bluuebunny/crossref_metadata_2025_split huggingface dataset:
RET rearrangements detected by FISH in “pan-negative” lung adenocarcinoma.
Authors: Varella-Garcia Marileila , Xu Liang Guo , Mahale Sakshi , Berge Eamon M , Bennati Chiara , Le Anh T. , Aisner Dara , Crinò Lucio , Bunn Paul A. , Camidge D. Ross , Doebele Robert Charles 
Published: March 2020

8024 Background: RET rearrangements have recently been reported in NSCLC and there is pre-clinical evidence that RET tyrosine kinase inhibitors (TKIs) block activated RET kinase. Efficient and accurate detection of RET rearrangements are crucial for the success of RET TKIs in clinical trials. RET rearrangements have been detected by specialized sequencing techniques with limited applicability to clinical practice. Methods: A 3-target FISH probe set was developed to detect KIF5B-RET fusions and identify patterns suggestive of RET rearrangements with non-KIF5B partners. 51 lung adenocarcinomas negative for EGFR, KRAS, ALK and ROS1 (36 were also negative for 7 other molecular markers) were investigated. Clinical and demographic characteristics were collected. Results: Eight patients (15%) had rearrangements in the RET gene: 5 with KIF5B-RET fusions, 2 with patterns consistent with the CCDC6-RET fusion, and 1 with extra copies of single 3’RET (loss of 5’RET). Atypical FISH patterns were detected both in RET + and negative specimens suggesting high genomic instability in the KIF5B – RET region. RT-PCR assay determined the exon/fusion variant in 4 cases including 2 patients with K15:R12, 1 with K16:R12 and 1 with C1:R12. Median age at diagnosis was 58.5 in the mutation negative and 63 in the RET+ patients. Both cohorts were predominantly male (66% and 56%, respectively), with a majority of never smokers (59 and 89%, respectively), and stage IV disease at diagnosis (72 and 89%, respectively). Two heavily pretreated RET+ patients had stable disease at their initial restaging scans following treatment with the RET inhibitor vandetanib (radiographic assessment per RECIST 1.1); two others had early radiographic progression with sunitinib. Conclusions: The FISH probe proved efficient to detect RET rearrangements in lung adenocarcinomas, involving KIF5B and non-KIF5B partners. Frequency of RET rearrangements in this enriched lung adenocarcinoma cohort was considerably higher than reported in unselected cohorts. Further molecular analyses are being performed to increase understanding of the natural history of this new molecular subtype of NSCLC. Support: B J Addario Foundation, NCI P50CA058187, NCI CCSG P30CA046934.
Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations.
Authors: Carter Corey Allan , Rajan Arun , Szabo Eva , Khozin Sean , Thomas Anish , Brzezniak Christina E. , Guha Udayan , Doyle L. Austin , Keen Corrine , Steinberg Seth M. , Xi Liqiang , Raffeld Mark , Reckamp Karen L. , Koehler Stephen , Gitlitz Barbara Jennifer , Salgia Ravi , Gandara David R. , Vokes Everett E. , Giaccone Giuseppe 
Published: March 2020

8026 Background: KRAS mutations are present in 20% of NSCLC and are associated with primary resistance to erlotinib (E). KRAS mutations result in constitutive activation of the Ras/Raf/MEK/ERK pathway. Selumetinib (S) (AZD6244, ARRY-142886) is a selective and uncompetitive inhibitor of MEK kinase. Preclinical studies demonstrated increased activity in NSCLC cell lines using S+E regardless of KRAS status. Methods: Advanced NSCLC patients with progressive disease after platinum based chemotherapy +/- one other treatment were stratified by KRAS status, which was centrally assessed using macrodissection and pyrosequencing for all mutations involving codons 12, 13, and 61. Patients were randomized to receive either the standard of care E or a combination of S+E in KRAS wild type (wt) and S alone or S+E in patients with KRAS mutations. Single agent E and S were administered orally at 150 mg daily and 75 mg twice daily respectively. Combination dosing were S 150 mg every morning and E 100 mg every evening. The primary endpoint for the KRAS wt group was PFS and for the KRAS mutant group objective response rate. Results: From March 2010 to January 2013, 79 patients screened; 78 enrolled: KRAS mutant, 39; KRAS wt, 40; M/F (39:39); median age: 64 years (33-84); median WHO PS 1(0-2); 66 former and 13 never smokers; 67 adenocarcinoma, 9 squamous cell. Three patients died of complications prior to first evaluation (1 coronary disease, 1 pulmonary fibrosis, and 1 disease progression) of which none were related to S. Dose reductions occurred in 5% E, 40% S, and 56% E+S. Most grade 3/4 AEs occurred in combination therapy; diarrhea (23%), fatigue (23%) lymphopenia (13%), myositis (10%), dyspnea (10%), rash (7%). Discontinuation due to AEs was 8% all occurring in S+E cohorts. Conclusions: This study failed to show improvement of combination therapy over single agent in KRAS wt and mutant patients. Toxicity was increased in the combination arms. Interestingly, the KRAS mutant cohort had longer PFS than KRAS wt patients, although not statistically significant (p=0.11). Clinical trial information: NCT01229150. [Table: see text]
Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial.
Authors: Gandara David R. , Hiret Sandrine , Blumenschein George R. , Barlesi Fabrice , Delord Jean-Pierre , Madelaine Jeannick , Infante Jeffrey R. , Reckamp Karen L. , Lara Primo , Audebert Christine , Cho Byoung Chul , Park Keunchil , Braiteh Fadi S. , Jotte Robert M. , Wu Yuehui , Schramek Daniel J. , Piepszak Alexandra M. , Gardner Olivia S. , Peddareddigari Vijay Gopal Reddy , Leighl Natasha B. 
Published: March 2020

8028 Background: KRAS-mutant NSCLC, usually reflecting tobacco-related carcinogenesis, represents an unmet medical need in lung cancer therapy. Trametinib plus docetaxel (doc) enhances growth inhibition and apoptosis of NSCLC cell lines in vitro with and without RAS/RAF mutations when compared with either agent alone. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib+doc in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib + doc at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 46 NSCLC pts (24 WT [67% had ≥ 2 prior therapies] and 22 KRAS [41% had ≥ 2 prior therapies]) have been treated at the trametinib + doc RP2D (2.0 mg + 75 mg/m2 + growth factors). Diarrhea, fatigue, asthenia, and nausea were the 4 most frequent toxicities. Dose reduction occurred in 10 pts (22%), mostly for diarrhea, fatigue, mucositis, neutropenia, and skin fissures (all 4%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 17%) and 8 stable disease (SD; 44%); additionally, 4 pts had > 20% tumor shrinkage. The current disease control rate (DCR) is 61%; 4 pts have not had postbaseline scans. In WT pts, 5 PR (RR=21%) and 11 SD (46%) were observed (67% DCR). Final response and progression-free survival data will be reported upon maturity. Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + doc (+ growth factors) demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.
Nimotuzumab plus chemotherapy versus chemotherapy alone in advanced non-small cell lung cancer: A phase II, open-label, multicenter, randomized study.
Authors: Prabhash Kumar , Govind Babu Kanaka , Vaid Ashok K. , Rangaraju Ranga Rao , Sirohi Bhawna , Diwakar Ravi , Rao Raghunadha , Kar Madhuchanda , Malhotra Hemant , Nag Shona Milon , Goswami Chanchal , Raina Vinod , Mohan Pedapenki Ravi 
Published: March 2020

8053 Background: To evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods: This multicenter, open-label, phase II study, randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab (200 mg) was administered once weekly for 13 weeks during the first 2 phases with 4 cycles of chemotherapy; docetaxel (75 mg/m2) and carboplatin (area under the curve [AUC] = 5 mg/ml*min), every 3 weeks for a maximum of 4 cycles during the concomitant phase. The primary endpoint was objective response rate (ORR; sum of complete response [CR] and partial response [PR]). Secondary endpoints, overall survival (OS), and progression-free survival (PFS) were estimated using Kaplan-Meier method. Efficacy was evaluated on the intent-to-treat (ITT) and efficacy-evaluable (EE) sets. Safety was assessed from adverse events (AEs) and serious adverse events (SAEs) data. Results: ORR was significantly higher in the nimotuzumab group than in the control group in the ITT (54% vs. 34.5%; P=0.04) population. CR and PR were achieved in 3.6% and 50% patients, respectively, in the nimotuzumab group, and in 4% and 30.9% patients, respectively, in the control group. No significant differences in median PFS and OS were observed. Safety profiles were comparable between the 2 groups. Conclusions: Nimotuzumab plus chemotherapy significantly improved ORR as compared to chemotherapy alone; the combination was safe and well tolerated in stage IIIB/IV NSCLC patients.
Phase II study of metronomic chemotherapy (MC) with bevacizumab (B) in patients (Pts) with advanced (Adv) nonsquamous non-small cell lung cancer (NS-NSCLC).
Authors: Marquette Carrie Lee , Grant Stefan C. , DeShazo Mollie , Reddy Vishnu , Cantor Alan , Miley Debi , Jerome Mary , Robert Francisco 
Published: March 2020

8057 Background: Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in pts with adv NS-NSCLC. The incorporation into MC regimens of antiangiogenic agents has been shown to further enhance efficacy in preclinical models. The goal of this pilot study was to achieve a 30% improvement in the 6.4 months (M) progression-free survival (PFS) observed in ECOG 4599. Methods: Untreated pts with stage 4 NS-NSCLC, PS 0-1 and measurable disease were treated with a 4-week (W) cycle of paclitaxel (80mg/m2 D1, 8, 15), gemcitabine (G) (200-300mg/m2 D1, 8, 15) and B (10mg/m2 D1, 15) for 6 cycles. Pts without progressive disease or significant toxicity (Tx) received maintenance B every 2 w. Primary endpoint:PFS. Secondary endpoints: ORR, OS, Tx and biomarker (BM) correlation. Blood samples for angiogenic (VEGF, sVEGFR2, BFGF, PLGF, PDGFα, Ang-2, IL-8, E-Selectin, ICAM-1, TGFβ-1, SDF-1α, endocan) and antiangiogenic (Thrombospondin-1, Ang-1) bm were collected at different intervals in 21 pts. Response assessment (RECIST) was performed every 8 w. Results: 33 evaluable pts were enrolled. Pt characteristics: median age 59 yrs (37-76), 60% female, 70% > 5% weight loss, 24% never/light smokers, 48% genetic testing (mut EGFR-4; ALK(+)-1), and 9% brain mets. Efficacy parameters are shown in the table. 24 pts had an OR (CR-1, PR-23) and 6 pts had stable disease. No significant differences were observed in the efficacy parameters between former smokers vs. never/light smokers. Worst hematologic and non-hematologic Tx: gr 3 neutropenia (N=1); gr 3/4 nausea/vomiting (N=1); gr 3/4 fatigue (N=2); ischemic colitis (N=1); cerebral ischemia (N=1); gr 3/4 pneumonitis [related to G] (N=2); gr 3/4 proteinuria (N=3), and no gr 3/4 hypertension. Conclusions: While conclusions are limited by the size of the trial, the results are consistent with the hypothesis that the addition of B to MC may result in enhanced anti-angiogenic effect and clinical benefits in adv NS-NSCLC. Analysis of prognostic or predictive bm of angiogenesis will be presented. Clinical trial information: NCT00655850. [Table: see text]
LUX-Lung 6: Patient-reported outcomes (PROs) from a randomized open-label, phase III study in first-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations.
Authors: Geater Sarayut Lucien , Zhou Caicun , Hu Cheng-Ping , Feng Ji Feng , Lu Shun , Huang Yunchao , Li Wei , Hou Mei , Shi Jian Hua , Lee Kye Young , Massey Dan , Lungershausen Juliane , Shi Yang , Zazulina Victoria , Wu Yi Long 
Published: March 2020

8061 Background: Afatinib (A) is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2; ErbB2) and ErbB4. In LUX-Lung 6, A was significantly better than gemcitabine/cisplatin (GC) in terms of progression free survival (PFS) and tumor response, with a more favorable safety profile. Here, we report the PRO results. Methods: 364 pts were randomized (2:1) to receive A or GC. PROs were measured using EORTC questionnaires QLQ-C30/LC13 at baseline and q3w until progression. Changes of ≥10 points (scale 0–100) were considered clinically significant. Analyses of cough, dyspnea and pain were prespecified. Time to deterioration (1st 10-point worsening from baseline) was analyzed using a stratified log-rank test. Percentage improved/worsened by ≥10 points or stable was determined. Mean scores over time were estimated using longitudinal (mixed-effects growth curve) models. Results: Compliance on treatment with questionnaires was >90%. Baseline symptom burden was low (cough: 35; dyspnea: 25; pain: 24). Compared with GC, therapy with A significantly delayed time to deterioration for cough (HR=0.45; p=0.0001), dyspnea (HR=0.54; p<0.0001) and pain (HR=0.70; p=0.03). A higher proportion of A-treated pts had ≥10-point improvements in cough (76% vs 55%; p=0.0003), dyspnea (71% vs 48%; p<0.0001) and pain (64% vs 47%; p=0.003) compared with GC, particularly among pts with baseline symptoms. Mean scores over time for cough, dyspnea and pain also significantly favored A. Consistent with their safety profiles, a significantly higher proportion of A-treated pts had worsening of diarrhea, sore mouth and dysphagia, while fatigue, nausea, and vomiting were significantly worse with GC. Overall, therapy with A significantly improved global health-related quality of life (HRQoL; p<0.0001), physical (p<0.0001), role (p=0.01) and social (p<0.001) functioning compared with GC. Conclusions: In LUX-Lung 6, prolongation of PFS with A was associated with significantly better HRQoL and significantly longer control of lung cancer-related symptoms compared with GC. Clinical trial information: NCT01121393.
First-line carboplatin, pemetrexed, and panitumumab in patients with advanced nonsquamous KRAS wild type (WT) non-small cell lung cancer (NSCLC).
Authors: Mekhail Tarek , Waterhouse David Michael , Hadley Terence J. , Webb Charles D. , Burris Howard A. , Hainsworth John D. , Greco F Anthony , Spigel David R. 
Published: March 2020

8062 Background: KRAS WT colorectal cancer (CRC) is responsive to the EGFR inhibitors panitumumab (P) and cetuximab. Phase III data suggest a small, but statistically significant overall survival (OS) advantage with cetuximab + chemotherapy in KRAS unselected NSCLC (Pirker, Lancet 2009); and phase I data suggest P alone has activity in non-CRC tumors including NSCLC (Weiner, Clin Ca Res. 2008). This single-arm phase II trial examined the safety and efficacy of P in combination with carboplatin (C) and pemetrexed (Pem) in patients (pts) with advanced non-squamous KRAS WT NSCLC. The addition of P was hypothesized to improve the median time-to-progression (TTP) from 3.6 months (mos) (historical) to 5.4 mos (1-sided α .10, 80% power). Methods: Pts with previously untreated, unresectable stage IIIB/IV non squamous KRAS WT NSCLC received P 9 mg/kg, Pem 500 mg/m2, and C AUC=6 IV day 1 every 21 days for 6 cycles, followed by P and Pem maintenance every 21 days until progressive disease or unacceptable toxicity. Responses were evaluated every 2 cycles per RECIST 1.1. KRAS mutation testing was performed centrally (DxS kit). Tissue was also collected for EGFR FISH testing. Results: 60 pts were enrolled; median age, 65 years; 58% female, ECOG PS 0-1 (98%), and prior adjuvant chemotherapy (10%). Median number of cycles was 5 (range 1-22). At a median follow-up of 8.7 mos, the median TTP was 6.2 mos (95% CI: 3.7, 9.5), PFS 6.2 mos (95% CI 3.0, 9.0), 1 year OS 65.5% (95% CI 44.8%, 80%). 23 pts (38%) had partial responses (PR); the disease control rate (PR + proportion with stable disease) was 68%. Treatment-related toxicity (TRT) included (all grades) nausea (38%), fatigue (30%), rash (30%), and mucositis (23%). Severe (grade 3/4) TRT in > 2 pts included: thrombocytopenia (11%), neutropenia (7%), and dehydration (5%). There were no treatment-related deaths. EGFR mutation and FISH analyses will be presented. Conclusions: The addition of panitumumab to carboplatin and pemetrexed in the first-line treatment of advanced KRAS WT NSCLC was safe and well-tolerated; the median TTP of 6.2 mos met the primary endpoint. Definitive assessment of the value of panitumumab in this setting requires a randomized trial. Clinical trial information: NCT01042288.
Phase II study of gefitinib and inserted cisplatin plus docetaxel as a first-line treatment for advanced non-small cell lung cancer haboring an epidermal growth factor receptor activating mutation.
Authors: Kanda Shintaro , Ohe Yuichiro , Horinouchi Hidehito , Fujiwara Yutaka , Nokihara Hiroshi , Yamamoto Noboru , Sekine Ikuo , Kunitoh Hideo , Kubota Kaoru , Tamura Tomohide 
Published: March 2020

8064 Background: Gefitinib yields a longer progression-free survival (PFS) period than platinum–doublet chemotherapy as a first–line treatment for patients with advanced non–small–cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum–doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib alone. Methods: We performed a phase ΙΙ study of the following first–line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1–56. After a two–week rest, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Gefitinib was re–started on day 134 and was continued until progression. The primary endpoint was the two–year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2–year PFS. Results: Thirty–three Japanese patients were enrolled. Twenty–five patients could re–start gefitinib, 12 achieved a PFS period of over 2 years, and 9 continued to receive the protocol treatment without experiencing progression. The 1–, 2–, and 3–year estimated PFS rates were 59.4%, 37.5%, and 33.8%, respectively, and the median PFS time was 19.2 months. The 1–, 2–, and 3–year estimated survival rates were 90.0%, 82.9%, and 62.4%, respectively, and the median survival time had not been reached at the time of analysis. Treatment–related deaths and unexpected severe toxicities were not seen. Conclusions: Our results indicated that first–line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising for patients with advanced NSCLC with EGFR mutation. A phase ΙΙΙ study of this treatment compared with gefitinib alone is warranted. Clinical trial information: 000001738.
Rebiopsy in TKI-resistance: A retrospective analysis.
Authors: Kuiper Justine Leonie , Heideman Danielle , Thunnissen Erik , Paul M A , Smit Egbert F. 
Published: March 2020

8065 Background: EGFR-TKI provides a clinical benefit in patients with EGFR-mutated NSCLC with median progression-free survival (PFS) of 12 months. Several resistance mechanisms (e.g. T790M mutation) have been described, however data are sparse. We analysed EGFR-mutation spectra in NSCLC patients with acquired resistance to TKI. Methods: Biopsies from patients with EGFR-mutation or TKI-response>24 weeks with both pre- and post TKI biopsy available were retrospectively analysed. Information was collected from the medical record. Response to TKI-treatment was assessed according to RECIST. PFS after TKI-treatment was calculated with a Kaplan-Meier curve. Results: 63 patients were included for analysis. Pre- and post TKI biopsy results are described in the Table. 32 patients received 1 (38%), 2 (10%) or 3 (3%) lines of chemotherapy before start of TKI and 18 patients received 1 (13%), 2 (11%), 3 (3%), or 5 (2%) lines of therapy after TKI treatment. Median PFS on TKI-treatment was 12,3 months (range: 1,4 – 43,2). Objective response rate was 61,9%. 47,6% of patients developed the T790M mutation. One patient developed transformation to SCLC with the original exon 19 deletion. One patient with pre-TKI an exon 18 + exon 21 mutation was found to have a KRAS-mutation post-TKI. Conclusions: In this cohort, frequency of development of T790M mutation was consistent with earlier reports. Transformation to SCLC occurred less than described earlier. Two patients did not retain their original mutation. Surprisingly, one patient developed a KRAS mutation: a second primary tumor is not excluded in this case. Rebiopsy in TKI-resistance provides important information on dynamic tumour characteristics and has management implications in certain patients. [Table: see text]