bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC).
Authors: Brahmer Julie R. , Horn Leora , Antonia Scott , Spigel David R. , Gandhi Leena , Sequist Lecia V. , Wigginton Jon , McDonald Dan , Kollia Georgia , Gupta Ashok Kumar , Gettinger Scott N. 
Published: March 2020

7509 Background: BMS-936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T cells. We report here that BMS-936558 mediates antitumor activity in heavily pretreated patients (pts) with advanced NSCLC, a tumor historically not considered to be responsive to immunotherapy. Methods: BMS-936558 was administered IV Q2WK to pts with various solid tumors, including NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Pts with advanced NSCLC previously treated with at least 1 prior chemotherapy regimen were eligible. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 75 NSCLC pts were treated at 1 (n=17), 3 (n= 19), or 10 mg/kg (n=39). ECOG performance status was 0/1/2 in 24/49/2 pts. Tumor histology was squamous (n=17), non-squamous (n=52), or unknown (n=6). The number of prior therapies was 1 (n=9), 2 (n=20), ≥3 (n=45), or unknown (n=1). Ninety-five percent of pts had received platinum-based chemotherapy and 40% had a prior tyrosine kinase inhibitor. Sites of metastatic disease included lymph node (n=50), liver (n=12), lung (n=62), and bone (n=13). Median duration of therapy was 10 wk (max 100 wk). Common related AEs were fatigue (17%), nausea (11%), pyrexia (7%), pruritus (7%), dizziness (7%), and anemia (7%). The incidence of grade 3-4 related AEs was 8%. There was 1 drug-related death due to pulmonary toxicity. Clinical activity was observed at all dose levels (Table) and in multiple histologies. Several pts had prolonged SD. Some had a persistent decrease in overall tumor burden in the presence of new lesions and were not categorized as responders. At the time of data lock, of 10 OR pts, 3 had responses lasting ≥6 mo and 5 were on study with response duration of 1.8-5.5 mo. Conclusions: BMS-936558 is well tolerated and has encouraging clinical activity in pts with previously treated advanced NSCLC. Further development of BMS-936558 in pts with advanced NSCLC is warranted. [Table: see text]
Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC).
Authors: Zhou Caicun , Wu Yi Long , Liu Xiaoqing , Wang Changli , Chen Gongyan , Feng Ji Feng , Zhang Shucai , Wang Jie , Zhou Songwen , Ren Shengxiang , Lu Shun , Zhang Li , Hu Cheng-ping , Luo Yi , Chen Lei , Ye Ming , Huang Jianan , Zhi Xiuyi , Zhang Yiping , Xiu Qingyu 
Published: March 2020

7520 Background: The OPTIMAL study demonstrated significant superiority for E versus GC in terms of progression-free survival (PFS), objective response rate, tolerability and quality of life (QoL) in first-line advanced NSCLC patients with EGFR activating mutations (Act Mut+). Here we report OS data from OPTIMAL (ClinicalTrials.gov NCT00874419). Methods: Chemotherapy-naive Chinese patients with advanced NSCLC and EGFR Act Mut+, ECOG performance status (PS) 0–2 and measurable disease were randomized to E (150 mg/day), or GC, and stratified by histology, smoking status and mutation type. OS at final data cut-off (15 Nov 2011) was evaluated for the entire intent-to-treat (ITT) population. Subgroup analysis of OS by gender, histology, smoking status, PS, presence of skin rash and type of mutation was performed. Details of second- or later-line therapy were also documented for each patient. Results: A total of 165 patients were randomized to treatment and 154 patients received at least one dose of study drug (ITT population; E, n=82; GC, n=72). A total of 7 patients are still responding to erlotinib in the E arm. Post-study therapy included chemotherapy (doublet, n=38, or mono, n=8), or experimental drugs in clinical trials (n=10) in the E arm, and EGFR tyrosine kinase inhibitor (TKI) therapy (n=49) or chemotherapy (n=7) in the GC arm. Post-study treatment was not received by 26 and 16 patients in the E and GC arms, respectively. A total of 84 deaths were reported (E, n=47; GC, n=37). OS did not differ significantly between the two treatment arms (HR=1.065, p=0.6849), and no significant difference in OS was observed in the different subgroups. Conclusions: The lack of a statistically significant difference in OS in the OPTIMAL study was possibly due to a high level of cross-over to EGFR TKI therapy in the GC arm. However, the significant benefits reported with E in terms of PFS, QoL and tolerability in this study suggest that E should be considered as one of the standard first-line treatments for patients with advanced EGFR Act Mut+ NSCLC.
Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion mutations within the tyrosine kinase domain of EGFR.
Authors: Costa Daniel Botelho , Yasuda Hiroyuki , Sng Natasha J , Yeo Wee-Lee , Figueiredo-Pontes Lorena Lobo de , Tenen Daniel G. , Kobayashi Susumu 
Published: March 2020

7523 Background: Epidermal growth factor receptor (EGFR) mutations (M) define an important subgroup of non-small-cell lung cancer (NSCLC). Most patients whose tumors harbor exon 19 deletions or L858R EGFR M have responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs using site-directed mutagenesis and introduced them into Ba/F3 cells for in vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel malignant pleural effusion-derived cell line. Results: The disease control rate of gefitinib or erlotinib was significantly higher in EGFR exon 20 insertion M located within the C-helix (3/3,100%) when compared to M following the C-helix (1/14, 7%; p=0.00059). The NSCLC with EGFR-A763_Y764insFQEA (located within the C-helix of EGFR) achieved a partial response to erlotinib that lasted 18 months. Most other exon 20 insertion M-positive NSCLCs did not respond (p=0.07). Eight representative exon 20 insertion M were studied (including EGFR-A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV, D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA, were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to nanomolar C of erlotinib. A patient-derived cell line with EGFR-A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion mutations are resistant to EGFR TKIs, and in specific EGFR-A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical implications for the care of the 10,000 cases of EGFR exon 20 insertion M NSCLC diagnosed yearly and points towards the need to define the molecular mechanisms that underlie differential responses to EGFR TKIs.
Continuation of EGFR/ALK inhibition after local therapy of oligoprogressive disease in EGFR mutant (Mt) and ALK+ non-small cell lung cancer (NSCLC).
Authors: Weickhardt Andrew James , Scheier Benjamin , Burke Joseph Malachy , Gan Gregory , Doebele Robert Charles , Bunn Paul A. , Gaspar Laurie E. , Kavanagh Brian D. , Camidge D. Ross 
Published: March 2020

7526 Background: This study aimed to investigate the benefits of local treatment of limited disease progression and continuation of crizotinib (C) or EGFR-TKI in patients with ALK+ or EGFR-Mt metastatic NSCLC, respectively. Methods: Patients with advanced ALK+ NSCLC treated with C (n=38) and EGFR-Mt NSCLC treated with EGFR TKIs (erlotinib or gefitinib) (n=27) were identified. Patients were evaluated for initial response, site of first progression (CNS or extra CNS (eCNS)) and median progression free survival (PFS1). A subset of patients with limited sites of progression (oligoprogressive disease) suitable for local therapy received either radiation or surgery to these sites and continued on the same TKI. The subsequent pattern of progression and median progression free survival from the time of first progression (PFS2) were recorded. Results: In 38 ALK+ patients, PFS1=9.0 months on C. In 27 EGFR-Mt patients, PFS1=13.8 months on EGFR-TKI. CNS was the first site of progression in 13/28 (46%) of ALK+ patients and 5/23 (22%) EGFR-Mt patients. 25 of 51 patients who progressed (49%) were deemed suitable for local therapy (15 ALK+, 10 EGFR-Mt; 24 with radiotherapy (Body: 3 XRT, 9 SBRT; CNS: 7 WBRT, 5 SRS), 1 with surgery (adrenalectomy)) and continuation of the same targeted therapy. 19/25 patients progressed post local therapy, median PFS2 = 6.2 months. In patients who progressed at PFS1 only in the CNS, there was a trend to longer PFS2 than patients who progressed at PFS1 in eCNS (7.1 months vs 4.0 months, p=0.26). 60% who progressed only in the CNS at PFS1, progressed eCNS at PFS2 (n=10). Conclusions: Progression of oncogene addicted NSCLC on relevant targeted therapies is often suitable for local therapy (oligoprogressive disease). Continuation of the targeted therapy following local therapy is associated with >6 months of additional disease control. [Table: see text]
Local therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors.
Authors: Yu Helena Alexandra , Sima Camelia S. , Drilon Alexander Edward Dela Cruz , Varghese Anna M. , Pietanza Maria Catherine , Azzoli Christopher G. , Rizvi Naiyer A. , Krug Lee M. , Kris Mark G. , Miller Vincent A. , Riely Gregory J. 
Published: March 2020

7527 Background: The utility of EGFR directed therapy for the treatment of EGFR mutant lung cancer is limited by the development of acquired resistance (AR) to EGFR tyrosine kinase inhibitor (TKI) therapy, which occurs after a median of 16 months (mos). There are no approved targeted therapies after disease progression on EGFR TKI therapy. Local therapy for oligometastatic disease is used with regularity in other solid tumors, and can lead to long term survival in selected individuals. EGFR mutant lung cancers with AR to TKI therapy can follow an indolent course that is amenable to local therapy to treat progression of disease when used in conjunction with continued EGFR inhibition. Outcomes following local therapy in this setting have not been assessed. Methods: Patients (pts) with AR to EGFR TKI’s who received local therapy excluding treatment of CNS metastases or local therapy prior to AR were identified in an IRB-approved prospective registry of 184 pts with AR enrolled from August 2004- November 2011. We collected treatments as well as progression free survival (PFS) and overall survival (OS) after local therapy. Results: 18 pts received local therapy. Treatments included surgical resection and radiation to lung, lymph nodes, adrenal gland or bone. Median age was 57, 56% were women, and 61% were never smokers. 14 had EGFR Exon 19 deletions, and 4 L858R. The median time to development of AR on TKI was 19 mo (range 5-33). Known mechanisms of AR included T790M (11 pts), MET amplification (1 pt) and small cell transformation (1 pt). The median PFS after local therapy was 10 mo (95% CI: 4-NA), median time from local therapy until change in systemic therapy was 22 mo (95%CI: 6 - 30), and median OS from local therapy was 41 mo (95% CI: 26-NA). Local therapy was tolerated well, with 85% of pts restarting TKI therapy within one month of completing local therapy. Conclusions: Local therapy is well tolerated and in combination with continued EGFR TKI therapy prolongs time until change in systemic therapy is required and may lead to outcomes that are superior to currently available treatment options in selected individuals.
Concordance of driver mutations in primary and matched metastasis from patients with non-small cell lung cancer (NSCLC) using next-generation sequencing (NGS).
Authors: Vignot Stéphane , Frampton Garrett , Yelensky Roman , Brambilla Christian , Toffart Anne-Claire , Miller Vincent A. , Palmer Gary A. , Cronin Maureen T. , Lazar Vladimir , Soria Jean-Charles , Stephens Philip , Brambilla Elisabeth 
Published: March 2020

7529 Background: Progress in treating NSCLC continues to be limited by high recurrence rates after definitive treatment of localized disease and frequent presentation with metastatic disease. In these pts, diagnostic samples are often limited in size and may be inadequate for genotyping necessary in this disease. In applying genomic profiling to aid treatment planning for patients with metastatic NSCLC, it is critical to determine whether archived primary tumor adequately reflects the genomic spectrum of the patient’s metastatic disease or whether biopsy of a metastatic site is required. We undertook this study using NGS technology to characterize paired primary-metastatic biopsy genomic profiles. Methods: Primary and matched metastatic tumor pairs plus adjacent normal tissue from 15 pts with NSCLC (adenocarcinoma 9/squamous 4/large cell 2) and heavy smoking history were analyzed using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 778X with 99% of bases covered >100X. Results: Among the 30 tumors, 373 somatic alterations were identified; 96 were known NSCLC drivers including: TP53 (14 pts), KRAS (4 pts), SOX2 (4 pts), STK11 (2 pts), CDKN2A (2 pts) and SMARCA4 (2 pts) in full agreement with their respective histological type. In all cases (15/15), primary and metastatic tumors from the same patient demonstrated 90% driver mutation concordance (74/82, 95 % CI, 82-95%). For other mutations, the majority of which are likely passengers, the 69% (201/291) concordance rate was significantly lower (p< .001).The total number of alterations between primaries (190) and metastases (183) was remarkably similar. Conclusions: These results suggest that genomic profiles of primary tumor can identify the key somatic alterations present in matched NSCLC metastases and therefore is a suitable specimen for clinical decision making in the majority of cases. Our data does not support the routine need for a new biopsy upon recurrence since variability in mutational status is low.
Native and rearranged ALK copy number and rearranged ALK cell count in NSCLC: Implications for ALK inhibitor therapy.
Authors: Camidge D. Ross , Skokan Margaret , Kiatsimkul Porntip , Helfrich Barbara , Schulte Nathan , Maxson DeLee , Aisner Dara L , Franklin Wilbur A. , Doebele Robert Charles , Varella-Garcia Marileila 
Published: March 2020

7534 Background: ALK rearranged NSCLC responds well to ALK inhibitors. Clinically, >15% cells showing rearrangements by break-apart FISH classifies tumors as ALK(+). Native ALK copy number gain has also been reported. We explored the significance of native and rearranged ALK copy number on crizotinib outcomes and whether >15% reflected a clear biological distinction in the frequency of ALK(+) cells. Methods: Copy number and genomic status of ALK assessed by FISH. A total of 1426 NSCLC clinical specimens, 174 ALK(+) and 1252 ALK(-) by standard criteria, and 26 NSCLC cell lines (2 ALK(+) and 24 ALK(-)) were investigated. Results: Native ALK gene mean copy number was significantly higher in ALK(-) than in ALK(+) cases (2.8, SD 0.93, range 1.2-11.4 vs. 1.8, SD 0.79; range 0.6 to 5.2; p<0.01). Frequency of native ALK copy number gain (≥3 copies/cell in ≥40% cells) was 19% in ALK(+) and 62% in ALK(-) tumors (p<0.001). In ALK(-) tumors, abundant focal amplification of native ALK was rare (0.8%); scanty amplification (<10% tumor cells) occurred in 1.1%, and duplication of the entire native ALK or of the ALK 3’ end occurred in 3.5%. Among ALK(-) cell lines, mean native ALK copy number ranged 2.1-6.9 and was not correlated with in vitro crizotinib sensitivity (IC50s 0.34-2.8 uM). In (+) patients, neither native or rearranged ALK copy number, nor percentage cell count correlated with maximal tumor shrinkage or PFS with crizotinib. Clinical specimens with 0-9%, 10-15%, 16-30%, 31-50% and >50% of ALK+ cells were found in 79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Conclusions: Lower native ALK copy number in ALK(+) NSCLC suggests ALK fusion occurs early, preceding chromosomal instability. Elevated native ALK copy number rarely reflects focal amplification and native ALK copy number increases alone are not associated with sensitivity to ALK inhibition in vitro. Neither native or rearranged copy number, nor positive cell count within ALK(+) tumors influences clinical benefit from ALK inhibition. As 8.5% of ALK(-) cases fall within 5% of the established >15% cell positive threshold, further investigation of ALK status by other diagnostic techniques in this subset may be warranted.
Association of epithelial to mesenchymal transition with efficacy of EGFR-TKIs in non-small cell lung cancer patients with EGFR wild type.
Authors: Ren Shengxiang , Su ChunXia , Chen Xiaoxia , Li Jiayu , Li Bing , Li Xuefei , Zhou Caicun 
Published: March 2020

7535 Background: The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype, it has a profound impact on cancer progression and treatment. The purpose of this study was to investigate the role of EMT to predict the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) patients. Methods: We evaluated the correlation between EMT and sensitivity to EGFR-TKIs in advanced NSCLC patients. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, fibronectin, N-cadherin and vimentin and ARMs was used to detect the EGFR mutation in tumor specimens obtained before the treatment. The EMT phenotype status was determined according to the expression of E-cadherin, fibronectin, N-cadherin and vimentin. Results: 101 patients enrolled into this study and 97 had enough tissue to perform the EMT examination. The median age was 59 years old, male/female:56/45, never smoker/smoker: 71/30, adenocarcinoma/non-adeno: 73/28, PS 0-1/2-3: 83/18, Stage IIIB/IV: 2/99, 1st /2nd-4th line: 13/88. The response rate and progression free survival(PFS) in the whole population were 45.5% and 7.6 months respectively. EMT test revealed that 46(47.4%) samples were epithelial phenotype, while 51(52.6%) were mesenchymal phenotype. 38 of 79 patients harbour activating EGFR mutation. Among the patients with EGFR wild type or unknown status, patients with an epithelial phenotype had a higher response rate(40% Vs 17.6%, P=0.056) and significantly longer PFS(7.6 m Vs 3.8 m, P=0.045) than these with a mesenchymal phenotype. However, the response rate(85.7% Vs 64.7%, P=0.249) and PFS(15.2 m Vs 12.2 m, P=0.420) were similar in the patients with activated EGFR mutation. Conclusions: Patients with an epithelial phenotype got more benefit from the treatment of EGFR-TKIs in the advanced EGFR wild type NSCLC patients, which indicated that the EMT might be a potential marker to guide the individual therapy of EGFR-TKIs in this subpopulation.
A randomized phase II study of axitinib in combination with pemetrexed/cisplatin (pem/cis) as first-line therapy for nonsquamous non-small cell lung cancer (NSCLC).
Authors: Belani Chandra Prakash , Yamamoto Nobuyuki , Bondarenko Igor , Orlov Sergey V , Tang Jie , Niethammer Andreas G. , Ingrosso Antonella , Kim Sinil , Scagliotti Giorgio 
Published: March 2020

7551 Background: Axitinib is a potent and selective second-generation inhibitor of VEGF receptors 1, 2, and 3 that has promising single-agent activity in advanced NSCLC. Efficacy and safety of axitinib (in 2 dosing schedules) combined with pem/ciswere evaluatedfor non-squamous NSCLC. Methods: Patients with confirmed stage IIIB, IV, or recurrent non-squamous NSCLC and ECOG performance status (PS) 0 or 1 were stratified by gender and PS, and randomized 1:1:1 to receive six 21-day cycles of axitinib continuously plus pem/cis (arm I); axitinib on Days 2 through 19 followed by a 3-day interruption plus pem/cis (arm II); or pem/cis alone (arm III). Axitinib was administered at a starting dose of 5 mg BID. Pem/cis (500/75 mg/m2) was infused on Day 1 of each cycle. Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics of patients in arm I (n=55), arm II (n=58), or arm III (n=57) ranged between 59–62 yr median age; 62–65% male; 71–85% White; 73–85% current/ex-smokers; and 43–47% PS 0. There were no significant differences in PFS or overall survival (OS) between axitinib-containing arms I and II compared with pem/cis alone, but objective response rates (ORR) were higher (Table). Most common all causality grade 3 adverse events (AEs) in arm I, II, and III, respectively, were hypertension (20%, 17%, 0%); neutropenia (18%, 10%, 9%); nausea (16%, 5%, 7%); vomiting (13%, 5%, 4%); fatigue (11%,16%,16%); and anemia (7%, 14%, 9%). Grade 4 AEs observed in >1 patient were asthenia and pulmonary embolism (2 patients each in arm II). Conclusions: Axitinib combined with pem/cis was generally well tolerated, but efficacy was not significantly better than pem/cis alone in non-squamous NSCLC. [Table: see text]