bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations.
Authors: Oizumi Satoshi , Sugawara Shunichi , Minato Koichi , Harada Toshiyuki , Inoue Akira , Fujita Yuka , Maemondo Makoto , Watanabe Satoshi , Ito Kazuhiko , Gemma Akihiko , Demura Yoshiki , Harada Masao , Isobe Hiroshi , Kinoshita Ichiro , Morita Satoshi , Kobayashi Kunihiko , Hagiwara Koichi , Kurihara Minoru , Nukiwa Toshihiro ,   North East Japan Study Group (NEJ) and Tokyo Cooperative Oncology Group (TCOG)
Published: September 2018

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.
Recurrent versus de novo metastatic NSCLC: Impact on outcomes.
Authors: Moore Sara , Leung Bonnie , Wu Jonn , Shokoohi Aria , Ho Cheryl 
Published: September 2018

9045 Background: Metastatic non-small-cell lung (NSCLC) cancer has a poor prognosis, with a 5 year survival less than 5%. The majority of patients present with stage IV and many patients treated curatively with stage I-III will develop recurrent metastatic disease. It is unknown if the natural history differs between patients with recurrent versus de novo metastatic NSCLC. We hypothesized that de novo metastatic disease is associated with decreased overall survival compared to recurrent metastatic disease. Methods: A retrospective review was completed of all patients with NSCLC referred to the BC Cancer Agency from 2005-2012. Two cohorts were created; de novo metastatic disease and patients treated with curative intent (surgery or radiotherapy) that developed recurrent, metastatic disease. Information was collected on known prognostic and predictive factors. Overall survival was calculated from the date of diagnosis of metastatic disease. Results: A total of 9656 patients were referred, 5783 (60%) with de novo stage IV disease, and 3873 (40%) with stage I-III disease. Of patients with initial stage I-III, 1801 received curative therapy (751 surgery, 1050 radiotherapy) and 802 developed metastases. Patients in the de novo cohort were more likely to be male (52% vs 47%), have poorer performance status (ECOG≥2 50% vs 43%), and receive no palliative chemotherapy (67% vs 61%). The median overall survival in the de novo cohort was 4.7 m vs 6.9 m in the recurrent cohort (p < 0.001). De novo status was associated with shorter overall survival and this remained significant in a multivariate model that incorporated gender, ECOG and lines of palliative chemotherapy (hazard ratio 1.228[95% confidence interval 1.134-1.330], p-value < 0.001). Conclusions: In a large population based study of NSCLC, de novo metastatic status was independently associated with decreased overall survival from the time of metastatic disease diagnosis. De novo versus recurrent status should be used as a prognostic factor to inform patient decisions and ensure balanced stratification of patients in clinical trials.
Clinical comparison of ABP 215 and bevacizumab in patients with NSCLC: Pharmacokinetic results and justification for extrapolation across bevacizumab indications.
Authors: Thatcher Nick , Thomas Michael , Pan Zhiying , Goldschmidt Jerome H. , Schenker Michael , Melara Rebeca , Hanes Vladimir 
Published: September 2018

9050 Background: Approval of biosimilars is based on totality of evidence (TOE) that includes demonstration of analytical, functional, and pharmacokinetic (PK) similarity, and comparable clinical efficacy, safety, and immunogenicity. The TOE supports scientific justification for extrapolation across other indications that a share common mechanism of action (MOA). The proposed biosimilar ABP 215 is similar to bevacizumab (BEV) with respect to inhibition of vascular endothelial growth factor (VEGF)-induced signaling; PK in healthy adults; and clinical efficacy, safety, and immunogenicity in patients with non-small cell lung cancer (NSCLC). The PK results from the NSCLC study are reported here. Methods: In this double-blind study, adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel were randomized 1:1 to ABP 215 or BEV (15 mg/kg IV Q3W for 6 cycles). Trough (pre-dose) PK samples were collected at baseline, at weeks 4, 7, and 13, and at end of study. Clinical evaluations included efficacy, safety, and immunogenicity. Results: 642 patients (ABP 215, n = 328; BEV, n = 314) were randomized. Demographic and baseline characteristics were well balanced. The primary endpoint of risk ratio for objective response rate was 0.93 (2-sided 90% CI, 0.80-1.09), which was contained within the pre-specified equivalence margin. The incidence of adverse events was comparable between ABP 215 and BEV. During the study, 4 (1.4%) and 7 (2.5%) patients in the ABP 215 and BEV group, respectively, developed binding antibodies; no patient tested positive for neutralizing antibodies. Steady-state trough serum concentrations for both ABP 215 and BEV were reached by week 13 (median 124.9 vs 124.4 µg/mL, respectively) and were consistent between ABP 215 and BEV throughout the study. Conclusions: ABP 215 is similar to BEV in multiple analytical, functional, and clinical assessments. PK results in patients presented here provide further evidence for similarity between ABP 215 and BEV and contribute to the TOE supporting extrapolation of clinical similarity across BEV indications based on its common MOA. Clinical trial information: NCT01966003.
Primary resistance to ALK inhibitor in ALK-positive non-small-cell lung cancer.
Authors: Kang Jin , Chen Huajun , Zhou Qing , Tu Hai-Yan , Zhang Xu-Chao , Jian Su , Wang Zhen , Wang Bin-Chao , Wu Yi-Long , Yang Jin-Ji 
Published: September 2018

9063 Background: Crizotinib is a standard of care in anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancers (NSCLC). Undoubtedly,the resistance to crizotinib is a current bottleneck which resists its clinical application. However, there are few reports about the primary resistance to crizotinib, especially the difference between the primary and acquired resistance. Methods: Totally,171 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China from October 2010 to July 2016. The status of an ALK gene rearrangement was assessed by Vysis ALK Break Apart fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or ALK Ventana immunohistochemistry (IHC). Among 18 patients with primary resistance, 12 had tumor tissue (n = 6) or plasma (n = 6) at the baseline and meanwhile tumor tissue (n = 2) or plasma (n = 2) specimens were collected for 4 patients after primary resistance. Next generation sequencing was used to test the tissue or plasma from 16 patients with primary resistance to crizotinib. Results: Among 171 patients treated with crizotinib, 47.9% (82/171) developed acquired resistance, and 10.5%(18/171) had primary resistance. Using the specimens at the baseline, there were 6 ( 33.0%) patients with uncommon ALK fusion partners, 4 (22.2 %) with BIM deletion polymorphism, 2 (11.1%) with PTEN/mTOR mutations, and 1 (5.5 %) with a pre-existing ALK G3709A mutation.These uncommon ALK fusion partners included ZC3H8-ALK, ALK-LOC102723854 and ALK-DTNB-ASXL2. In addition, one patient was found to coexsist with KIT mutation after primary resistance. Median PFS was significantly shorter in patients with primary resistance than those with acquired resistance (2.2 vs. 10.8 months, P < 0.001). Conclusions: Uncommon ALK fusion partners, BIM deletion polymorphism, PTEN/mTOR mutation, pre-existing ALK G3709A mutation and KIT mutation might contribute to molecular mechanisms of primary resistance to crizotinib in ALK-positive NSCLC. Further investigations are warranted to overcome these primary resistances.
Cost-effectiveness analysis comparing companion diagnostic tests for EGFR, ALK and ROS-1 versus next-generation sequence (NGS) in advanced adenocarcinoma lung cancer patients.
Authors: Schluckebier Luciene , Caetano Rosangela , Aran Veronica , Ferreira Carlos G. M. 
Published: September 2018

9068 Background: Success of a target therapy is directly correlated with the accuracy of its companion diagnostic test. Without a corresponding biomarker, target therapy may yield shorter survival, waste time, increase burdens and costs. As important as conducting cost-effectiveness studies for therapies, it is also valuable to compare different molecular tests. In lung cancer, the mutational status of EGFR and translocation of ALK and ROS-1 are commonly tested to offer the best intervention. Our objective is to evaluate the cost-effectiveness of a unique exam using NGS versus other routinely used tests such as the ones which involve RT-PCR and FISH. Methods: Target population is NSCLC, adenocarcinoma, and candidates to first-line therapy. Strategy 1: test EGFR mutation if EGFR test is negative, individual follow to FISH for ALK; if FISH is negative, follow to FISH for ROS-1. Strategy 2: differs from 1 since FISH for ALK and ROS are requested together. Strategy 3: all individuals are submitted to NGS (multicomplex platform which include EGFR, ALK, ROS-1 and other genes). Tests could also be classified as unknown due to the quality of tumor sample. Prevalence of biomarker, test accuracy and proportion of unknown results were used to calculate each decision tree branch. Sensitivity and specificity was obtained from literature review using Sanger as reference standard for RT-PCR tests and NGS. The study was analyzed from a healthcare-payer perspective based on Brazilian private sector. Costs were based on data from diagnostic companies, ANS and AMB-CBHPM 2016. Results: The use of NGS added 24% extra cases correct identified as well as extra costs (US$ 800.76; PPP 2015) attributed to the molecular testing. The ICER comparing NGS with sequential tests was US$ 3,381.82/correct case detected. Comparing strategy 2:1, the ICER was US$937.86/correct case detected. Conclusions: this study is part of an effort to integrate companion diagnostics discussions on precision medicine and covered drugs in the Brazilian health system. These findings can also subsidy cost-effectiveness studies that incorporates subsequent treatments and survival.
A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Hodi F. Stephen , Rao Uma N. M. , Cohen Gary I , Hamid Omid , Hutchins Laura Fulper , Sosman Jeffrey Alan , Kluger Harriet M. , Sondak Vernon K. , Koon Henry B. , Lawrence Donald P. , Kendra Kari Lynn , Minor David R. , Lee Carrie B. , Albertini Mark R , Flaherty Lawrence E. , Petrella Teresa M. , Kirkwood John M. 
Published: September 2018

9500 Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. Clinical trial information: NCT01274338. [Table: see text]
A randomized multicenter phase 3 trial of adjuvant fotemustine versus surveillance in high risk uveal melanoma (UM) patients (FOTEADJ).
Authors: Piperno-Neumann Sophie , Rodrigues Manuel Jorge , Servois Vincent , Pierron Gaëlle , Gastaud Lauris , Negrier Sylvie , Levy-Gabriel Christine , Lumbroso Livia , Cassoux Nathalie , Bidard Francois-Clement , Michielin Olivier , Lacour Jean-Philippe , Durando Xavier , Mariani Pascale , Plancher Corine , Asselain Bernard , Armanet Sebastien , Mosseri Veronique , Desjardins Laurence 
Published: September 2018

9502 Background: Up to 30% of UM patients will develop metastases, with a median survival of 12 months in the metastating setting. Prognostic factors combine clinical features of the primary tumor (diameter, thickness, retinal detachment, extra-scleral extension) and genetic factors (monosomy 3, 8 q gain and class 1 /2 gene expression profiling).The genomic analysis is feasible by fine needle aspiration biopsies before radiotherapy for small UM or on enucleated eyes. Methods: Multicenter randomized phase 3 trial with adjuvant fotemustine, 6 cycles, 100 mg/m2 versus surveillance for 3 years (liver tests/3 months, liver MRI or CT/6 months, whole body CT/12 months) in patients with high risk of recurrence, defined by clinical criteria (diameter > 15 mm with extra scleral extension and/or retinal detachment or diameter > 18 mm) or genomic high risk signature by array-CGH (monosomy 3 or deletion of 3p associated with gain of chromosome 8). The primary objective was 5-year Metastasis Free Survival (MFS). With an expected increase of 5-year MFS from 50 to 70%, 302 patients and 99 events were required to achieve an 95%-power with a 5% type I error rate. Secondary objectives were overall survival (OS), safety (NCI-CTC v3), quality of life (QLQ-C30). Interim analyses were planned for safety and after 50 events, disclosed to an independent safety monitoring board. Results: The trial was stopped for futility after 244 patients had been recruited between June 2009 and January 2016. No unexpected toxicity was found in the chemotherapy group. The study was amended to go on with intensive surveillance in new high risk patients. Ninety-one metastases and 43 deaths were reported, with no treatment-related death. With a median follow-up of 3 years, the 3-year MFS is 60.3% in the chemo group and 60.7% in the surveillance group (HR 0.97 [0.64-1.47]). The 3-year OS is 79.4% [73.2-85.7], with no difference between the 2 groups of patients. Conclusions: FOTEADJ is the first adjuvant randomized phase 3 trial based on genomic analysis in high risk UM patients. Despite negative results, it shows the feasibility of multicenter adjuvant studies in this rare cancer and provides genomic data in small tumors for future trials. Clinical trial information: NCT02843386.
Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.
Authors: Chesney Jason Alan , Puzanov Igor , Ross Merrick I. , Collichio Frances A. , Milhem Mohammed M. , Chen Lisa , Kim Jenny J. , Garbe Claus , Hauschild Axel , Andtbacka Robert Hans Ingemar 
Published: September 2018

9509 Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1o endpoint was ORR by immune-related response criteria. Key 2o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]
A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients (Pts) with BRAF V600-mutant solid tumors and melanoma.
Authors: Ascierto Paolo Antonio , Bechter Oliver , Wolter Pascal , Lebbe Celeste , Elez Elena , Miller Wilson H. , Long Georgina V. , Omlin Aurelius Gabriel , Siena Salvatore , Calvo Emiliano , Pickard Mike , Gollerkeri Ashwin , Wollenberg Lance , Germa Caroline , Dummer Reinhard 
Published: September 2018

9518 Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with BRAF V600-mutant ( BRAFV600) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and BRAF + MEK (triple combo) to improve antitumor activity. We report safety and preliminary efficacy from a phase 1b/2 study (NCT01543698) of encorafenib (ENCO; a selective BRAF kinase inhibitor), binimetinib (BINI; a MEK inhibitor), and ribociclib (RIBO; a CDK 4/6 inhibitor). Methods: Phase 1b of this open-label, multicenter study enrolled pts with confirmed BRAFV600advanced solid tumors. Escalating doses of RIBO 100 mg-600 mg QD for 3 wk on/1 wk off were administered with ENCO 200 mg QD + BINI 45 mg BID in successive cohorts (6 pts each) until the maximum tolerated or recommended phase 2 dose (RP2D) was reached. Due to potential pharmacokinetic interactions with RIBO, the ENCO dose was lower than the dual combo RP2D (450 mg QD). Dose escalations followed an adaptive Bayesian model. In phase 2, the triple combo was tested in pts with BRAFV600melanoma naïve to prior BRAF inhibitor treatment; the primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In phase 1b (n = 21), no dose-limiting toxicities were reported and the triple combo RP2D was ENCO 200 mg QD + BINI 45 mg BID + RIBO 600 mg QD. ENCO AUC was slightly lower than at the dual combo RP2D. In phase 2 (n = 42), 59.5% pts had an ECOG PS of 0 and 43% of pts had elevated lactate dehydrogenase. The most common (≥5%) grade 3/4 toxicities were neutropenia (26.2%), increased alanine transaminase (14.3%), diarrhea (7.1%), and anemia (7.1%). Ten pts (23.8%) discontinued treatment due to an AE, of which 4 were increased transaminases. The confirmed ORR was 52.4%, including 4 complete responses, 18 partial responses, and 15 pts with stable disease. Median duration of exposure in phase 2 was 9.1 mo (range, 0.0-21.6). Median progression-free survival was 9.0 mo (95% confidence interval, 7.0-11.1). Conclusions: Triple therapy with ENCO + BINI + RIBO in this small trial of pts with high disease burden was associated with responses in over half of pts and some evidence of increased toxicity. Clinical trial information: NCT01543698.