bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial.
Authors: Kelly Karen , Mazieres Julien , Leighl Natasha B. , Barlesi Fabrice , Zalcman Gerard , Gordon Michael S. , Reckamp Karen L. , Gandara David R. , Gomez-Roca Carlos Alberto , Bennouna Jaafar , Cho Byoung Chul , Park Keunchil , Infante Jeffrey R. , Richards Donald A. , Wu Yuehui , Schramek Daniel J. , Cox Donna S. , Gardner Olivia S. , Peddareddigari Vijay Gopal Reddy , Blumenschein George R. 
Published: March 2020

8027 Background: Lung cancer patients with mutated KRAS tumors present a treatment challenge. Trametinib + pemetrexed (pem) enhanced growth inhibition and apoptosis compared with either agent alone in lung cancer cell lines with WT or mutated RAS/RAF. 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 + pem 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 + pem 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, 42 NSCLC pts (22 WT [82% had ≥ 2 prior therapies], 20 KRAS [55% had ≥ 2 prior therapies]) have been treated at the trametinib + pem RP2D (1.5 mg + 500 mg/m2). Nausea, fatigue, and peripheral edema were the 3 most frequent toxicities. 26% of pts reported grade 3-4 hematologic toxicity. Dose reduction occurred in 15 pts (33%), most often for diarrhea, decreased ejection fraction, and fatigue (all 7%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 15%) and 10 stable disease (SD; 50%); additionally, 3 pts had > 20% tumor shrinkage. The disease control rate (DCR) was 65%. Final response and progression-free survival (PFS) data will be reported upon maturity. In WT pts, 3 PR (RR = 14%) and 13 SD (59%) were observed (73% DCR); preliminary median PFS was 5.8 months (95% CI, 2.8-6.7 months). Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + pem 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.
Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy.
Authors: Hanna Nasser H. , Kaiser Rolf , Sullivan Richard N. , Aren Osvaldo Rudy , Ahn Myung-Ju , Tiangco Beatrice , Zvirbule Zanete , Barrios Carlos H. , Demirkazik Ahmet , Gaschler-Markefski Birgit , Voccia Isabelle , Barrueco Jose , Kim Joo-Hang 
Published: March 2020

8034 Background: Nintedanib (N) is an oral inhibitor of VEGFR, FGFR, and PDGFR. This global phase 3 study investigated the safety and efficacy of N + pemetrexed (PEM) vs placebo (P) + PEM in patients (pts) with advanced, non-squamous NSCLC previously treated with chemotherapy. Methods: Pts were randomized 1:1 to N 200 mg po bid + PEM 500 mg/m2 iv q21d (n=353, Arm A) or P + PEM (n=360, Arm B). Continuation until PD or unacceptable toxicity with N, P, PEM, or a combination was permitted. 1° endpoint was centrally reviewed PFS. The null hypothesis was tested on the ITT population after 394 events had occurred (two sided α=5%). 2° endpoints included OS, investigator-assessed PFS, response rate (RR), safety, and QoL. Results: Baseline pt characteristics were balanced between Arm A vs B (median age 59 y, female 45–42%, ECOG PS 1 62-61%, adenocarcinoma 95–93%, prior bevacizumab 8%). Based on a planned DMC futility analysis of investigator-assessed PFS, enrolment was halted after randomizing 713/1300 planned pts (no safety issues identified). Ongoing pts were unblinded and follow-up continued per protocol. Subsequent ITT analysis of the 1° endpoint (centrally reviewed PFS) favored Arm A vs B (median 4.4 vs 3.6 mo, HR 0.83 [95% CI: 0.7–0.99], p=0.04). Disease control was also significantly improved in N-treated pts (61 vs 53%, odds ratio 1.37, p=0.039). No difference in OS (HR 1.03) or RR (9%) was found. Exploratory analyses identified time since start of 1st-line therapy as a predictive marker of improved outcome with N + PEM (ASCO 2013). There was no increase in SAEs or G5 AEs with N + PEM. Addition of N to PEM resulted in a higher incidence of ≥G3 elevated ALT (23 vs 7%), elevated AST (12 vs 2%), and diarrhea (3 vs 1%), but no difference in ≥G3 hypertension, bleeding, thrombosis, mucositis, or neuropathy. Conclusions: The 1° endpoint was met even though the study was stopped prematurely. Treatment with N + PEM significantly improved centrally reviewed PFS vs P + PEM in pts with advanced non-squamous NSCLC previously treated with chemotherapy, and had a manageable safety profile. Clinical trial information: NCT00806819.
Combination chemotherapy with irinotecan and cisplatin (IP) for advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung: A multicenter phase II study.
Authors: Niho Seiji , Kenmotsu Hirotsugu , Sekine Ikuo , Ishii Genichiro , Ishikawa Yuichi , Noguchi Masayuki , Oshita Fumihiro , Watanabe Shun-ichi , Nakajima Ryu , Tada Hirohito , Nagai Kanji 
Published: March 2020

8037 Background: LCNEC and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinoma of the lung. A differential diagnosis between LCNEC and SCLC using a tiny biopsy specimen is frequently difficult. Consequently, prospective clinical trials examining chemotherapy for advanced LCNEC have seldom been reported. We conducted a phase II study of combination chemotherapy with IP in patients (pts) with advanced LCNEC. Methods: The eligibility criteria included a chemotherapy-naïve status, a histological diagnosis of advanced LCNEC, an age of 20-75 years, and an ECOG PS of 0-1. Pts received I (60 mg/m2, days 1, 8, and 15) and P (60 mg/m2, day 1) every 4 weeks for up to 4 cycles. The primary endpoint was the response rate (RR). The sample size was determined to be 44, with a one-sided alpha of 0.1, a beta of 0.2, and expected and threshold values for the primary endpoint of 50% and 30%. Results: 44 pts from 11 institutes were enrolled between Jan 2005 and Nov 2011. The median age was 62.5 years; 21 pts had a PS of 0, and 35 pts were male. 5 pts had stage IIIB, 28 had stage IV, and 11 had recurrences after surgical resection. The RR was 54.5% (95% CI, 38.8-69.6). Grade 3 or 4 neutropenia was observed in 24 pts, but only 3 pts experienced febrile neutropenia. Other toxicities were mild and manageable. The median progression-free survival (PFS) was 5.9 months (95%CI, 5.5-6.3), and the median survival time (MST) was 15.1 months (95%CI, 11.2-19.0). Pathological specimens for a pre-planned central review were available for 41 pts. 30 pts were diagnosed as having LCNEC, whereas 10 pts were diagnosed as having SCLC, and 1 patient was diagnosed as having non-SCLC with a neuroendocrine morphology. Subgroup analyses were shown in the Table. Conclusions: Combination chemotherapy with IP was active in pts with advanced LCNEC, but the RR and the overall survival period in pts with LCNEC seemed to be inferior to those in pts with SCLC. Clinical trial information: UMIN000004796. [Table: see text]
A phase II trial comparing pemetrexed with gefitinib as the second-line treatment of nonsquamous NSCLC patients with wild-type EGFR (CTONG0806).
Authors: Yang Jinji , Cheng Ying , Zhao Mingfang , Zhou Qing , Yan Hong hong , Zhang Li , Song Yong , Chen Jianhua , Feng Weineng , Xu Chong-Rui , Wu Yi Long ,   Chinese Thoracic Oncology Group (CTONG)
Published: March 2020

8042 Background: Pemetrexed or gefitinib is one of the standard second-line treatments for advanced non-squamousNSCLC in East Asia. The CTONG 0806 a multi-center, randomized, controlled, open-label phase II trial was designed to explore the efficacy of pemetrexed versus gefitinib as the second-line treatment in advanced NSCLC patients without EGFR mutation. Methods: The patients with locally advanced or metastatic, non-squamous NSCLC previously treated with platinum-based chemotherapy and no EGFR mutation in exons 18-21 were enrolled. Patients were 1:1 randomized to receive either gefitinib 250 mg per oral every day (G arm) or pemetrexed 500 mg/m2 iv day 1 with vitamin B12 and folic acid supplement every 21 days (P arm) until disease progression, unacceptable toxicity, or discontinuation of treatment due to other reason. The primary endpoint was progression-free survival (PFS). The secondary endpoints were 4-month and 6-month progression-free survival rate, overall survival (OS), objective response rate (ORR), quality of life using the FACT-L questionnaire and safety, EGFR and K-ras mutation status were evaluated and correlated with outcomes. Results: From Feb. 2009 to Aug. 2012, 157 evaluable patients were randomized (81 cases in G arm and 76 in P arm). Baseline age, gender, and ECOG performance status were balanced between arms. The primary endpoint of PFS was met with 1.6 months for G arm versus 4.8 months for P arm, the HR is 0.51 (95% CI 0.36~0.73, P<0.001). Overall response rates were 14.7 % and 13.3 % (P=0.814) and DCR were 32.0% and 61.3% (P<0.001) for G arm and P arm, respectively. OS data were not yet mature. More skin rash and diarrhoea were seen in G arm, but more fatigue and ALT increased in P arm. CTCAE grade 3 or 4 of AEs was 12.3% in G arm and 32.9% in P arm (p=0.002). The further analyses of efficacy evaluated by IRR and biomarkers analysis will be presented on the ground. Conclusions: CTONG0806 is the first trial to show significant improvements in PFS and DCR with pemetrexed compared with gefitinib in second-line setting for advanced NSCLC with EGFR wild type. Patients with EGFR wild type did not benefit from EGFR TKI gefitinb in second-line setting. Clinical trial information: NCT00891579.
Prospective randomised phase II trial of oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P in first-line metastatic or locally advanced non-small cell lung cancer (M or LA NSCLC) with nonsquamous (Non SCC) histological type. NAVoTRIAL01: Final results.
Authors: Bennouna Jaafar , Havel Libor , Krzakowski Maciej , Kollmeier Jens , Gervais Radj , Dansin Eric , Serke Monika , Favaretto Adolfo G. , Cobo Manuel , Szczesna Aleksandra , Ciuffreda Libero , Jassem Jacek , Nicolini Mario , Ramlau Rodryg , Amoroso Domenico , Melotti Barbara , Almodovar Teresa , Vaissiere Nathalie , Riggi Marcello , Tan Eng Huat 
Published: March 2020

8043 Background: NVBo+P is considered as a standard treatment in M or LA NSCLC. The recent approval of Pem+P as front line chemotherapy (CT) for non SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). The importance of histological types was highlighted in a phase III trial (Scagliotti. JCO 2008). Moreover, the higher chemosensitivity of non SCC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). In GLOB 3 study, NVBo+P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan. Ann Oncol. 2009). This trial was set up to assess the efficacy of NVBo+P (Arm A) and Pem+P (Arm B) for pts with Non SCC histological type, evaluated in terms of Disease Control Rate (DCR) (SD+PR+CR). Methods: Pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, pts with DCR received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 11/09 to 02/11, 153 pts were randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively. Conclusions: Even if the current results should be confirmed in a phase III study, the choice of a platinum-based doublet with oral vinorelbine as front-line chemotherapy could be a useful alternative in non SCC. Clinical trial information: 2009-012001-19.
Association between baseline tumor dimensions and survival in advanced non-small cell lung cancer (NSCLC).
Authors: Ahn Daniel H. , Dahlberg Suzanne Eleanor , Sandler Alan , Perry Michael C. , Schiller Joan H. , Brahmer Julie R. , Johnson David H. , Gerber David E. ,   Eastern Cooperative Oncology Group
Published: March 2020

8046 Background: It is not known to what extent radiographic tumor burden is associated with survival in patients with advanced NSCLC. The purpose of this study is to assess whether baseline tumor dimensions are associated with patient survival in advanced NSCLC. Methods: Data were derived from the Eastern Cooperative Oncology Group (ECOG) 4599 trial of carboplatin-paclitaxel (CP) ± bevacizumab (B) for advanced nonsquamous NSCLC. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD) and progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. Results: 759 of 850 patients (89%) enrolled in E4599 had measurable disease and were included in the analysis. 76% of patients were age < 70 years, 46% were female, and 86% were white. Median number of target lesions was 2; median BSLD was 7.5 cm. In univariate Cox models, BSLD predicted OS (HR 1.41; P<0.001) and had a trend toward association with PFS (HR 1.14; P=0.08). OS was 12.6 months (mos) for BSLD < 7.5 cm, compared to 9.5 mos for BSLD ≥ 7.5 cm. This association persisted across both treatment groups (CP: median OS 11.5 vs 8.5 mos; CP+B: median OS 14.1 vs 10.7 mos), when BSLD was categorized according to quartile (median OS: 13.3, 11.5, 11.6, and 8.3 mos; P<0.001), and in a multivariable model controlling for prognostic factors and the presence and site of extrathoracic disease (OS HR 1.24; P=0.01). Conclusions: Radiographic disease burden, as determined by RECIST BSLD, is associated with survival in the E4599 trial. If validated in other populations, this parameter merits consideration in the stratification of patients for clinical trials and may provide important prognostic information for patients and clinicians.
Occurrence of HER2 amplification in EGFR-mutant lung adenocarcinoma with acquired resistence to EGFR-TKIs.
Authors: Altavilla Giuseppe , Arrigo Carmela , Tomasello Chiara , Santarpia Mariacarmela , Mondello Patrizia , Benecchi Sara , Pitini Vincenzo 
Published: March 2020

8047 Background: Patients with EGFR-mutant lung adenocarcinoma develop progression of disease on TKIs therapy after a median of 12 months;this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30% and a SCLC transformation in some pts. Recently, Takezawa and colleagues pointed out that HER2 amplification is a mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers without EGFR T790M mutation. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 41 lung adenocarcinomas pts. (20 male, 21 female, median age 55 years) with EGFR mutations at 19 or 21 exons received TKIs as first line of treatment. 31 pts. (75%) showed a clinical response and relapsed after a mTTP of 12 months. At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR, MET and HER-2 amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all 31 pts. retained their original activating EGFR mutations, 16 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 5, 4 pts. developed MET amplification, 3 pts. were found to have a diagnosis of small cell lung cancer. HER2 amplification was observed in four pts. (13%), with dramatic progression and a median OS of 5 months after treatment with CDDP + pemetrexed. Notably all 4 cases were EGFR T790M negative. Conclusions: Among pts. with acquired resistence to EGFR TKIs the presence of HER2 amplification defines a clinical subset with a more adverse prognosis and rapid progression. Interestingly, recent data suggest that afatinib combined with cetuximab could have promising activity in pts. with acquired resistance due to HER2 amplification.
Randomized phase III trial of gemcitabine and cisplatin versus gemcitabine alone in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) 2: CAPPA-2 study.
Authors: Morabito Alessandro , Gebbia Vittorio , Cinieri Saverio , Viganò Maria Grazia , Bianco Roberto , Barbera Santi , Cavanna Luigi , De Marinis Filippo , Montesarchio Vincenzo , Costanzo Raffaele , Sandomenico Claudia , Montanino Agnese , Mancuso Gianfranco , Nacci Angelo , Giordano Pasqualina , Daniele Gennaro , Gridelli Cesare , Rocco Gaetano , Gallo Ciro , Di Maio Massimo 
Published: March 2020

8066 Background: Platinum-based chemotherapy (CT) is the standard treatment for patients (pts) with advanced NSCLC, but the evidence of its efficacy among ECOG PS2 pts is weak, because these pts are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard CT in these pts. No prospective randomized trial has tested the addition of cisplatin to single-agent CT in pts with advanced NSCLC and PS2. Methods: CAPPA-2 was a multicentre, randomized phase III study for first-line treatment of PS2 pts with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI ed.) and adequate organ function. Patients in standard arm received gemcitabine 1,200 mg/m2 dd1 and 8.Patients in experimental arm received cispaltin 60 mg/m2 d1 plus gemcitabine 1,000 mg/m2 dd1 and 8. All treatments were repeated q3w, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. Results: The study was stopped in June 2012 after the enrolment of 57 pts, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin + gemcitabine (HR 0.52, 95% CI 0.28-0.98, p=0.039). Combination CT produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p=0.017) and higher response rate (4% vs. 18%, p=0.19), without substantial increase in toxicity. Conclusions: Addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC. Clinical trial information: NCT00526643.
Screening for RET and ROS1 fusions in an enriched cohort of pan-negative never-smokers with advanced lung adenocarcinomas to identify patients for treatment in targeted therapy trials.
Authors: Drilon Alexander Edward Dela Cruz , Wang Lu , Hasanovic Adnan , Joubert Philippe , Kris Mark G. , Riely Gregory J. , Ladanyi Marc , Rizvi Naiyer A. 
Published: March 2020

8067 Background: RET and ROS1 fusions have been identified pre-clinically as drivers of tumor growth in lung adenocarcinomas. In addition, based on response to crizotinib in ROS1-positive tumors and emerging data on RET inhibition in some tumors, these fusions represent druggable targets. While each occurs in 1-2% of unselected patients, a screening paradigm based on testing never-smokers whose tumors have no known oncogenic mutations or fusions may enrich identification for ongoing clinical trials. Methods: Patients with a never-smoking history (<100 lifetime cigarettes) and advanced pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, and AKT, and ALK fusions) were selected for testing. Screening for RET and ROS1 fusions was performed in real-time via dual-probe FISH breakapart assays, RT-PCR, and next-generation sequencing in selected cases. We enrolled patients onto a phase II trial of cabozantinib for RET fusion-positive lung cancers (NCT01639508) and, as part of the Lung Cancer Mutation Consortium (LCMC), a phase I trial of crizotinib for ROS1-positive lung cancers (NCT00585195). Results: Thirty five (n=35) never-smokers with advanced pan-negative lung adenocarcinomas were identified. A RET or ROS1 fusion was found in 31% [n=10/32, 95% CI, 15-47%] of patients. RET and ROS1 fusions were found in 15% [n=5/34, 95% CI, 3% - 27%] and 15% [n=5/33, 95% CI, 2%-27%] of patients, respectively. 1 patient had a novel TRIM33-RET fusion. 3 of 5 patients with RET fusion-positive tumors were eligible for treatment with cabozantinib, 2 of which had partial responses to therapy. 1 of 5 patients with ROS1 fusion-positive tumors was treated on-protocol with crizotinib and achieved a partial response. Conclusions: 31% of never-smokers with pan-negative advanced lung adenocarcinomas harbor a gene fusion involving either RET or ROS1. Until multiplexed mutation and fusion testing is routinely available, targeting this population for screening represents an interim enrichment strategy for patient identification and enrollment on clinical trials where responses are already being documented.