bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular panel sequencing of pre-treatment samples to reveal mechanisms of innate resistance to 3rd generation EGFR TKI treatment in T790M-positive NSCLC patients.
Authors: Michels Sebastian Yves Friedrich , Heydt Carina , Deschler-Baier Barbara , Ruesseler Vanessa , Stratmann Jan , Steinhauser Susanne , Fischer Rieke Nila , Scheffler Matthias , Fassunke Jana , Nogova Lucia , Brandes Vanessa , Kostenko Anna , Griesinger Frank , Gautschi Oliver , Sebastian Martin , Hellmich Martin , Heukamp Lukas C. , Merkelbach-Bruse Sabine , Buettner Reinhard , Wolf Juergen 
Published: September 2018

9041 Background: Resistance to early generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKI) inevitably develops in EGFR-mutant lung cancer. The secondary EGFR p.T790M mutation is the driving factor in 60% of cases and 3rd generation EGFR TKIs have been developed to overcome T790M-mediated resistance. However, besides T790M other genetic aberrations such as amplifications of MET may contribute to resistance to EGFR inhibition in the same patient. We here report on the systematic analysis of co-occurring genetic aberrations that may influence response to 3rd generation EGFR TKIs. Methods: Thirty-six patients were treated with 3rd generation EGFR TKIs in the setting of acquired resistance to EGFR inhibition in cancer centers in Germany and Switzerland. Pre-treatment samples were analyzed for co-occurring genetic aberrations in a subset of resistance-related genes including MET, HER2, RAS-gene family, PIK3CA, CTNNB1 and PTEN using next-generation sequencing and fluorescence in-situ hybridization assays. We investigated the association between clinical, epidemiological and molecular data and response to treatment (RECIST 1.1). Results: Co-occurring genetic aberrations were found in 68% of the pre-treatment samples where both, analyses by sequencing and FISH were feasible (N = 25). Efficacy of 3rd generation EGFR TKIs significantly dropped in the presence of high-level MET amplification as compared to wild-type MET (ORR, 0.0%; 95% CI, 0.0-60.4 vs. 70.0%; 95% CI, 45.7-87.2; p = 0.02; median PFS, 1.0 month; 95% CI, 0.37-1.72 months vs. 8.2 months; 95% CI, 1.69-14.77 months; p ≤ 0.001). No statistically significant association was found between treatment efficacy and the molecular status of the genes analyzed or the number of prior EGFR TKIs. Conclusions: Prevalence of additional genetic aberrations is frequent in the setting of acquired resistance to early generation EGFR TKIs and may not necessarily mediate resistance to 3rd generation EGFR TKIs. However, in our analysis high-level amplification of MET was associated with primary treatment failure and might be the main factor underlying resistance in this setting.
Microwave ablation in combination with chemotherapy versus chemotherapy in advanced non small cell lung cancer: A prospective, randomized, phase III clinical trial.
Authors: Wei Zhig , Ye Xin , Geng Dian zhong , Dong Yu ting , Wang Chun tang , Bi Jing wang , Sun Ya hong , Wang Jun ye , Feng Qing liang , Xu Xing lu , Zhang Ben hua , Zhang Li cheng , Ren Hai peng , Zhang Kai xian , Sun Deng jun 
Published: September 2018

9048 Background: Previous studies showed that advanced non small cell lung cancer (NSCLC) benefited from microwave ablation in combination with platium-based doublet chemotherapy. This prospective, randomized, phase III clinical trial aimed to determining the survival benefit and safety of MWA combined with chemotherapy compared with chemotherapy alone, which was registered in Clinical Trials. gov (NCT02455843). Methods: Patients with untreated, stage IIIB or IV NSCLC and at least one additional measurable site other than the primary tumor site were recruited. They were divided into MWA/chemotherapy group and chemotherapy group, the former received MWA in the primary tumor sites, followed by chemotherapy and the latter treated with chemotherapy only. The primary endpoint was progression-free survival (PFS), the second endpoint included objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: From Mar 1st, 2015 to Oct 31th, 2016, Two hundreds and eighty-six patients were enrolled, including 141 in MWA/chemotherapy group and 145 in chemotherapy group. Complete ablation was observed in 95.0 % patients. ORR were 38.3 % and 34.1 % in the MWA/chemotherapy group and chemotherapy group, respectively(p = 0.677). MWA prolonged PFS [MWA/chemotherapy group 7.3 (95 % CI,5.3–13.6) ms vs. chemotherapy group 5.2 (95 % CI, 4.0–12.4) ms, p = 0.003]. Multivariate analyses showed that MWA was an independent prognostic factor of PFS. OS was immature. AEs of MWA were observed in 67.4 % patients, mainly was pheumothorax, and only 15% needing chest tube insertion. No ablation associated death was observed. Chemotherapy-associated AEs were observed in 49.1 and 53.6 % of patients in the MWA/chemotherapy and chemotherapy group, respectively. Conclusions: MWA plus chemotherapy combination improved the PFS of advanced NSCLC compared to chemotherapy alone. Adverse events of MWA was tolerable. Clinical trial information: NCT02455843.
Updated survival of patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study.
Authors: Planchard David , Besse Benjamin , Kim Tae Min , Quoix Elisabeth A. , Souquet Pierre Jean , Mazieres Julien , Barlesi Fabrice , Groen Harry J.M. , Smit Egbert F. , Baik Christina S. , Cho Byoung Chul , Kelly Ronan Joseph , Socinski Mark A. , Novello Silvia , Rigas James R. , Giannone Vanessa , D'amelio Anthony Michael , Zhang Pingkuan , Mookerjee Bijoyesh , Johnson Bruce E. 
Published: September 2018

9075 Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as oncogenic drivers. Initial cohorts of the BRF113928 (NCT01336634) trial evaluated efficacy and safety of D monotherapy (cohort A; n = 78) or D + T (cohort B; n = 57) in pts with previously treated BRAFV600E–mutant metastatic NSCLC. At primary analysis, overall response rates (ORRs) were 33.3% and 63.2% in pts who received D or D + T, respectively. Furthermore, durable response (median duration of response [DOR], 9.0 mo) was observed in D + T pts. Here, we present an updated survival analysis based on additional follow-up. Methods: In this phase 2 trial, 2 cohorts (A and B) of pts with previously treated metastatic BRAFV600E–mutant NSCLC were enrolled sequentially. The primary endpoint was investigator-assessed ORR. Secondary efficacy endpoints included progression-free survival (PFS), DOR, and overall survival (OS). D and T were dosed orally at the established phase 2 dose of D 150 mg twice daily and T 2 mg once daily. Results: This updated analysis had a median follow-up of 16.2 mo, which represented an additional 10 mo of follow-up. Median OS was 12.7 mo (95% CI, 7.3-16.3) with 57 deaths reported for pts treated with D monotherapy and 18.2 mo (95% CI, 14.3-not estimable [NE]) with 33 deaths reported for pts treated with D + T. Detailed efficacy results are presented in the table. Investigator-assessed ORR, DOR, and PFS were supported by independent review committee assessments. No new safety signals were observed for D + T. Conclusions: This update of the BRF113928 study confirms that durable responses and encouraging survival were achieved with combination D + T in pts with BRAFV600E–mutant NSCLC. Clinical trial information: NCT01336634. [Table: see text]
Exposure-response and PD-L1 expression analysis of second-line avelumab in patients with advanced NSCLC: Data from the JAVELIN Solid Tumor trial.
Authors: Gulley James L. , Spigel David R. , Kelly Karen , Aisner Joseph , Chand Vikram K. , Koenig Andre , Dolgos Hugues , Wang Shaonan , Verschraegen Claire F. 
Published: September 2018

9086 Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody showing promising efficacy and safety in patients (pts) with non-small cell lung cancer (NSCLC) and other tumors. Here, we present exposure–response (E–R) and PD-L1 expression analyses of second-line (2L) avelumab treatment in pts with NSCLC from a phase 1 trial (NCT01772004). Methods: Pts with NSCLC received 2L avelumab 10 mg/kg IV every 2 weeks (Q2W) until progression or unacceptable toxicity. Serum samples were taken at various time points for pharmacokinetic (PK) analysis. Trough concentrations after first dose (Ctroughfirst-dose) were predicted using an identified linear 2-compartment population PK (popPK) model without covariates other than pt body weight. Objective response rate (ORR) was evaluated (RECIST v1.1), and correlated with tumor cell (TC) PD-L1 expression (clone 73-10). Pooled safety data from various tumors in the large phase 1 trial were assessed. Results: In 184 avelumab-treated pts, unselected for PD-L1 expression, ORRs were 8.7%, 10.9%, 19.6%, and 17.4% for increasing quartiles of Ctroughfirst-dose (Q1–4). Using ≥1%, ≥5%, ≥50%, and ≥80% PD-L1 staining cutoffs, pts in the upper half of exposure (Ctroughfirst-dose Q3–4 [n = 92]), had ORRs of 25% (n = 59), 26% (n = 39), 33% (n = 21), and 43% (n = 14), respectively. Higher avelumab exposure was associated with a modest increase in immune-related adverse events (irAEs). PopPK modeling suggested Ctroughfirst-dose could be optimally increased with alternate avelumab dosing (10 mg/kg weekly vs Q2W, or 20 mg/kg Q2W [simulated median Ctroughfirst-dose 48 μg/mL vs 18 μg/mL, or 36 μg/mL]). Conclusions: Avelumab has shown clinical activity and acceptable safety in multiple tumors similar to other agents in class. Preliminary analysis of a cohort of pts with 2L advanced NSCLC shows a trend for higher ORR with increasing avelumab Ctroughfirst-dose quartiles and with higher levels of TC PD-L1 expression. Although this apparent E–R observation may be confounded by single-dose testing or other factors, this analysis provides rationale for studies of more intensive avelumab dosing regimens to assess further clinical benefit in pts with advanced NSCLC. Clinical trial information: NCT01772004.
The demand for psycho-oncological support in 820 melanoma patients: What are the determinants for the development of distress?
Authors: Forschner Andrea , Riedel Petra , Gassenmaier Maximilian , Scheu Alexander , Kofler Lukas , Garbe Claus , Schäffeler Norbert , Mayer Simone , Eigentler Thomas K. 
Published: September 2018

9514 Background: There is limited data about the impact of melanoma on the psychological burden of patients. Despite some known predictors for distress like female gender or younger age, melanoma stages have not been found being related to distress in melanoma patients and there is no data concerning distress in melanoma patients under systemic treatment for metastases. Methods: Between July and September 2016, 820 melanoma patients at the outpatient clinic at the Department of Dermatology at the University of Tuebingen underwent psycho-oncological screening. The patients routinely completed the distress thermometer (DT), supplemented by a problem list, before consulting the physician. DT scores ≥ 5 are above-threshold, indicating the need for psycho-oncological support. We matched psycho-oncological data with tumor and patient specific data to examine tumor or patient specific influence on distress using logistic regression. Results: 406 (49.5%) men and 414 (50.5%) women were included, mean age was 62.35 years (IQR 52-75), mean time since primary diagnosis of melanoma was 54.84 months (IQR 15-76). 359 (44%) of the patients suffered from advanced melanoma (stage III n = 182, stage IV n = 177). 120 patients (14.6%) received systemic treatment for metastases: 90/120 (75%) checkpoint inhibitors, 27/120 (22.5%) targeted therapy and 3/120 (2.5%) chemotherapy. 338/820 (41.2%) of the patients met the cut-off score for distress. Significant influencing factors (p < 0.05) for DT values of ≥ 5 were: female gender, younger age, melanoma stage III and IV. Interestingly we found a lower risk for values above-threshold for patients under systemic treatment, although this was not significant (p = 0.252). Conclusions: This is the first analysis to demonstrate the impact of advanced melanoma stages on DT scores above-threshold. Our study is also the first to indicate a lower risk for distress in patients under systemic treatment. This might be due to the closer contact between these patients and their physicians. Nevertheless, more than 40% of our patients needed psycho-oncological support. Departments that care for melanoma patients should therefore be fitted by a sufficient number of psycho-oncologists.
Management of gastrointestinal (GI) toxicity associated with nivolumab (NIVO) plus ipilimumab (IPI) or IPI alone in phase II and III trials in advanced melanoma (MEL).
Authors: Weber Jeffrey S. , Larkin James M. G. , Schadendorf Dirk , Wolchok Jedd D. , Wagstaff John , Dummer Reinhard , Hogg David , Guidoboni Massimo , Sosman Jeffrey Alan , Chmielowski Bartosz , Gerritsen Winald , Bhore Rafia , Walker Dana , Gonzalez Rene 
Published: September 2018

9523 Background: NIVO and IPI are approved as monotherapy and in combination for treatment of MEL. These treatments are associated with select (potentially immune-related) adverse events (AEs) of the GI tract, most commonly diarrhea and colitis. We describe the management of GI toxicity in patients (pts) treated with NIVO+IPI or IPI from phase II (CheckMate 069) and III (CheckMate 067) trials. Methods: Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until progression or unacceptable toxicity, or IPI 3 mg/kg Q3W x 4, followed by placebo. Minimum follow-up was 2 yrs for CheckMate 069 and 18 months for CheckMate 067. Results: Of 407 pts treated with NIVO+IPI, 195 (48%) experienced any grade select GI AEs, and of 357 pts treated with IPI, 132 (37%) experienced any grade select GI AEs. Grade 3/4 select GI AEs were reported in 67 (16%) pts treated with NIVO+IPI and in 41 (11%) pts treated with IPI; median time to onset was 7.1 weeks (range 0.9-48.9) with NIVO+IPI and 7.3 weeks (range 0.6-14.9) with IPI. To manage these AEs, immune-modulating medications (IMM) were used in 61/67 (91%) pts in the NIVO+IPI group and in 41/41 (100%) in the IPI group. Corticosteroids (CS) were used in 61/67 (91%) and 41/41 (100%) pts, and infliximab (IFX) was used in 21/67 (31%) and 14/41 (34%) pts in the NIVO+IPI and IPI groups, respectively. In the NIVO+IPI group, the resolution rate of grade 3/4 select GI AEs was 96%, 97%, and 95% with a median time to resolution of 3.3, 3.0, and 3.9 weeks in all treated pts, CS, and CS+IFX managed pts, respectively; 88%, 92%, and 79% resolved with a median time to resolution of 3.9, 2.4, and 7.8 weeks in the IPI group, respectively. Objective response rates (ORR) were unchanged in the presence of any grade select GI AEs, or by using CS or CS+IFX (Table). Conclusions: NIVO+IPI or IPI alone is associated with a high incidence of GI select AEs, but most are effectively managed by IMMs, which do not appear to inhibit tumor response. Clinical trial information: NCT01844505; NCT01927419. [Table: see text]
Distinct gene expression, mutational profile and clinical outcomes of V600E and V600K/R BRAF-mutant metastatic melanoma (MM).
Authors: Pires Da Silva Ines Esteves Domingues , Wang Kevin Y. X. , Wilmott James S. , Holst Jeffrey , Park John J , Quek Camelia , Wongchenko Matthew , Yan Yibing , Mann Graham J , Carlino Matteo S. , Kefford Richard , Scolyer Richard A. , Yang Jean , Long Georgina V. , Rizos Helen , Menzies Alexander M. 
Published: September 2018

9541 Background: BRAF V600E and V600K/R mm have distinct clinicopathologic features suggesting different etiology. V600K/R mm appears less responsive to MAPK inhibitors (MAPKi) compared to V600E MM. We investigated potential mechanisms for this by comparing the gene expression and mutation profiles of these two melanoma subgroups. Methods: BRAF V600 mutant mm patients (pts) treated with MAPKi (BRAFi +/- MEKi) between July/2009 and July/2013 were selected. Demographics, clinicopathologic features and clinical outcomes were examined. Pre-treatment FFPE tumors underwent RNA expression profiling (795-gene nanostring panel) and DNA sequencing (239 gene NGS panel). Molecular results were validated using an independent cohort from the The Cancer Genome Atlas (TCGA). Results: 95 mm pts were included (78 V600E, 17 V600K/R), with median (med) follow-up of 18.4 months (mo). 74 (78%) had BRAFi, 21 (22%) had BRAF/MEKi. At MAPKi start, there were no differences between subgroups regarding age, gender, ECOG, AJCC stage or LDH level. V600K/R pts had a trend to less tumour regression by RECIST (med 30% vs 51%, p = 0.08) and shorter PFS (med 5.1 vs 7.1mo, p = 0.08) than V600E, with no difference in OS (20.8mo vs 17.9mo, p = 0.64). V600K/R had lower expression of the MAPK-pathway feedback regulator DUSP6 and glycosyltransferase GCNT1, compared to V600E (p < 0.05). Analysis of TCGA data (122 V600E, 21 V600K/R) confirmed these findings. There was a trend toward higher mutational load in V600K/R than V600E, confirmed with TCGA data (p < 0.05). V600K/R had a higher proportion of mutations in PIK3CA and several tumour suppressor genes (FBXW7, NF2, RB1 and SMAD4), with only FBXW7 confirmed using TCGA data. Conclusions: V600K/R mm has inferior response and shorter survival with MAPKi than V600E, potentially due to less reliance on MAPK pathway activation (lower DUSP6 expression) and greater use of alternative drivers of oncogenesis (higher mutational load, particularly in tumor suppressor genes). Further analyses will be performed, including comparison of MAPK and additional pathway signalling in cell models. Response to immunotherapy will also be examined.
Survival trends among patients with metastatic melanoma in the United States: A population based study.
Authors: Kunwor Ranju , Nepal Mahesh , Ho Dominic , Ghimire Krishna Bilas 
Published: September 2018

9555 Background: Ipilimumab was approved by FDA in March 2011 for the treatment of Metastatic Melanoma. We conducted this study to compare survival outcome in patients with Metastatic Melanoma in pre- (1973-2010) and post- (2011-2013) ipilimumab era in the United States using U.S. Surveillance, Epidemiology, and End Result (SEER) registry database. Methods: We selected patients with metastatic melanoma age ≥ 20 years from the SEER database. We used SEER 18 registry database to evaluate relative survival (RS) rate during 1973-2010 and 2011-2013. The RS rate at 1year and 2 year were analyzed for cohorts by age (20-49 years, 50-74 and ≥75 years), race [White, African American (AA), and others] and gender. The RS rates (%) accompany standard error (SE). We used SEER Stat software for statistical analysis. Results: There were a total of 129,362 (106,516 and 22,846 in pre and post ipilimumab era) metastatic melanoma patients, male (n = 71,220), female (n = 58,142), white (n = 121,843), AA (n = 854) other (n = 1,315) reported in the registry. RS in pre vs post-ipilimumab era for age group 20-49 was: 96.50 ± 0.1% vs 97.20 ±0.3%, P = 0.013; and 94.10 ± 0.1% to 95.60 ±0.40, P = 0.0009; for age group 50-74 was: 94.10 ± 0.1% vs 95.30 ± 0.2%, P = 0.0001; and 90.70 ± 0.1%vs 92.90 ± 0.3%, P = 0.0001; and for age group ≥75 was 90.80 ± 0.3% vs 91.40 ± 0.7%, P = 0.23; and 85.0 ± 0.4% vs 88.10 ± 1.0%, P = 0.011 at 1 and 2 years respectively. Overall RS in pre and post ipilimumab era for white population was: 93.83 ± 0.16% vs 94.567 ± 0.4%, P = 0.017; and 90.0 ± 0.2% vs 92.033 ± 0.6%, P = 0.0008 at 1 and 2 years respectively. Similarly RS for AA was: 78.07 ± 2.93% vs 73.33 ± 8.23%, P = 0.37; and 65.87 ± 3.47% vs 65.33 ± 9.73%, P = 0.94; and for other race was: 85.2 ± 2.13% vs 77.97 ± 5.6%, P = 0.04; and 74.43 ± 5.2% vs 69.67 ± 6.7%, P = 0.1 at 1 year and 2 years. Conclusions: Our study showed that younger (20-74 years) patients with metastatic melanoma have improvement in 1 and 2-year RS rates in post ipilimumab era. Subgroup analysis by race showed no improvement in RS in AA and other races patients during this period. There was also no significant survival benefit seen in older (≥ 75 years) patients of all races and gender in post ipilimumab era.
Clinical presentation of immune-related colitis associated with PD-1 inhibitor monotherapy (MONO) and combination PD-1/CTLA-4 inhibitors (COMBO) in melanoma.
Authors: Wang Daniel Ying , Kim Dae Won , Shah Neil J. , Conry Robert Martin , Mehta Rutika Jitesh , Silk Ann W. , Zhou Alice , Voorhees Amber L , McKee Svetlana B , Norrell Jacqueline , Mehnert Janice M. , Puzanov Igor , Gibney Geoffrey Thomas , Rapisuwon Suthee , Eroglu Zeynep , Johnson Douglas Buckner 
Published: September 2018

9566 Background: Ipilimumab-related colitis has been well described, but the clinical presentation of colitis related to MONO or COMBO therapy has not. We aimed to characterize clinical features that define this serious adverse event. Methods: This retrospective study included melanoma pts with colitis screened from 6 academic centers treated with either MONO or COMBO therapy. Clinically relevant colitis was defined as diarrhea/colitis symptoms requiring systemic steroids. The onset, management, and outcomes related to colitis were summarized. Results: We screened 866 pts and identified 72 with clinically relevant colitis. For the MONO cohort, the incidence was 3.5% (23/657) and 23.4% (49/209) in the COMBO cohort. MONO-colitis occurred at a median 33 weeks (wks) into therapy, while median onset was 8 wks with COMBO therapy. One pt had grade 5 colitis from COMBO therapy. Despite the use of systemic steroids, COMBO-colitis needed more infliximab therapy (38.8% vs 26.1%). The median prednisone equivalent dose was higher for COMBO therapy (1.5 vs 1 mg/kg), and the median taper was shorter for MONO-colitis (4 vs 6 wks). Steroid dose-escalation for worsening symptoms during taper was more common with COMBO-colitis (42.9% vs 17.3%). Relapse was similar between cohorts (MONO: 26.1%, COMBO: 20.4%). Relapses occurred more frequently in COMBO therapy with tapers shorter than the median (38.1% vs 25.0%), and more frequently in MONO therapy with steroid doses lower than the median (60% vs 21.7%). MONO-colitis pts (17.4%) were less likely than COMBO-colitis pts (46.9%) to be restarted on PD-1 therapy. When restarted, only 13% with COMBO therapy relapsed as compared to 50% with MONO therapy. Objective response rates for MONO and COMBO cohorts were 72.7% and 56.1%, respectively. Conclusions: Colitis occurred with a much higher incidence in COMBO therapy. MONO-colitis was associated with a milder course with later onset, shorter duration and lower dose of steroids, fewer dose-escalations, and need for infliximab as compared to COMBO therapy. Relapse of colitis was generally associated with shorter steroid tapers for COMBO therapy and lower steroid doses for MONO therapy.