bluuebunny/crossref_metadata_2025_split huggingface dataset:
A retrospective analysis of the prevalence of EGFR or KRAS mutations in patients (pts) with crizotinib-naïve and crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC).
Authors: Gainor Justin F. , Varghese Anna M. , Ou Sai-Hong Ignatius , Kabraji Sheheryar , Awad Mark M , Katayama Ryohei , Pawlak Amanda , Mino-Kenudson Mari , Yeap Beow Y. , Riely Gregory J. , Iafrate Anthony John , Arcila Maria E. , Ladanyi Marc , Engelman Jeffrey A. , Dias-Santagata Dora , Shaw Alice Tsang 
Published: March 2020

8083 Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC. Recently, several studies have reported that ALK+ pts occasionally harbor concomitant mutations in other oncogenic drivers. Methods: We retrospectively analyzed tumor genotyping data from 1,683 pts with NSCLC seen at 3 U.S. centers from 2009 – 2012 to determine rates of overlapping alterations in EGFR, KRAS and ALK. Mutations in EGFR and KRAS were mainly identified using the SNaPshot multiplexed assay (>95% of cases). ALK FISH was performed in all cases. To determine if this prevalence is impacted by crizotinib, we also updated our earlier analysis (Katayama et al., Sci Transl Med, 2012) of a series of repeat biopsy specimens from 34 crizotinib-resistant, ALK+ pts. Resistant specimens were examined using ALK FISH, SNaPshot, and direct sequencing of the ALK tyrosine kinase domain (TKD). Results: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. 4 pts with KRAS mutations also had abnormal ALK FISH patterns, involving isolated 5’ green probes (3/4 cases) and an isolated 3’ red probe that was unusually small (1/4 cases). Sufficient tissue was available for confirmatory ALK immunohistochemistry (clone 5A4, Novacastra, UK) in 3 of these cases, all of which were negative for ALK expression. Among pts with ALK+ NSCLC and acquired crizotinib resistance, repeat biopsy specimens remained ALK fusion positive in 28/28 (100%) cases. Secondary mutations in the ALK TKD (1151Tins, L1196M, G1202R, S1206Y, and G1269A) were identified in 7/34 (20.6%) cases. L1196M was the most common secondary mutation (3/34, 8.8% cases). ALK gene amplification was present in 3/28 (10.71%) pts. No EGFR or KRAS mutations were identified in 23 crizotinib-resistant, ALK+ pts with sufficient tissue for testing. Conclusions: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK+ pts with acquired resistance to crizotinib.
Multitargeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials.
Authors: Liang Wenhua , Zhang Li 
Published: March 2020

8089 Background: Novel multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have showed promising advantages in combination with chemotherapy or as monotherapy in treatments of advanced non-small cell lung cancer (NSCLC). Since the efficacy and safety of these small molecules have been evaluated by several phase II/III randomized controlled trials (RCTs), we seek to summarize the current evidences by performing a meta-analysis. Methods: PubMed, EMBASE, the Cochrane Library as well as the ASCO and ESMO databases were searched for eligible literatures. We defined the experimental arm as MATKI-containing group while the control arm as MATKI-free group. The endpoints being evaluated included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR), as well as adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data, with 95% confidence intervals (CI) were calculated using REVMAN 5.0. Subgroup analysis was conducted according to each agent respectively. Results: Five agents (vandetanib, sunitinib, cediranib, sorafenib, motesanib) with comparable data could be analyzed. Fifteen phase II/III RCTs that involved a total of 8854 participants were included. Compared to MATKI-free group, MATKI-containing group was associated with significant longer PFS (HR 0.824, 95% CI 0.759 to 0.895, P<0.001), superior ORR (OR 1.27, 95% CI 1.13 to 1.42, P<0.0001) and DCR (OR 1.14, 95% CI 1.04 to 1.25, P=0.006). However, although some improvement in OS was observed, the benefit did not reach statistical significance (HR 0.962, 95% CI 0.912 to 1.015, P=0.157). In terms of subgroup results, sorafinib was revealed to yield no improvement in all endpoints. The specific AEs in patients who received these agents were rash, diarrhea and hypertension. Conclusions: Regimens consisting of multitargeted antiangiogenic TKIs were superior to those without these agents in terms of tumor response and PFS in patients with advanced NSCLC. However, no significant benefits in OS were observed. In addition, sorafinib seemed to has no substantial efficacy for NSCLC patients.
Potential chemo-sensitization effect of tergenpumatucel-L immunotherapy in treated patients with advanced non-small cell lung cancer (NSCLC).
Authors: Morris John Charles , Rossi Gabriela R. , Harold Nancy , Tennant Lucinda , Ramsey William Jay , Vahanian Nicholas N. , Link Charles J. 
Published: March 2020

8094 Background: Lung cancer is the leading cause of cancer-related mortality. Tumor progression after initial chemotherapy has a poor prognosis. A major obstacle is chemo-resistance, thus targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents with limited toxicities are needed. We report that tergenpumatucel-L (HyperAcute-Lung immunotherapy, HAL) shows signs of chemo-sensitization to follow-up treatment after progression in immunized patients. This drug exploits a potent innate immune mechanism that normally functions to destroy cells expressing a common xenoantigen (αGal). HAL immunotherapy consists of injecting patients with genetically modified allogeneic NSCLC cells bearing αGal moieties on their cell surface. Methods: This phase II study included 28 patients with metastatic or recurrent NSCLC, age ≥18, ECOG PS ≤2, ≤2 prior systemic therapies. Trial objectives were response rate, safety and immunogenicity. Patients received 300 x 106HAL cells q2wks x 8 doses. Adverse events were assessed using CTCAE v3. Immunogenicity was assessed by changes in serum anti-αGal titers and IFN-γ response. Patients progressing on study trial (n=16) received follow up chemotherapy. Response was evaluated using RECIST criteria. Results: Twenty-eight (28) patients were evaluable for response and 16 progressing patients received salvage chemotherapy. Median overall survival (OS) was 11.3 months (95% CI 3.8-21.9). Eight of 28 patients demonstrated stable disease (SD) ≥16 wks including one patient that progressed and later regressed to survive >50 months. Fifty six percent (9/16) of the progressing patients receiving follow up chemotherapy showed a response. Five (31%) achieved a PR and 25% (4/16) had SD after initial progression during the trial suggesting a chemo-sensitization effect of tergenpumatucel-L. Conclusions: HAL immunotherapy is safe and feasible. The median OS compared favorably to that reported in patients receiving 2nd line chemotherapy for relapsed or advanced NSCLC. The potential chemo-sensitization effect of tergenpumatucel-L is highly encouraging and currently being studied in a phase IIB/III trial. Clinical trial information: NCT00073398.
Randomized, blinded, placebo-controlled phase II trial of docetaxel and bavituximab as second-line therapy in locally advanced or metastatic non-squamous non-small cell lung cancer.
Authors: Shtivelband Mikhail , Spigel David R. , Gerber David E. , Jain Minish Mahendra , Ponomarova Olga V. , Giorgadze Davit , Shan Joseph , Menander Kerstin B. , Belani Chandra Prakash 
Published: March 2020

8095 Background: Bavituximab (B) is a monoclonal antibody against phosphatidylserine (PS) with a selective tumor vascular-directed immune response. The purpose of this trial is to evaluate the efficacy and safety of B or placebo (P) combined with docetaxel (D) in patients with locally advanced or metastatic non-squamous NSCLC. Methods: Patients were randomized 1:1:1 to receive 75 mg/m2 of D every 21 days for up to 6 cycles combined with weekly blinded infusions of P, 1mg/kg B or 3 mg/kg B until disease progression or unacceptable toxicity. Primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). Safety was evaluated by adverse events (AEs), vital signs, CBC, biochemistry, urinalysis, coagulation, ECG. Post study unblinding, a PK substudy revealed vial coding discrepancies in the P and 1 mg/kg vials. As a result, data from these two groups were pooled to form the control (C) arm in the analysis. Results: Forty-one patients were entered into the 3mg/kg B+D arm and 80 into the control arm. No significant differences were seen in age, gender, ethnicity or disease stage. ECOG 2 was 13% in C and 24% in 3 mg/kg B+D arms. At this analysis, 54% death events have been reported in 3 mg/kg B+D and 71% in C arm. ORR is 17.1%/13.8% and median PFS is 4.5/3.3 months for 3 mg/kg B+D/C. Median OS is 11.7 months for 3 mg/kg B+D and 7.3 months for C. The safety profile for 3 mg/kg B+D was similar to that of C in severity and frequency. No other safety signal was identified. Conclusions: This randomized, placebo-controlled phase 2 trial demonstrated a positive trend favoring 3 mg/kg B+D in ORR, PFS and OS. 3 mg/kg B in combination with D was well tolerated and is the planned dose forPhase 3. Clinical trial information: NCT01138163.
Subgroup analysis of crizotinib versus either pemetrexed (PEM) or docetaxel (DOC) in the phase III study (PROFILE 1007) of advanced ALK-positive non-small cell lung cancer (NSCLC).
Authors: Solomon Benjamin J. , Gettinger Scott N. , Riely Gregory J. , Gadgeel Shirish M. , Nokihara Hiroshi , Han Ji-Youn , Hida Toyoaki , Satouchi Miyako , Baldini Editta , Siena Salvatore , Yamamoto Nobuyuki , Horn Leora , Tassell Vanessa Roberts , Polli Anna , Camidge D. Ross 
Published: March 2020

8105 Background: PROFILE 1007 compared the efficacy and safety of crizotinib with that of standard-of-care chemotherapy in patients with ALK+ NSCLC. Although the study was not designed for formal assessment of patient outcomes on crizotinib vs. PEM or crizotinib vs. DOC, due to later interest, we performed retrospective efficacy and safety analyses of patient subgroups treated with crizotinib or each chemotherapy individually. Methods: Patients with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive crizotinib 250 mg PO BID or chemotherapy (PEM 500 mg/m2 or DOC 75 mg/m2, IV q3 wk). Patients with progressive disease on chemotherapy were offered crizotinib treatment in a separate study. In these subgroup analyses, PFS and ORR based on independent radiologic review, and safety were evaluated. Results: Of 347 patients randomized, 172 received crizotinib, 99 PEM, 72 DOC, and 4 no treatment. At data cutoff (Mar 2012), 85 crizotinib patients, 21 PEM patients, and 7 DOC patients were receiving treatment. Median treatment duration was longer in the crizotinib arm (7.1 mo) than in either the PEM (4.1 mo) or DOC (2.1 mo) treatment subgroups. Median PFS was significantly longer on crizotinib (7.7 mo) than on either PEM (4.2 mo; HR, 0.59; P=0.0004) or DOC (2.6 mo; HR, 0.30; P<0.0001). 1-year PFS rates were 31% on crizotinib, 16% on PEM, and 6% on DOC. The ORR on crizotinib (66%) was significantly higher than on either PEM (29%; risk ratio, 2.31; P<0.0001) or DOC (7%; risk ratio, 9.65; P<0.0001). The most common all-causality adverse events with crizotinib were diarrhea (60%), vision disorder (60%), and nausea (55%); with PEM, nausea (38%), fatigue (36%), and decreased appetite (26%); and with DOC, alopecia (47%), neutropenia (43%), and nausea (36%). Conclusions: Crizotinib’s superior efficacy over chemotherapy, with a distinct but generally tolerable and manageable side effect profile in patients with advanced ALK+ NSCLC, was also observed in separate comparisons with either PEM or DOC. In patients receiving chemotherapy, median PFS, 1-year PFS rates, and ORR were all numerically higher on PEM than on DOC. Clinical trial information: NCT00932893.
Clinical implications of routine testing for epidermal growth factor receptor (EGFR) mutations in patients with nonsquamous non-small cell lung cancer (NSCLC).
Authors: Zhu Hui , Arrossi Andria Valeria , Elson Paul , Farver Carol , Tubbs Raymond R. , Murthy Sudish C. , Mason David P. , Mazzone Peter J. , Pennell Nathan A. 
Published: March 2020

8113 Background: EGFR mutation (Mut) testing is recommended for all patients (pts) with advanced NSCLC to identify pts who may benefit from front-line EGFR tyrosine kinase inhibitor (TKI) therapy. In July 2010 the Cleveland Clinic initiated reflex EGFR testing of all new diagnoses of nonsquamous NSCLC, prior to which testing was done only by physician request. A retrospective study was designed to review how this change affected clinical practice in a large academic health center. Methods: All pts with NSCLC that had EGFR Mut testing performed at the Cleveland Clinic from 07/2009 to 02/2012 were included (n=287). Pt characteristics, tumor histology and stage, Mut status, treatments, and pt outcomes were collected from electronic medical records. Special attention was given to pts with EGFR Mut+ who received erlotinib (E). Data were analyzed using Fisher’s exact, chi-square and the Wilcoxon rank-sum tests. Results: See Table. Conclusions: Automatic EGFR mutation testing, recommended in an ASCO provisional clinical opinion in April 2011, was feasible in a large academic center and significantly shortened the time between diagnosis and EGFR status becoming available to guide treatment decisions. Although not statistically significant due to the small sample size, there were positive trends towards increased first line usage of E in pts with EGFR Mut+, better performance status, lower rates of E discontinuation due to toxicity, and higher response rate to E in the automatic testing group. There was no difference in overall survival between the two groups. [Table: see text]
Erlotinib beyond progression study: Randomized phase II study comparing chemotherapy plus erlotinib with chemotherapy alone in EGFR tyrosine kinase inhibitor (TKI)-responsive, non-small cell lung cancer (NSCLC) that subsequently progresses.
Authors: Halmos Balazs , Pennell Nathan A. , Otterson Gregory Alan , Gadgeel Shirish M. , Mekhail Tarek , Snell Michael Robert , Kuebler J. Phillip , Fu Pingfu , Sharma Neelesh , Dowlati Afshin 
Published: March 2020

8114 Background: In EGFR-TKI responsive NSCLC, at progression only some tumor clones might carry resistance mechanisms. This provides a rationale for maintenance therapy with TKIs on progression and is supported by “tumor flares” noted in patients taken off of TKI therapy. Methods: Randomized, phase II study of chemotherapy (pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) in patients with progressive NSCLC following clinical benefit from erlotinib for > 12 weeks. In Arm A Pemetrexed or Docetaxel were given at standard doses every 3 weeks to a maximum of 8 cycles. In Arm B chemotherapy was given with ERL at 150 mg oral daily dose on days 2-19 of each cycle. The primary endpoint was that continuation ERL in this patient population could extend PFS by 50%, from 3 to 4.5 months. The original enrollment goal was 39 pts per arm to allow 80% power to detect such a difference. Results: 46 patients were randomized (Arm A: 24; Arm B: 22). Early termination was due to slow enrollment. Patient characteristics were well balanced except for more females on Arm A (p=0.075). The median PFS on Arm A was 5.4 months and for Arm B was 4.6 months (p=0.569). The median overall survival (OS) on Arm A was 18.7 months and for Arm B 14.7 months (p=0.295). Multiple Cox regression analysis showed an impact of female gender on OS (HR 0.1) but not PFS (HR=0.49). EGFR status was available on 39/46 patients. 17 patients in Arm A and 14 Arm B were mutation positive. In analyzing mutation + only patients, no difference in PFS (p=0.332) or OS (p=0.346) was seen amongst the 2 groups. In the mutation + patients the 6 months PFS for Arm A was 39% and for Arm B was 32%. More toxicity was seen on Arm B as compared to Arm A. Irrespective of causal attribution, 1 grade 5 event occurred on Arm A as opposed to 2 events on Arm B. A total of 7 grade 3/4 events occurred on Arm A while 24 occurred on Arm B. Conclusions: No benefit was seen with the continuation of ERL in addition to chemotherapy as compared to chemotherapy alone in patients who had previously benefited from ERL but then showed progression. The combination arm showed significantly more toxicity. Clinical trial information: NCT00660816.
A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue: Dose response and patient satisfaction data.
Authors: Fife Kate , Spathis Anna , Dutton Susan J. , Blackhall Fiona Helen , Bahadori Ronja , Wharton Rose , O'Brien Mary , Stone Patrick , Benepal Tim , Wee Bee 
Published: March 2020

9503 Background: Fatigue is a very common, disabling symptom in cancer, and particularly severe in lung cancer. Modafinil is a novel central nervous system stimulant, which, along with methylphenidate, is cautiously recommended by the 2013 National Comprehensive Cancer Network Guidelines for fatigue. In this phase IV randomized placebo-controlled trial, we assessed the efficacy of modafinil for managing fatigue in lung cancer. Methods: Adults with locally advanced or metastatic non small cell lung cancer (stages III and IV), ECOG performance status (PS) 0-2 and suffering from fatigue (score 5/10 or greater) were randomised 1:1 to modafinil or matched placebo, 100mg daily for 14 days and 200mg daily for a further 14 days. The primary outcome measure was change in the Functional Assessment of Chronic Illness Therapy fatigue subscale (FACIT-fatigue) at 28 days. The trial was powered to detect a 5-point difference with 80% power and 5% significance allowing for 25% attrition. Dose-response, patient satisfaction and safety were also evaluated. Results: 208 patients were recruited from 24 UK centres. Baseline characteristics were well-balanced. 160 patients completed both baseline and 28 day questionnaires and were included in the modified-ITT analysis. FACIT-fatigue mean change from baseline was modafinil=5.28, placebo=5.11, difference=0.17, (95%CI -4.17, 3.82). Adjustment for baseline fatigue and PS had no impact on outcome. No dose response was seen; the majority of improvement on all scales was seen at 14 days and sustained to 28 days. 47% of the modafinil group and 23% of the placebo group stated the study treatment was not helpful (p=0.132). Adverse events were equal. Conclusions: Both modafinil and placebo led to a clinically significant 5-point improvement in FACIT-fatigue score, but there was no significant difference between the two groups. This well-powered study suggests that there is a large placebo effect and NCCN guidelines should be reviewed. Clinical trial information: NCT00829322. [Table: see text]
Effect of renal function (RF) on outcomes in the adjuvant treatment of older women with breast cancer (>65 years): CALGB/CTSU 49907 (CC) ancillary data study.
Authors: Lichtman Stuart M. , Cirrincione Constance , Hurria Arti , Jatoi Aminah , Theodoulou Maria , Wolff Antonio C. , Gralow Julie , Morganstern Daniel , Magrinat Gustav , Cohen Harvey Jay , Muss Hyman ,   The Alliance for Clinical Trials in Oncology
Published: March 2020

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(<60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function >grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.
End-of-life care for Medicare beneficiaries with ovarian cancer: Evaluation of intensity and rate of hospitalizations.
Authors: Wright Alexi A. , Earle Craig , Keating Nancy Lynn 
Published: March 2020

9523 Background: Patients with advanced cancer are receiving increasingly aggressive medical care at the end-of-life (EOL). Population-based studies have not examined the medical care that ovarian cancer patients receive near death. Methods: We identified a national cohort of 6,956 Medicare beneficiaries who were living in Surveillance, Epidemiology, and End Results (SEER) areas, were diagnosed with epithelial ovarian cancer between 1996 and 2007, and died from ovarian cancer by December 2007. Using multivariable models, we examined rates of aggressive medical care within 30 days of death over time and examined indications for hospitalizations near death. Results: Adjusted rates of intensive care unit (ICU) admissions and emergency department (ED) visits increased significantly between 1996 and 2007 (ICU: 6.4% to 16.6%, p<0.0001 and ≥2 ED visits: 19.7% to 32.1%, p<0.0001). In contrast, late (within 7 days death) or absent hospice referrals decreased (63.1% to 47.8%, p<0.001) and chemotherapy use within 30 days of death decreased slightly (8.1% vs. 7.1%; p=0.04). Although terminal hospitalizations decreased (28.0% to 19.1%, p=0.001), rates of hospitalizations near death increased over time (41.4% vs. 45.3%, p=0.01). The most common indications for hospitalization included: bowel obstructions (20.0%), infections (10.4%), fluid or electrolyte abnormalities (9.2%), and malignant effusions (8.1%). Conclusions: Despite significant increases in the use of hospice near death, utilization of ICUs, EDs, and acute inpatient care at the EOL rose significantly between 1997 and 2007 for older ovarian cancer patients. Future studies should examine whether this high-intensity health care is avoidable given evidence that high-intensity care is associated with lower patient quality-of-life near death and increased complications in bereaved caregivers.