bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prophylactic cranial irradiation in patients ≥ 70 years old with limited stage small cell lung cancer: A Surveillance, Epidemiology, and End Results analysis.
Authors: Eaton Bree Ruppert , Marcus David Mitchell , Kim Sungjin , Chen Zhengjia , Ramalingam Suresh S , Curran Walter J. , Higgins Kristin 
Published: March 2020

7589 Background: Prophylactic cranial irradiation (PCI) improves survival in patients with limited stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiation (RT). Yet in clinical practice, concerns exist regarding PCI-related toxicity and the extent of benefit in elderly patients. This exploratory analysis evaluates the effect of PCI on survival among patients ≥ 70 years old. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 4,003 patients ≥70 years old with localized or regional SCLC diagnosed between 1988 and 1997. Patients with no brain RT information (n=974) were excluded. Patients with overall survival (OS) <6 months (n=1103) were also excluded to eliminate patients with an aggressive disease course and minimize selection bias. Survival rates for patients who received brain RT versus no brain RT were estimated by the Kaplan Meier method and compared with the Log-rank test. A Cox proportional hazards model was further fitted to estimate the effect of brain RT on OS after adjusting for age, race, gender, and stage. Results: Of the 1926 patients included, the median age was 75 years (range, 70-94). The majority of patients were white (68%) and male (52%). According to SEER Historic Stage A, 68% of patients had regional stage and 32% had localized stage. One-hundred and thirty-eight patients (7.2%) received brain RT. Patients treated with brain RT were younger at diagnosis (p<0.01) and more likely to have regional stage disease (p=0.02). Five-year OS was 11.6% (95% CI: 6.9-17.6) among patients who received brain RT versus 8.6% (95% CI: 7.32-9.91) among patients who did not (p=0.03). Younger age, female gender, white race, and localized stage were also significant factors associated with improved OS. On multi-variable analysis, receipt of brain RT remained an independent predictor of OS (HR 0.825, 95% CI: 0.69-0.98, p=0.03). Conclusions: The receipt of brain radiotherapy is associated with improved overall survival in patients ≥70 years old with localized or regional stage SCLC, suggesting the benefit of PCI is maintained in the elderly population.
A multicenter phase III randomized double-blind placebo controlled trial of pravastatin added to first-line standard chemotherapy in patients with small cell lung cancer (SCLC).
Authors: Seckl Michael , Ottensmeier Christian , Cullen Michael H. , Schmid Peter , James Lindsay E. , Wadsworth Christina , Farrant Hannah , Muthukumar Dakshinamoorthy , Thompson Joyce , Harden Susan , Middleton Gary William , Fife Kate , Crosse Barbara , Taylor Paul , Khan Iftekhar 
Published: March 2020

7595 Background: Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in order to determine if overall survival (OS) was affected by the addition of pravastatin in SCLC. Methods: Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity. Results: Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed > 4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Updated results showing OS, PFS, local PFS and toxicity will be presented. Conclusions: This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients. Clinical trial information: ISRCTN56306957.
Exploratory analyses of efficacy and safety of pemetrexed (Pem) plus bevacizumab (Bev) and bev alone as maintenance therapy (MT) in patients (Pts) with stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC).
Authors: Patel Jyoti D. , Garon Edward B. , Govindan Ramaswamy , Reynolds Craig H. , Spigel David R. , Olsen Mark R. , Hermann Robert C. , Liu Jingyi , Guba Susan C. , Pennella Eduardo J. , Obasaju Coleman K. , Bonomi Philip D. , Socinski Mark A. 
Published: March 2020

8012 Background: In a phase III superiority study, Pem+carboplatin (Cb)+Bev followed by Pem+Bev improved PFS compared with paclitaxel (Pac)+Cb+Bev followed by Bev in NS-NSCLC pts. Superior OS (primary endpoint) was not met. These analyses assessed the efficacy and safety in pts who received MT. Methods: Prespecified exploratory analyses were performed in the maintenance population (MP) and timed from the start of induction. Pts ≥18 years with stage IIIB/IV NS-NSCLC (ECOG status 0–1) from the multicenter, randomized, open-label, phase III superiority study were included in the MP if they received at least one dose of MT. For MT, pts received intravenous Pem 500 mg/m2+Bev 15 mg/kg (n=292) or Bev 15 mg/kg (n=298). OS, PFS, and safety were evaluated. Comparison is made to the intent-to-treat (ITT; Pem=472, Pac=467) or safety population (SP; Pem=442, Pac=443; received at least one dose of one drug). Results: Baseline pt and disease characteristics for the ITT and MP were similar between arms. In the ITT/MP population, the median number of cycles was 7/10 (range, 1-41/4–41) in the Pem arm and 6/9 (range, 1-39/5–39) in the Pac arm. In the ITT/MP, OS was 12.6/17.7 months (mos; Pem) and 13.4/15.7 mos (Pac). Survival rates (%) at 12 and 24 mos with Pem (ITT/MP) were 52.7/71.7 and 24.4/34.5; Pac, 54.1/66.5 and 21.2/26.5%. In pts not receiving MT, OS was 4.7 mos (Pem) and 6.1 mos (Pac). PFS (mos) in the ITT/MT was 6.0/8.6 (Pem) and 5.6/6.9 (Pac). In pts not receiving MT, PFS was 2.3 mos and 2.5 mos with Pem and Pac, respectively. From induction, both SP/MP had significantly more grade 3/4 thrombocytopenia, anemia, and fatigue with Pem and neutropenia and sensory neuropathy with Pac (p≤0.001). During MT only, the difference in grade 3/4 neutropenia rates between arms was no longer significant. Conclusions: Improved efficacy outcomes were consistent with previous Pem maintenance and Bev studies and no new toxicities were observed. Clinical trial information: NCT00762034.
65 plus: A randomized phase III trial of pemetrexed and bevacizumab versus pemetrexed, bevacizumab, and carboplatin as first-line treatment for elderly patients with advanced nonsquamous, non-small cell lung cancer (NSCLC).
Authors: Schuette Wolfgang , Nagel Sylke , Schneider Claus-Peter , Engel-Riedel Walburga , Schumann Christian , Kohlhaeufl Martin , Serke Monika , Hoeffken Gert , Kortsik Cornelius , Reck Martin 
Published: March 2020

8013 Background: Pemetrexed (P) and bevacizumab (B) are efficacious drugs for treatment of non-squamous NSCLC. In this trial the benefit of combining PB with carboplatin (C) was investigated in elderly patients (pts) ≥ 65 years with NSCLC. Methods: In this German multicenter (27 centers), open-label phase III trial pts with stage IIIb/IV non-squamous NSCLC were recruited. Pts were randomized 1:1 to P (500 mg/m2) + B (7.5 mg/kg) or P+B+C (AUC5) d1 q3 wks for 4 to 6 cycles followed by maintenance therapy with B or P+B. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), 1-year survival rate, overall response rate (ORR) as well as tolerability (AEs/SAEs). Results: 271 pts were enrolled from Sep 2009 to Jan 2012, the ITT population consists of 251 evaluable pts, less than 10 pts are still receiving maintenance therapy. Baseline characteristics were balanced between both treatment groups (PB 118 pts, PBC 133 pts). Median age was 71 years in PB and 72 in PBC. Median PFS time was 4.8 mo in PB and 6.8 mo in PBC. Treatment comparison for ECOG performance status (PS) 0-1 subgroup (PB 112 pts, PBC 126 pts): p=0.0426 (Wilcoxon test), hazard ratio (HR) = 1.31 (95% CI 0.99-1.73). ORR was 31.4% in PB vs. 44.4% in PBC (p=0.0343). Median OS time was 11.6 mo in PB vs. 15.2 mo in PBC. Treatment comparison ECOG PS 0-1: p=0.2050, HR = 1.20 (95% CI 0.85-1.70). 1-year survival rates were 48.2% and 58.8%, respectively. Compared to this the median OS time in the small group of pts with ECOG PS 2 was 11.5 mo in PB vs. 3.8 mo in PBC. AE grade 3/4 and SAE profiles were comparable in both treatment arms, 76 pts (64.4%) with AEs grade 3/4 in PB and 87 pts (65.4%) in PBC, 58 pts (49.2%) with SAEs in PB and 64 pts (48.1%) in PBC. 46 pts (39.0%) in PB vs. 69 pts (51.9%) in PBC received maintenance therapy. Conclusions: Combination of PBC demonstrates with a median OS of 15.2 mo a strong efficacy with acceptable toxicity profile for elderly patients. Addition of carboplatin is recommended for eligible patients. However, in patients with ECOG PS 2 the administration of carboplatin must be carefully reviewed. Clinical trial information: NCT00976456.
NTRK1 gene fusions as a novel oncogene target in lung cancer.
Authors: Doebele Robert Charles , Vaishnavi Aria , Capelletti Marzia , Le Anh T. , Kako Severine , Butaney Mohit , Mahale Sakshi , Aisner Dara L. , Haas Julia , Andrews Steven W. , Lipson Doron , Stephens Philip J. , Varella-Garcia Marileila , Janne Pasi Antero , Miller Vincent A. 
Published: March 2020

8023 Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIP-NTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.
A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) for patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Authors: Johnson Melissa Lynne , Hart Eric M , Rademaker Alfred , Weitner Bing Bing , Urman Alexandra , Simm Hala D , Fountas Leanne M , Worden Rebekah , Patel Jyoti D. , Miller Vincent A. , Riely Gregory J. 
Published: March 2020

8036 Background: AUY922 is a synthetic HSP90 inhibitor that degrades client onco-proteins including EGFR. Preclinical studies demonstrate HSP90 inhibitors are effective agents against models of AR in EGFR-mutant lung cancer cell lines and xenografts harboring the “gatekeeper” mutation EGFR T790M. Pts with EGFR mutations who develop AR often continue E with 2nd-line therapies to avoid “disease flare” associated with discontinuing TKI. This phase II study combines AUY922 and E for the treatment of pts with EGFR-mutant lung cancer and RECIST-progression on 1st-line EGFR TKIs. Methods: Eligible pts had EGFR mutations and developed AR (Jackman, JCO 2010) after treatment with EGFR TKIs. Pts underwent tumor biopsies after developing AR and prior to study entry. Pts received AUY922 70 mg/m2 IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment occurred at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR+PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (≥2 responses needed to proceed to stage II), stage II: 9 pts; α=10%, β=10%, p0=10%, p1=30%). Tumor tissue from re-biopsy at study entry was analyzed for EGFR T790M. Results: Sixteen pts have been treated (10 women, median age 58 [range 47-76]). The median time on EGFR-TKI prior to the development of AR was 12 mo (range 2-42 mo). Seven pts had EGFR T790M confirmed by tumor re-biopsy. ORR was 2/16 (13%, 95% CI 2-37%). Both pts with PR had EGFR T790M. Four other pts had stable disease for at least 8 wks, two remain on study after more than 12 wks. Adverse events reported in ≥20% of pts were diarrhea, fatigue, myalgias, nausea, and transient flashing lights or night blindness. One pt each experienced grade 3 diarrhea and cardiac abnormalities. Conclusions: AUY922 and E is a well-tolerated regimen for pts with EGFR-mutant lung cancer and AR to EGFR TKIs. Two pts remain on study and 9 additional pts will be accrued in stage II; final response rate and survival outcomes will be reported. Supported by Novartis, Inc. Clinical trial information: NCT01259089.
A randomized phase II trial comparing continuation maintenance therapy with pemetrexed and switch maintenance therapy with docetaxel after first-line therapy with carboplatin and pemetrexed in patients with advanced nonsquamous non-small cell lung cancer.
Authors: Karayama Masato , Inui Naoki , Kuroishi Shigeki , Yokomura Koshi , Toyoshima MIkio , Shirai Toshihiro , Masuda Msafumi , Yamada Takashi , Yasuda Kazumasa , Suda Takafumi , Chida Kingo 
Published: March 2020

8038 Background: Emerging evidence suggests that maintenance chemotherapy could prolong survival in patients with advanced non-small-cell lung cancer (NSCLC), whereas the optimal treatment strategy remains controversial. Methods: We conducted a randomized phase II study to compare the efficacy and safety of continuation maintenance with pemetrexed (500 mg/m2) and switch maintenance with docetaxel (60 mg/m2) in patients with non-squamous NSCLC who achieved disease control after first-line chemotherapy with four cycles of carboplatin (AUC 6) and pemetrexed (500 mg/m2). Results: Eighty-five patients participated in the study, and 26 and 25 patients were randomized to the pemetrexed and the docetaxel maintenance therapies, respectively. The docetaxel group showed a trend toward longer progression-free survival (median 8.2 months, 95% CI; 3.9-12.2 months) compared with the pemetrexed group (median 4.1 months, 95% CI; 3.0-6.1 months), but not significantly (log-rank p=0.084). Grade 3/4 hematologic toxicity was significantly more frequent in the docetaxel group (80%) than the pemetrexed group (20%, p<0.0001). Conclusions: Continuation maintenance with pemetrexed after induction therapy with carboplatin and pemetrexed may be an efficacious treatment with less toxicity. In contrast, switch maintenance with docetaxel frequently causes severe hematologic toxicity but may be more efficacious. Further studies are warranted to evaluate the risks and benefits of maintenance therapies. Clinical trial information: 000004075.
Exploratory analysis of angiotensin converting enzyme (ACE) and aldosterone (Ald) serum levels as prognostic and predictive biomarkers on the NCIC CTG BR24 trial.
Authors: Bar Jair , Ding Keyue , Zhao Huijun , Laurie Scott Andrew , Han Lei , Shepherd Frances A. , Addison Christina L. , Goss Glenwood D. , Dimitroulakos Jim , Bradbury Penelope Ann 
Published: March 2020

8048 Background: Benefit from angiogenesis inhibitors (AI) has been linked to high blood pressure. One of the main determinants of blood pressure is the renin-angiotensin axis. We undertook an exploratory, retrospective analysis of ACE and Ald serum levels on specimens banked during the conduct of the BR24 study. The aim was to evaluate these markers for their prognostic significance and their predictive value regarding Cediranib (Ced) treatment. Methods: The NCIC CTG BR24 study randomized advanced non-small cell lung cancer patients (pts) to carboplatin and paclitaxel (CP) +/- Ced. ACE and Ald serum levels were retrospectively tested on baseline samples using commercial ELISA kits. A graphic method, differentiating treatment effect by the range of marker, was used to determine cutoff points (JCO 2010, 28: 5247). Exploratory analyses were performed to correlate biomarkers levels with pts characteristics and overall survival (OS). Association between categorical variables was assessed by Chi-square test or Fisher’s exact test; time to event correlation with biomarkers was tested using a Cox regression model. Potential confounding factors including medications were integrated into the statistical model. Results: Biomarker data was available in 226 of 296 randomized pts. The tested pts vs. all the randomized pts were more likely to have a lower performance status (PS, p=0.03), a normal LDH (p=0.05) and to be ever-smokers (p=0.015). The determined cutoffs were ACE: 115ng/ml and Ald: 250 pg/ml. High ACE was associated with a better PS (p=0.03). High ACE levels were prognostic for longer OS (adjusted HR 0.52 [95%C.I. 0.29-0.92], p=0.025). High ACE pts had no OS benefit (HR 1.27 [95% C.I. 0.78–2.08], p=0.34), while low ACE predicted OS benefit from the addition of Ced to CP (HR 0.64 [95%CI 0.42-0.97], p=0.03). Interaction p value=0.03; this remained significant after adjustment in multivariate analyses. Ald levels were neither prognostic nor predictive. Conclusions: This exploratory analysis suggests high ACE serum levels maybe prognostic for better OS, while low ACE may predict benefit from Ced when added to CP.
Molecular marker assessments for epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) and histoscore (H-score) in the phase III SELECT trial.
Authors: Kim Edward S. , Chittoor Sreenivas , Reynolds Craig H. , Simms Lorinda , Saxman Scott 
Published: March 2020

8052 Background: SELECT was a phase III study that investigated whether the addition of cetuximab (C) to pemetrexed (P) improved outcome in previously treated patients (pts) with recurrent or progressive non-small cell lung cancer (NSCLC). Clinical results have been reported previously and demonstrated that adding C to P did not improve progression-free survival (PFS) or overall survival (OS). H-score has been reported to be a potential predictor of outcome for C therapy. Prespecified biomarker analyses, including EGFR IHC and H-score, are reported here. Methods: EGFRexpression in tumor tissue was not required for eligibility; however, tissue was collected and analyzed for EGFR expression by IHC using standard methods. In addition, H-score evaluation was performed by trained central pathologists and correlated with clinical outcome using a predefined cutoff for “low” and “high” of <200 and ≥200, respectively. Results: A total of 449 (IHC) and 406 (H-score) pt specimens were evaluable. Demographics for pts with tissue available for EGFR analysis were similar to the overall population. For IHC+ pts (n=396), median PFS for C+P was 3.02 months (95% CI, 2.76–3.45) compared with 2.99 months (95% CI, 2.63–4.14) for P (HR, 1.02 [95% CI, 0.83–1.24]; p=.86). For pts with low H-score (N=99 [C+P] and N=111 [P]), median PFS was 2.7 months (95% CI, 1.8–3.2) with C+P and 3.1 months (95% CI, 2.6–4.1) with P (HR, 1.11 [95% CI, 0.84–1.46]; P=.48); median OS was 6.7 months (95% CI, 5.3–8.6) with C+P and 6.6 months (95% CI, 4.7–9.2) with P (HR, 0.96 [95% CI, 0.72–1.27]; P=.76). Among pts with high H-scores (N=101 [C+P] and N= 95 [P]), median PFS was 3.2 months (95% CI, 2.7–4.6) with C+P and 3.7 months (95% CI, 1.7–4.5) with P (HR, 1.02 [95% CI, 0.77–1.37]; P=.86); median OS was 7.7 months (95% CI, 6.5–10.9) with C+P and 8.0 months (95% CI, 7.0–9.1) with P (HR, 1.17 [95% CI, 0.86–1.57]; P=.32). Conclusions: EGFR H-score was not predictive of benefit for the addition of C to P in this population of pts with NSCLC. There was also no treatment effect in the IHC+ group. Clinical trial information: NCT00095199.