bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors influencing outcome in thymic epithelial tumors (TET).
Authors: Porter Ryan Frederick , Radovich Milan , Rojas Luis , Suleiman Yaman , Conces Madison , Shirar Kristen L , Nelson Robert P , Spittler Aaron John , Burns Matthew , Kesler Kenneth , Badve Sunil S. , Schneider Bryan P. , Loehrer Patrick J. 
Published: March 2020

7108 Background: TET represent a heterogeneous collection of rare tumors, thymoma and thymic carcinoma (TC). Prognosis is often based on WHO histology and Masaoka Stage (MS) with small series often lacking long-term follow-up or advance stage disease. We examined predictors of relapse, disease-free survival (DFS) and overall survival (OS) based on WHO classification and MS. Methods: A retrospective analysis was performed on patients(pts) with TET seen at IUSCC from 1976 to 2011 with available tissue blocks. MS, WHO histology, demographics, autoimmune co-existence and non-TET neoplasms were correlated with DFS and OS (via Kaplan-Meier analysis). Results: Of 251 pts identified, MS at diagnosis was I(n=74), II(n=43), III(n=71), IVa(n=38), IVb(n=12) and indeterminate (n=13). The histology were thymoma (n=195) and TC (n=56). Median age was 51(10-88) and (M:F =121:130). Autoimmune disease was present (n=82) (myasthenia gravis n=52) and non-TET neoplasms (n=36). Therapy after diagnosis included surgery alone (n=115), radiation (n=29), chemo (n=71), chemo-radiotherapy (n=29), indeterminate(n=7). Median follow up was 69 months (1 to 399.5). DFS for stages I,II,III at 5 years was 83%, 71% and 39%; DFS was associated with MS (p<.001) and WHO classification (p=.028). The 5yr and 10yr OS for stages I, II, III, IVa, IVb were 90%, 94%, 80%, 55%, 14% and 65%, 52%, 53%, 28%, 0%. The 5yr OS for WHO classification were: A/AB-89%, B1/B2/B3-98% and C-30% and 10yr survivals were 89%, 62%, 0%. OS was associated with MS (p<.01) , WHO classification (p<.001) and autoimmune disease (p=.03). Late relapses (>5yr) occurred in 13 (23%) pts, including 3 with Stage I and 2 with WHO A classification. Conclusions: MS, WHO classification and autoimmune disorders were statistically significant with OS and with DFS for MS and WHO. TC prognosis is significantly worse than thymoma. The improved OS with autoimmune disease requires further investigation but raises the possibility of benefit derived from earlier diagnosis and/or heightened immune surveillance. These data support the notion that all TET, regardless of histologic subtype or clinical stage, are malignant with a capacity for metastasis. As relapses beyond 5 years are common, lifelong follow-up for TET is recommended.
SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) with or without cetuximab (C) in recurrent or progressive non-small cell lung cancer (NSCLC) after platinum-based therapy.
Authors: Kim Edward S. , Neubauer Marcus A. , Cohn Allen Lee , Schwartzberg Lee Steven , Garbo Lawrence E. , Caton John Robert , Robert Francisco , Katz Terry , Chittoor Sreenivas , Simms Lorinda , Saxman Scott 
Published: March 2020

7502 Background: SELECT investigated whether the addition of C to standard chemotherapy improved progression-free survival (PFS) in patients (pts) with recurrent or progressive NSCLC after failure of platinum-based therapy. Methods: SELECT was a multicenter, open label, randomized phase III trial. Per investigator choice, pts received either P (500 mg/m2) or D (75 mg/m2) on day 1 and then were randomized within each group to chemotherapy plus C (400/250 mg/m2) (initial/weekly) or chemotherapy alone. Therapy was given for up to six 3-week cycles; pts randomized to C continued weekly monotherapy until disease progression or unacceptable toxicity. The primary objective was PFS for PC vs. P as determined by an Independent Review Committee (IRC). Secondary endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by IRC, and safety. Preplanned subgroup analyses for epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry and histology were performed. Results for PC vs. P only are presented. Results: Between Jan 2005 and Feb 2010, 938 total pts were randomized. Baseline demographics were comparable between PC (n=301) and P (n=304): median age 64 years; male 60%; Caucasian 88%; KPS 80-100/60-70 84%/16%; squamous/non-squamous 24%/76%. Median PFS (months) PC: 2.89 and P: 2.76 (hazard ratio [HR] =1.03 [95% confidence interval (CI)=0.87-1.21]; p=0.76). Median OS (months) PC: 6.93 and P: 7.79 (HR=1.01 [95% CI=0.86-1.20]; p=0.86). ORR PC: 6.6% and P: 4.3% (odds ratio =1.59 [95% CI=0.78-3.26]; p=0.20). Median DOR (months) PC: 4.17 and P: 6.93 (HR=1.58 [95% CI=0.74-3.36]; p=0.24). There were no statistical differences in efficacy based on histology or EGFR staining intensity. More drug-related AEs/SAEs were observed in the PC arm, with differences mainly attributable to skin toxicities, GI (diarrhea/stomatitis), and hypomagnesemia. Conclusions: The addition of C to P did not improve efficacy in this pt population. Further biomarker analyses are planned. The safety profiles for C and P were consistent with existing data and no new safety signals were observed.
Analysis of resistance mechanisms to ALK kinase inhibitors in ALK+ NSCLC patients.
Authors: Doebele Robert Charles , Aisner Dara L , Le Anh T , Berge Eamon M , Pilling Amanda B. , Kutateladze Tatiana G. , Weickhardt Andrew James , Franklin Wilbur A. , Varella-Garcia Marileila , Camidge D. Ross 
Published: March 2020

7504 Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover, next generation ALK kinase inhibitors are in development. Unfortunately, drug resistance develops after initial benefit (acquired) or occurs in patients who never derive a benefit (intrinsic). This study aimed to define molecular mechanisms of resistance to ALK kinase inhibitors in ALK+ non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK+ crizotinib-treated NSCLC patients experienced radiologic disease progression, of whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS progression, a biopsy was attempted on 19. One of the patients without tissue post-crizotinib then proceeded to a second generation ALK inhibitor and tissue was obtained post progression on this drug. We performed molecular analysis and initiated cell lines from tumor tissue for these 19 patients. Results: 15 patients had material evaluable for molecular analysis. Six patients (40%) developed secondary mutations in the kinase domain of ALK. Two novel mutations were identified in samples from ALK+ NSCLC patients, F1174C and D1203N. Two patients each demonstrated G1269A or L1196M mutations. Two patients each, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). Four patients demonstrated the presence of another oncogenic driver (1 with EGFR mutation; 3 with KRAS mutation) with or without a persistent ALK gene rearrangement. One patient lacked an ALK gene fusion on progression biopsy, but had no identifiable alternate oncogene alteration. 3 patients retained ALK positivity with no identifiable resistance mechanism. Data on additional patients and an in vitro model of copy number gain will be presented. Conclusions: ALK kinase inhibitor resistance in ALK+ NSCLC occurs through a diverse array of kinase domain mutations, ALK gene fusion CNG, and emergence of second (same cell) or separate (different cell) oncogenic drivers. In order to overcome resistance it will be important to differentiate patients that preserve ALK dominance (secondary mutations and CNG) versus those that have diminished ALK dominance (separate or second oncogenic drivers).
SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (adenoBAC), and in never-smokers with primary NSCLC adenocarcinoma (adenoCa).
Authors: West Howard Jack , Moon James , Hirsch Fred R. , Mack Philip C , Wozniak Antoinette J. , Lau Derick , Fehrenbacher Louis , Bury Martin Joseph , Redman Mary Weber , Gandara David R. 
Published: March 2020

7517 Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung adenoCa, have emerged as relevant clinical subpopulations with a high probability of clinical benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), likely related to the high proportion of activating mutations in the EGFR gene in such pts. Based on these results and the potential for increased clinical activity conferred by addition of B to E, SWOG initiated a pair of phase II trials of this combination in pts with adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV q21 days until progression or prohibitive toxicity. Tumor tissue submission for pathologic review and assessment of molecular markers was mandated. Results: Pt demographics of the two trials are as shown in the table below. RECIST response rate among 61 BAC pts on S0635 with measurable disease was 18%, and among 53 NS pts on S0636, it was 47%. Median progression-free survival is 5 and 8 months (mo) on S0635 and S0636, respectively; median overall survival (OS) is 17 and 26 mo on S0635 and S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and hypertension; no treatment-related deaths were reported. Molecular marker studies will be presented separately. Conclusions: In populations selected by clinical parameters, E withB is associated with modest toxicity and encouraging clinical efficacy that exceeded the prespecified OS threshold of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS pts. [Table: see text]
EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study.
Authors: Rosell Rafael , Molina-Vila Miguel Angel , Taron Miquel , Bertran-Alamillo Jordi , Mayo Clara , Vergnenegre Alain , De Marinis Filippo , Massuti Bartomeu , De Castro Javier , Gervais Radj , Carcereny Enric , Buges Cristina , Moran Teresa , Santarpia Mariacarmela , Felip Enriqueta , Majem Margarita , Bosch Joaquim , Cardenal Felipe , Drozdowskyj Ana , Bivona Trever Grant 
Published: March 2020

7522 Background: When EGFR compound mutants (exon 19 deletions or L858R plusT790M) are present at the time of clinical resistance to erlotinib, patients attain longer overall survival (OS) (Oxnard et al. CCR 2011). The H1975 cell line, harboring L858R plus T790M prior to treatment, is sensitive to gefitinib (Sordella et al. Science 2004; Faber et al. Cancer Discovery 2011), though the compound mutant may become dominant after multiple passages in vitro, leading to resistance (Pao et al. PLoS Med 2005). Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). No differences in OS were observed.123 p with remaining available pre-treatment tumor tissue were re-analyzed for the concomitant presence of the T790M mutation with an allelic discrimination Taqman assay in the presence of a PNA clamp designed to inhibit the amplification of the exon 20 wild-type (wt) allele. This assay is capable of detecting the T790M allele at a ratio of 1:5000 wt alleles. Results: The T790M mutation was detected in 21/64 (32.8%) p in the erlotinib arm and 26/59 (44.1%) in the chemotherapy arm. PFS was 12.1 m for p with mutant T790M in the erlotinib arm, 8.8 m for p with wt T790M in the erlotinib arm, 6.3 m for p with mutant T790M in the chemotherapy arm, and 4.5 m for p with wt T790M in the chemotherapy arm (P<0.0001). OS was not reached for p with mutant T790M in the erlotinib arm, 16.1 m for p with wt T790M in the erlotinib arm, 22.6 m for p with mutant T790M in the chemotherapy arm, and 18.4 m for p with wt T790M in the chemotherapy arm (P=0.04). Conclusions: Our unexpected finding that p with EGFR compound mutants attain the maximum benefit from erlotinib suggests a need for more sensitive assays to detect EGFR compound mutants and for studies of inhibitors targeting the EGFR T790M mutation. Whole genome sequencing may provide greater understanding of the genetic factors involved in the differences in OS.
Chemotherapy with erlotinib or chemotherapy alone in advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors (TKI).
Authors: Goldberg Sarah B. , Oxnard Geoffrey R. , Digumarthy Subba , Muzikansky Alona , Jackman David Michael , Lennes Inga Tolin , Sequist Lecia V. 
Published: March 2020

7524 Background: EGFR-mutant NSCLC has an oncogene-addicted phenotype that confers sensitivity to EGFR TKIs. Prior data suggests EGFR addiction persists after development of TKI resistance, leading many clinicians to continue TKI along with chemotherapy (chemo); however, this strategy has not been formally evaluated. Methods: An institutional database was reviewed to identify patients (pts) with advanced NSCLC and acquired resistance to EGFR TKIs by Jackman criteria. Pts were included if they subsequently received chemo. Objective response rate (RR) to chemo/erlotinib or chemo alone was assessed by blinded radiographic review and compared by Fisher’s exact test and multivariable logistic regression. Progression-free survival (PFS) and overall survival (OS) from TKI failure (defined as chemo initiation date) were compared by log-rank test and multivariable Cox analysis. Results: 78 pts were eligible (34 chemo/erlotinib, 44 chemo alone). 70 pts (90%) had a documented EGFR mutation and were on TKI for a median of 15 months (range 4-51); in the 8 pts with unknown genotype the median duration on TKI was 11 months (range 5-16). Baseline characteristics were well balanced except more pts received erlotinib as initial TKI in the chemo/erlotinib group. RR was evaluable in 57 pts and was higher with chemo/erlotinib compared to chemo alone (41% vs 18%; OR 0.31, 95% CI 0.09, 1.04; p=0.08). RR adjusted for chemo regimen and time to TKI failure yielded OR 0.20 (95% CI 0.05, 0.78; p=0.02), favoring chemo/erlotinib. Median PFS was 4.4 months in the chemo/erlotinib group and 4.2 months in the chemo alone group (crude HR=0.84, 95% CI 0.52, 1.38; p=0.50; adjusted HR 0.79, 95% CI 0.48, 1.29; p=0.34). There was no significant difference in OS in the crude or adjusted analyses. Conclusions: This is the first study, to our knowledge, to show that continuation of an EGFR TKI with chemo compared to chemo alone significantly increases the RR in pts with advanced NSCLC and acquired TKI resistance, though we did not observe an impact on PFS or OS. Continued concurrent TKI may be a valuable strategy, particularly for pts with symptomatic progression, when a higher response rate may be beneficial. Further study is warranted.
Characteristics of NSCLCs harboring NRAS mutations.
Authors: Ohashi Kadoaki , Sequist Lecia V. , Sos Martin , Chen Xi , Rudin Charles M. , Moran Teresa , Arcila Maria E. , Lovly Christine Marie , Vnencak-Jones Cindy L , Sasaki Hidefumi , Dias-Santagata Dora , Dubinett Steven M. , Riely Gregory J. , Ladanyi Marc , Franklin Wilbur A. , Kris Mark G. , Camidge D. Ross , Bunn Paul A. , Pao William 
Published: March 2020

7532 Background: We sought to determine the frequency and clinical characteristics of patients with non-small cell lung cancers (NSCLCs) harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS mutant lung cancer cells. Methods: We reviewed data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and clinical history from patients with NSCLC whose tumors underwent systematic screening for driver mutations including NRAS. Patient characteristics examined included age, gender, race, smoking history, disease stage, treatment history, and overall survival (OS). 6 NSCLC cell lines with NRAS mutations were screened for sensitivity against multiple targeted agents. Gene expression was profiled using Affymetrix U133A arrays in 5 NRAS mutant NSCLC cell lines, 8 with EGFR mutations and 17 with KRAS mutations. Results: Among 4524 patients with NSCLC tested, NRAS mutations were present in 29 (0.64%). The types of substitutions found were Q61H/K/L/R and G12A/C/D/R/S, with NRAS Q61L the most common (n=14; 48%). One tumor had a concurrent KRAS mutation. 83% had adenocarcinoma histology, with no significant differences in gender. While 90% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS than in KRAS-mutant NSCLC (KRAS: 66%, NRAS: 13%, p<0.05). Systemic chemotherapy showed limited efficacy in 7 patients with metastatic disease (median OS 7 mos). 5 of 6 NRAS mutant lung cancer cell lines were sensitive to the MEK inhibitors, AZD6244 and GSK1120212, while other targeted agents (against EGFR, ALK, MET, IGF-1R, PIK3CA, BRAF) were minimally effective. Gene expression profiles of NRAS mutant cell lines were distinct from those with KRAS or EGFR mutations. Conclusions: NRAS mutations define a distinct subset of NSCLCs (~1%) with potential sensitivity to MEK inhibitors. While NRAS gene mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.
Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Asian subgroup analysis.
Authors: Ichinose Yukito , Kubota Kaoru , Scagliotti Giorgio , Spigel David R. , Kim Joo-Hang , Shinkai Tetsu , Takeda Koji , Kim Sang-We , Hsia Te-Chun , Li Rubi , Tiangco Beatrice , Yau Stephen , Lim Wan-Teck , Yao Bin , Hei Yong Jiang , Park Keunchil 
Published: March 2020

7549 Background: MONET1 evaluated overall survival (OS) in patients (pts) with nonsquamous NSCLC receiving motesanib (an oral VEGFR 1, 2 and 3, PDGFR and Kit inhibitor) plus C/P compared with pts receiving placebo plus C/P. Analysis of the total population (N=1090) showed that motesanib + C/P did not significantly improve OS vs C/P alone (primary endpoint). Here we present results of a subgroup analysis of Asian pts. Methods: Asian pts (Japan, S. Korea, Philippines, Hong Kong, Taiwan, Singapore) with stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC were analysed. Pts were randomized to up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. Results: 227 Asian pts (incl. 106 Japanese pts) with nonsquamous NSCLC were randomized (Arm A/B, n=110/117); 198 had adenocarcinoma (n=97/101). Median age was 60 y (range 30–78); 80% had stage IV disease. At the time of analysis, 139 pts had died (118 pts with adenocarcinoma). Pts received a median of 164 days of motesanib vs 125 days of placebo (vs 106 and 126 days in non-Asian pts). Median follow-up was 63 wks. Efficacy results are shown in the table. Motesanib/placebo-related AEs were seen in 94/74% of pts respectively; Gr ≥3 related AEs in 48/22%. Most common emergent AEs were (Arm A/B) alopecia (78/76%), diarrhea (63/33%), and nausea (55/43%); gallbladder disorders (Gr 1–2) were seen in 9/2% of pts. Gr ≥3 AEs more frequent in Arm A vs B included neutropenia (36/22%) and hypertension (13/3%). Emergent Gr 5 events were seen in (Arm A/B) 5/4% vs 16/11% in non-Asian pts. Conclusions: In contrast to non-Asian pts, in the subgroup of Asian pts with advanced nonsquamous NSCLC, motesanib plus C/P treatment was associated with increased OS, PFS, and objective response rates (ORR) compared with C/P alone, with no excess of treatment-related mortality. [Table: see text]
Targeting EGFR and ERBB3 in lung cancer patients: Clinical outcomes in a phase I trial of MM-121 in combination with erlotinib.
Authors: Sequist Lecia V. , Modiano Manuel R. , Rixe Olivier , Jackman David Michael , Andreas Karen , Pearlberg Joseph , Moyo Victor M. , Harb Wael A. 
Published: March 2020

7556 Background: Erlotinib is effective in NSCLCs with wild-type EGFR and shows enhanced benefit in EGFR mutation-positive cancers. However, resistance invariably develops, often involving persistent ErbB3 signaling and activation of the PI3K/AKT survival pathway. We present the full results of the Phase 1 study evaluating the safety and tolerability of erlotinib plus MM-121 a fully human IgG2 monoclonal antibody (mAb) to ErbB3. Methods: Eligible patients had advanced stage NSCLC, and ECOG 0-2. Seven cohorts were enrolled, evaluating varying levels of the MM-121 and erlotinib, as well as alternate MM-121 infusion schedules. Tumor response was assessed every 8 weeks. Dose levels were determined by safety and pharmacokinetic (PK) data, and immunogenicity, efficacy endpoints and exploratory biomarker evaluations were performed. Results: From February 2010 – July 2011 32pts entered the study (median age 63y; 45% male; 18% ECOG 0, 82% ECOG 1. 56% had adenocarcinoma and 30% pts received 3 or more lines of prior therapies (range 0-7) with 91% having had prior platinum. 65% had wild-type EGFR status and were never treated or never responded to EGFR-TKIs (EGFRwt) and 28% had acquired resistance to erlotinib treatment (EGFRresist). The most common toxicities (any grade) observed were diarrhea (82%), rash (64%), and fatigue (64%). DLTs observed in different cohorts were diarrhea, mucositis, rash and failure to thrive. Clinical activity was observed including 1 PR (an EGFR TKI naïve EGFR mutant) and 14 SD. Average duration of disease stabilization was 21.6 wks (range 7.1 -89.3 wks). Median PFS is 8.1 weeks and the 16 week PFS rate was 41% in the overall population. For EGFRwt and EGFRresist pts the median PFS were 7.7 weeks and 15.1 weeks, and the 16 week PFS rates were 32% and 44%, respectively. 7/20 EGFRwt pts and 5/9 EGFRresist pts achieved SD. Conclusions: This study suggests that the combination of erlotinib and MM-121 has an acceptable safety profile in heavily pre-treated NSCLC patients with and without EGFR mutations. Early signals of patient benefit were seen and a large randomized phase II study is ongoing.