Disease status was assessed by CT scans and physical exams every two months. Results: Among the 23 evaluable pts, 8 were classified as RECIST responders, 5 with stable disease and 10 with progression. RECIST responder microbiomes were significantly enriched with Methanobrevibacter smithii(p = 0.03; LDA coupled with effect size measurements, LEfSe; Kruskal-Wallis test) , Bacteroides thetaiotamicron(p = 0.03) , Lactobacillus plantarum(p = 0.04), and Eubacterium limosum(p = 0.01) compared to those with progressive disease. Conclusions: MSS identified 4 specific gut microbiota associated with improved response to ICT therapy in melanoma pts. All of these bacteria have been shown to modulate host immune response (Bang PLoS One 2014; Hickey Cell Host Microbe 2016; Rigaux Allergy 2009; Kaunachi World J Gastroentertol 2006). To gain mechanistic insight and confirm causality, shotgun metabolomics on the same fecal specimens used for MSS, in vitroimmune cell assays using the gut microbiota identified, and preclinical modeling in a mouse melanoma model with ICT are underway. These studies may lay the foundation for optimizing the host response to ICT.
Targeting EZH2 in acral lentiginous melanoma (ALM).
Authors: Izsak Allison , Giles Keith Michael , Lui Kevin Paul , Weiss Sarah A. , Moran Una , Vega-Saenz de Miera Eleazar , Stein Jennifer , Lee Ann Yeelin , Darvishian Farbod , Shapiro Richard L. , Berman Russell S. , Pavlick Anna C. , Wilson Melissa , Osman Iman
Published: September 2018

9534

Background: Efforts to identify targeted therapies that can improve treatment outcome in metastatic ALM have been unsuccessful. In a previous genomic screening, we identified copy number amplification of the histone methyltransferase EZH2 in 47% of ALM cases, a higher frequency than previously reported in cutaneous melanomas (CM) (5%). Here, we tested the hypothesis that increased EZH2 expression contributes to ALM progression and may confer selective sensitivity to EZH2 inhibition. Methods: EZH2 expression was examined by immunohistochemistry (IHC) in 51 primary (21 stage I, 13 Stage II and 17 Stage III) and 23 metastatic (11 in transit, 8 nodal and 4 visceral) ALM cases with extensive clinicopathological data and protocol-driven follow up. Colony formation and cell proliferation was assessed following treatment of ALM and CM cell lines with three EZH2 inhibitors, including GSK126, currently in clinical trials. The effect of GSK126 on H3K27me3 and downstream EZH2 targets was analyzed by western blotting. Results: EZH2 is commonly overexpressed in both primary (30/51; 65%) and metastatic (20/23; 87%) ALM cases, with a significant increase in mean IHC score between primary and metastatic tumors (1.9 vs. 2.7, respectively, p = 0.047). EZH2 expression increased in 6/10 metastatic ALM tumors compared to their matched primary tumors. ALM tumors with EZH2 gene amplification showed increased EZH2 protein expression; however more cases showed overexpression with no amplification suggesting a potential epigenetic component of EZH2 regulation. GSK126 significantly suppressed ALM colony formation at lower doses compared to CM (1 µM vs. 5 µM, respectively). EZH2 inhibition also increased expression of the downstream tumor suppressor E-cadherin in ALM but not in CM cell lines. Finally, ALM cell lines had significantly lower basal H3K27me3 levels than CM cell lines, suggesting an additional, histone methyltransferase-independent function of EZH2 in ALM. Conclusions: Our data demonstrate thatEZH2 upregulation is common in ALM, and suggest that it may play a role in ALM’s metastatic progression that requires further investigation. Selective sensitivity of ALM cell lines to EZH2 inhibitors supports the therapeutic potential of EZH2-targeted therapy in ALM.
Exploratory biomarker analysis in avelumab-treated patients with metastatic Merkel cell carcinoma progressed after chemotherapy.
Authors: Shapiro Irina , Grote Hans Juergen , D'Urso Vittorio , von Heydebreck Anja , Mahnke Lisa , Kaufman Howard , Nghiem Paul , Cai Ti
Published: September 2018

9557

Background: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer. Tumor oncogenesis is linked to Merkel cell polyomavirus (MCPyV) integration and UV exposure. PD-L1 is often expressed in MCC tumors, suggesting that patients with MCC could benefit from anti-PD-L1 therapy. Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody that has demonstrated clinical efficacy in patients (pts) with metastatic MCC (mMCC) in a Phase 2 trial with an objective response rate (ORR) of 31.8% in the primary analysis. Assessment of candidate predictive biomarkers may help to identify patients with a greater probability of response to avelumab and to improve understanding of MCC biology. Methods: Patients in a Phase 2 trial (NCT02155647) with mMCC and tumor progression on prior chemotherapy received avelumab at 10 mg/kg Q2W. PD-L1 expression, MCPyV status and CD8+ T-cell infiltration in pretreatment tumor samples were evaluated by immunohistochemistry (IHC). MCPyV status was also evaluated by real-time PCR. Results: Tumor PD-L1 expression was evaluable in 74 of 88 (84.1%) pts with mMCC treated with avelumab, of which 58 (65.9%) and 19 (21.6%) pts were positive at 1% and 5% cut-offs. ORR was 34.5% and 18.8% for PD-L1 positive and negative pts at 1% cutoff, and 52.6% and 23.6% for PD-L1 positive and negative pts at 5% cutoff. MCPyV status was positive in 60% (46/77) pts evaluable by IHC and 63% (45/71) pts evaluable by PCR; of 66 pts tested by both IHC and PCR, concordance was 90.9%. MCPyV+ and MCPyV– pts had similar frequencies of PD-L1+ tumors (80% and 73%) with an ORR of 26.1% and 35.5% respectively. Baseline CD8+ T-cell infiltration was assessed at tumor invasive margin and tumor center in 53 pts, ORR was 44.4% vs 19.2% and 32.1% vs 28% for pts with high or low CD8+ T-cell density at respective locations. Conclusions: In an international cohort of pts with mMCC, avelumab had clinical activity among biomarker subgroups analyzed, including PD-L1 expression, MCPyV status and density of CD8+ tumor-infiltrating T-cells. The current biomarkers were not predictive of response but further research into understanding how avelumab mediates anti-tumor activity in MCC may identify novel biomarkers. Clinical trial information: NCT02155647.
Validation, in silico and in vitro, of a gene-signature based risk score in cutaneous melanoma.
Authors: Brunner Georg , Falk Thomas M. , Ertas Beyhan , Berking Carola , Schulze Hans-Joachim , Blödorn-Schlicht Norbert
Published: September 2018

9560

Background: Melanoma staging, as defined by the American Joint Committee on Cancer (AJCC), is limited in its ability to predict outcome. We have previously identified and validated a prognostic gene signature expressed in primary cutaneous melanoma and adjacent stroma. The signature comprises seven protective genes (down-regulated with tumor progression) and one risk-associated gene (up-regulated). A signature-based risk score independently predicts patient survival, across AJCC stages IA-IIIC, in formalin-fixed, paraffin-embedded (FFPE) melanomas (training cohort, n = 125; p = 0.0003, hazard ratio 1.85). The score has been validated in 206 melanomas, selected to be significantly mis-prognosticated by AJCC staging regarding patient survival (40.8% mis-prognostication). In this cohort, the score outperforms AJCC staging (p = 0.0005, hazard ratio 1.41 vs. p = n.s.), correcting 34.9% of AJCC-based mis-prognostications. Methods: Here, we report twofold external validation of the risk score, (i) prognostic performance in silico using the SurvExpress web tool (Aguirre-Gamboa et al., 2013), and (ii) technical performance in vitro(Dermatologikum Hamburg; IMGM Munich) . Results: (i) Kaplan Meier analysis and log-rank testing demonstrated that all signature genes combined predicted survival in four different cohorts of metastatic melanoma (from GEO Expression Omnibus or Cancer Genome Atlas; cohorts dichotomized at the median): see table. (ii) The risk score was re-analyzed in melanomas of the training cohort (n=69). The overall concordance of duplicate determinations was 90% (average scores of 1.12 ± 0.14 and 0.97 ± 0.14). Conclusions: In conclusion, we have validated a signature-based FFPE melanoma risk score, complementary to AJCC staging in predicting outcome: (i) Signature genes predicted patient survival in silico(n=449) (ii) The risk score proved to be reproducible and technically robust in vitro. The score improves risk stratification and decision making in melanoma, particularly regarding new adjuvant therapies. [Table: see text]
Multidimensional spatial characterization of the tumor microenvironment (TME) in synchronous melanoma metastases (SMM) to yield insights into mixed responses to therapy in metastatic melanoma (MM) patients (pts).
Authors: Reuben Alexandre , Tetzlaff Michael T. , Spencer Christine , Ong Giang , Barker Kristi , Prieto Peter A. , Vellano Christopher , Lee Jinho , Hudgens Courtney , McKean Meredith Ann , Gopalakrishnan Vancheswaran , Szczepaniak Sloane Robert , Reddy Sangeetha , Merritt Chris , Warren Sarah , Beechem Joseph M , Davies Michael A. , Hwu Patrick , Mills Gordon B. , Wargo Jennifer Ann
Published: September 2018

9575

Background: Although both targeted and immune therapies have significantly improved outcomes for mm pts, only a minority of pts experience durable responses with many pts with multiple SMM demonstrating differential responses to therapy. We performed multidimensional spatial characterization of immune markers in SMM from mm patients treated with targeted and immune therapies to improve our understanding of correlations and determinants of response. Methods: NanoString's Digital Spatial Profiling research platform was used on 6 SMM from 3 pts (treatment-naïve; BRAF + MEK targeted therapy treated; anti-PD-1 immunotherapy treated) for 30 immune and signaling proteins. For analysis, we selected and compared immune-rich (CD45+) and tumor-rich (S100B+) regions across SMM. Results were compared to lesion-specific clinical responses. Results: Striking differences in patterns of expression across SMM from individual pts were detected, including in Ki67, CD68 myeloid cells, and the potent immunosuppressor B7-H3. SMM progressing after targeted therapy demonstrated higher pAKT and PD-L1 expression, consistent with described resistance mechanisms. Large differences in expression of PD-L1 were noted following anti-PD-1 therapy, which could contribute to heterogeneous responses. Differential expression patterns in the TME associated with response were also detected, including in increases in CD4 and CD14 cells in progressing lesions. Conclusions: Striking differences in responding and non-responding SMM were observed, providing potential explanations for the heterogeneous clinical responses frequently observed in mm pts. Studies are ongoing to further characterize interactions and spatial distribution of cell types, as well as integrate these findings with previous molecular and immune profiling data (whole exome sequencing, gene expression profiling, flow cytometry, IHC, TCR sequencing) in these and additional SMM to identify actionable strategies to homogenize responses across metastases in mm pts.