bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosome 1 abnormalities and clinical outcomes in multiple myeloma in the era of novel agents.
Authors: Giri Smith , Huntington Scott F. , Wang Rong , Zeidan Amer Methqal , Podoltsev Nikolai Alexandrovich , Gore Steven , Ma Xiaomei , Gross Cary Philip , Davidoff Amy J. , Neparidze Natalia 
Published: March 2020

8044 Background: Abnormalities of chromosome 1 (C1A) are common genetic mutations in patients (pts) with Multiple Myeloma (MM). While several small studies have reported worse outcomes for C1A, the prevalence, real-world treatment and outcomes for pts with C1A are unknown. Methods: We used the Flatiron Health Electronic Health Record (EHR)-derived database to identify pts with newly diagnosed MM from 01/2011 to 03/2018 with Fluorescence In situ Hybridization (FISH) testing within 90 days of diagnosis and defined lines of therapy. We identified pts with C1A and other high-risk mutations (HRM; 17p deletion, t14;16 and t4;14). Pts were followed until 3/31/2018 or death. The primary outcome was overall survival (OS). We used Kaplan Meier methods and compared OS for pts with/without C1A using log-rank tests stratified for HRM. We used Cox regression analysis to compare OS across groups, adjusting for age, gender, performance status, stage, HRM and treatment (triple regimen vs other). Results: The total sample included 3,578 pts: median age at diagnosis was 69 yrs (IQR 31-85), with 54% males and 60% whites. IgG(57%) and IgA(22%) were the most common M-protein subtypes. At baseline, 844 (24%) had C1A. Pts with C1A had higher stage (ISS III 35% vs 26%; p < 0.01) and other HRM (27% vs 14%, p < 0.01). Common first line-therapies included bortezomib(V), lenalidomide(R) and dexamethasone (D) (35%), RD (20%) followed by VD(15%). Use of VRD was higher with C1A vs without (40% vs 33% respectively, p < 0.01). Median OS was 66.9 months for the entire cohort and was lower for pts with C1A vs without (median OS 46.6 vs 70.1 months; log rank p < 0.01). Multivariable Cox survival analysis showed that C1A was independently associated with worse OS (adjusted HR 1.64; 95% CI 1.23-2.19); p < 0.01). Other predictors of worse survival included older age, black ethnicity, higher ISS stage, poor performance status and HRM. Conclusions: In this large study of real-world practice, C1A was associated with inferior OS independent of other HRM, despite higher use of VRD. Future studies are needed to assess whether specific regimens improve outcomes for C1A compared to patients without HRM.
Project Switch: Lenalidomide and dexamethasone (Len-Dex) as a potential synthetic control arm (SCA) in relapsed or refractory multiple myeloma (rrMM).
Authors: Kanapuru Bindu , Gong Yutao , Mishra-Kalyani Pallavi Shruti , Menefee Michael E. , Sridhara Rajeshwari , Farrell Ann T. , Blumenthal Gideon Michael , Pazdur Richard 
Published: March 2020

8047 Background: Len-Dex is a common comparator arm to test novel therapies in rrMM trials. There is interest in evaluating if the control data from one clinical trial can be borrowed to another clinical trial, thus creating SCAs which could potentially improve accrual to trials, make better go/no-go decisions, and increase patients access to promising experimental therapies (ETs). We looked at legacy rrMM trials to assess the impact of switching and pooling Len-Dex control arms among different trials when evaluating ETs. Methods: We identified 4 contemporary rrMM trials that enrolled 2,729 patients testing ET + Len-Dex vs. Len-Dex alone. We calculated progression-free survival (PFS), Hazard Ratio (HR) and 95% Confidence Interval (CI) for ET compared to the original trial control, the switch Len-Dex controls, a pooled Len-Dex control, and a matched pooled control using bootstrapping sampling methods to match the experimental arm baseline demographics and prior lines with the pooled control. Results: See table. Conclusions: In this analysis, the switch and pooled controls matched the original control for Trials 1 and 2, but not for Trials 3 and 4. The bootstrapping methods did not substantially assist in replicating the original results. This could be due to several factors including heterogeneity of the enrolled populations including different lines of therapy, different pharmacologic classes of drugs studied in the ETs, and missing prognostic data including cytogenetics. Further investigations into propensity score matching will be explored to determine if SCAs can be improved.[Table: see text]
Randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine /cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small-cell lung cancer (Ns-NSCLC): The JIPANG study.
Authors: Kenmotsu Hirotsugu , Yamamoto Nobuyuki , Yamanaka Takeharu , Yoshiya Katsuo , Takahashi Toshiaki , Ueno Tsuyoshi , Goto Koichi , Daga Haruko , Ikeda Norihiko , Sugio Kenji , Seto Takashi , Toyooka Shinichi , Date Hiroshi , Mitsudomi Tetsuya , Okamoto Isamu , Yokoi Kohei , Saka Hideo , Okamoto Hiroaki , Takiguchi Yuichi , Tsuboi Masahiro 
Published: March 2020

8501 Background: Although previous trials demonstrated the efficacy and safety of postoperative cisplatin–based adjuvant chemotherapy for resected NSCLC, no phase III study has so far evaluated Pem/Cis in this population. Methods: Patients with completely resected pathological stage II-IIIA Ns-NSCLC were randomized in a 1:1 ratio to receive either Pem (500 mg/m2, day 1)/Cis (75 mg/m2, day 1) or vinorelbine (Vnr) (25 mg/m2, days 1 and 8)/Cis (80 mg/m2, day 1), and stratified according to sex, age, pathologic stage, EGFR mutation status and institution. The primary endpoint was recurrence-free survival (RFS), and, the planned sample size was 800 patients in total to detect the superiority of Pem/Cis over Vnr/Cis (Trial Identifier, UMIN000006737). Results: Between March 2012 and August 2016, 804 patients were randomized. Of 784 for the efficacy analysis (389 in Pem/Cis and 395 in Vnr/Cis), median age was 65/65 years; stage IIIA 52/52%; Adenocarcinoma, 96/96%; and EGFR mutation, 24/25%. With a median follow-up of 45.2 months (mo), median RFS was 38.9mo in Pem/Cis and 37.3mo in Vnr/Cis with a hazard ratio (HR) of 0.98 (95% CI, 0.81—1.20; log-rank test, P= 0.948), whereas HRs in patients with and without EGFR mutations were 1.38 (95% CI, 0.95—1.99) and 0.87 (95% CI, 0.69—1.09), respectively (Interaction, P= 0.046). Overall survival rate at 3 years was 83.5% versus 87.2% with a HR of 0.98 (95% CI, 0.71—1.35). Incidences of grade 3 or 4 febrile neutropenia (0.3/11.6%, P< 0.001), neutropenia (22.8/81.1%, P< 0.001), and anemia (2.8/9.3%, P< 0.001); any grade alopecia (12.8/30.1%, P< 0.001). One treatment-related death was observed in each arm. Rates of treatment completions were 87.9% (Pem/Cis) and 72.7% (Vnr/Cis), respectively (P < 0.001). Conclusions: Although this phase III study did not meet the primary endpoint, Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. A significant interaction for RFS was found between treatment and EGFR mutation status. Clinical trial information: UMIN000006737.
Phase II trial of carfilzomib and irinotecan in relapsed small cell lung cancer (NCT01941316).
Authors: Arnold Susanne M. , Chansky Kari , Baggstrom Maria Quintos , Thompson Michael A. , Sanborn Rachel E. , Villano John , Waqar Saiama Naheed , Hamm John Turner , Leggas Mark , Willis Maurice , Rosales Joseph G , Crowley John 
Published: March 2020

8513 Background: Relapsed small cell lung cancer (SCLC) is incurable with limited therapeutic options. This phase II study evaluated efficacy and tolerability of carfilzomib + irinotecan in SCLC pts who progressed after prior platinum-based therapy, based on expected synergy of proteosome inhibitor carfilzomib and topisomerase 1 inhibitor irinotecan. Methods: SCLC pts who progressed after one platinum-containing regimen (no maintenance therapy allowed) for recurrent/metastatic disease were eligible. Pts were stratified by response to platinum-based therapy: sensitive (progressive disease (PD) > 90 days after chemo) versus refractory (PD 30 to 90 days after chemo). Pts were treated with up to 6 cycles of carfilzomib (20/36 mg.m2 D1, 2, 8, 9, 15, 16 q28D) and irinotecan (125 mg/m2 D1, 8, 15 q28D), imaging was performed every 2 cycles. The primary efficacy endpoint was 6-month overall survival (OS). Results: 62 pts enrolled and were evaluable for efficacy and adverse events. The 6-month OS was 59% in the platinum sensitive stratum and 54% in the platinum refractory stratum. Overall response rate: sensitive stratum 21.6% (1.6% CR + 16.4% PR) and refractory stratum 12.5% (all PR). Disease control (SD+PR+CR) was 68% in platinum sensitive and 56% in refractory patients. Progression free survival and OS were 3.6 months (95% CI 2.6 - 4.6) and 6.9 months (95% CI 4.3 - 12.3) in the sensitive stratum, and 3.3 months (95% CI 1.8 – 3.9) and 6.8 months (95% CI 4.1-11) in the refractory stratum. Twenty-nine pts (47%) experienced at least one grade 3 AE and 8 subjects had grade 4 toxicities: decreased neutrophils, leukocytes, and lymphocytes, diarrhea, vomiting, sepsis, hypokalemia, hypocalcemia, and dehydration. There were three treatment related deaths: myocardial infarction (possible), lung infection (possible), sepsis (probable). Conclusions: In previously treated pts with relapsed SCLC, irinotecan and carfilzomib was effective in platinum-sensitive and, notably, platinum-refractory pts with similar toxicity profile. This combination is a viable option in relapsed SCLC, can be considered following progression on immunotherapy (IO) or in subjects who cannot receive IO, and should be further explored in a randomized phase III trial. Clinical trial information: NCT01941316.
Phase II, prospective single-arm study of adjuvant pembrolizumab in N2 positive non-small cell lung cancer (NSCLC) treated with neoadjuvant concurrent chemoradiotherapy followed by curative resection: Preliminary results.
Authors: Ahn Myung-Ju , Park Sehhoon , Jung Hyun Ae , Cho Jong Ho , Sun Jong-Mu , Lee Se-Hoon , Choi Yong Soo , Ahn Jin Seok , Kim Jhingook , Park Keunchil , Zo Jae Ill , Shim Young Mog , Kim Kyung Hwan , Shin Eui-Cheol , Kim Hong Kwan 
Published: March 2020

8520 Background: The standard treatment option for stage IIIA-N2 subgroup is still under discussion with controversies. We hypothesize that immune checkpoint inhibitor consolidation therapy could have an additional role in prolongation of the disease-free survival (DFS) for stage IIIA-N2 NSCLC treated with tri-modalities therapy. Methods: This is a phase 2 study evaluating the clinical efficacy of pembrolizumab treatment after CCRT with curative resection in stage IIIA-N2 NSCLC pts. Pathologically confirmed pts were treated with five cycles of CCRT, weekly paclitaxel (50mg/m2) and cisplatin (25mg/m2) combined with radiotherapy (total of 44Gy over 22 fractions) followed by curative resection. Adjuvant Pembrolizumab (200mg fixed dose) is applied every three weeks up to 2 years or until disease recurrence. The primary objective is disease-free survival of more than 20 months. The first patient was recruited in October 2017, and the data for this abstract was locked at 20th of January, 2019. Results: Total of 40 pts were screened, and 37 pts received treatment. Median age was 64 years (range 39-74), and twenty-three pts were male (62.2%). As a curative surgery, pts received lobectomy (n=34), bi-lobectomy (n=2), or pneumonectomy (n=1). Adenocarcinoma was predominant (n=27, 73.0%). After the neoadjuvant CCRT, down-staging were observed in nine pts (24.3%). The median follow-up duration was 10.6 months (range 3.1-17.2), and pts received a median of 11 cycles (range 1-22) of adjuvant pembrolizumab. DFS is not reached. Fourteen patients discontinued treatment due to disease progression (n=9), adverse events (n=4) and withdraw consent (n=1). There was a case of grade 4 pneumonitis and a case of grade 3 autoimmune hepatitis which lead to discontinuation of the treatment. Otherwise, grade 1-2 hypothyroidism (n=6), pneumonitis (n=5), skin rash (n=3) were observed. Patients with sever immune-related adverse event showed a significantly high percentage of Ki-67 + cells among CD8 T-cells in peripheral blood. Conclusions: This study is the first study to demonstrate the feasibility of adjuvant pembrolizumab monotherapy in stage IIIA-N2 patients. Updated and detail clinical and exploratory biomarker outcome will be presented at the annual meeting. Clinical trial information: NCT03053856.
Neoadjuvant pembrolizumab (Pembro) for early stage non-small cell lung cancer (NSCLC): Updated report of a phase I study, MK3475-223.
Authors: Bar Jair , Urban Damien , Ofek Efrat , Ackerstein Aliza , Redinsky Ilanit , Golan Nir , Kamer Iris , Simansky David , Onn Amir , Raskin Stephen , Shulimzon Tiberiu , Peled Michael , Zeitlin Nona , Halparin Sharon , Jurkowicz Menucha , Abukhalil Ramez , Perelman Marina , Ben-Nun Alon 
Published: March 2020

8534 Background: Resected NSCLC clinical stage I or II harbor a 5 year survival of only 30-50%. Immunotherapy might be more effective in low-burden disease. We hypothesized that neo-adjuvant immunotherapy is a feasible, safe and effective treatment (Tx) for early stage NSCLC. Methods: MK3475-223 is an ongoing phase I study of neoadjuvant pembrolizumab in stage I-II NSCLC. All Pembro Txs are 200mg q 3 weeks (wks). Objectives: determine safety; recommended phase 2 dose/schedule; pathological & radiological response. Doses-schedule limiting toxicities (DLT) were defined as significant surgical complications (bleeding, delayed wound healing, ARDS, prolonged air-leak) or a significant delay of surgery. The doses-schedule escalation cohorts were (i) single pembro dose 3 wk prior to surgery; (ii) 2 pembro doses, 2 wks later surgery; (iii) 2 pembro doses, 1 wk later surgery. Expansion cohort received the doses-schedule of cohort (iii). Percentages of remaining viable tumor in the post-Tx were assessed, 10% or less was considered amajor pathological response (MPR). IHC for pre-Tx PDL1 was done. Efficacy was evaluated for the patients who had received 2 doses of pembrolizumab. Results: No DLT occurred in the dose-schedule escalation cohorts. 10 patients received 2 cycles of neo-adjuvant pembrolizumab. 4 patients achieved a MPR (4/10 who received 2 cycles of pembro; 40%; 95% C.I. 16.7-68.8%). No correlation is seen between the levels of PDL1 pre-Tx and the pathologic response. Size of the tumor and N status was also not in any apparent correlation with MPR (data not shown). Interestingly, all of the MPR cases had a relatively long interval from 1st Tx till surgery. Clinical trial information: NCT02938624. Conclusions: Neo-adjuvant pembro is safe and feasible. A promising sign of efficacy is seen. Achieving MPR might require a longer 1st-Tx-surgery interval. Predictive biomarkers for response might be different from those in advanced disease. Recruitment and correlative studies are ongoing.[Table: see text]
Comprehensive genomic profiling in Chinese patients with lung squamous cell carcinoma.
Authors: Lian Zuping , Li Heng , Lei Youming , Xian Lei , Bu Kunpeng , Wang Xiangping , Chen Zhonghai , Guo Honglin , Chen Xiaoqian , Guo Fei , Zhang Lin 
Published: March 2020

8540 Background: Lung squamous cell carcinoma (LUSC) is a major histological subtype of non-small cell lung cancer (NSCLC) and accounts for 30% of NSCLC. Previous studies had revealed the genomic characterization of LUSC in Western patients (pts). However, the comprehensive genomic features of LUSC in Chinese pts have not been well understood. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples collected from 311 LUSC pts. Genomic alterations (GAs) including single nucleotide variations, short and long insertions and deletions, copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. Results: The median age of LUSC pts was 63 years old (range 57-68.5), of which 88% were male. The most frequently mutated genes were TP53 (88%), PIK3CA (34%), CDKN2A (33%), SOX2 (26%), LRP1B (22%), KLHL6 (21%), KMT2D (19%), PRKCI (19%), NFE2L2 (18%) and MAP3K13 (17%). Interestingly the mutation rates of PIK3CA (p = 1.93e-05) and CDKN2A (p = 2.48e-05) were significantly higher than that in TCGA cohort. Genomic alterations in eight druggable genes recommended by the NCCN guideline occurred in 32% of pts, and alterations to PI3K/mTOR signaling pathway related genes occurred in 52% of pts. One patient with PIK3CA amplification achieved stable disease for eight months after everolimus treatment. Moreover, variants in the homologous recombination (HR) pathway were identified in 17% of pts. The median TMB of LUSC pts was 10.8 Muts/MB (range 6.9-14.5 Muts/MB) which was higher than Western populations [PMID: 28420421]. The 1st Quartile (TMB-L), median and 3rd Quartile (TMB-H) TMB value was 6.9, 10.8 and 14.5 Muts/Mb respectively. Comparing with the TMB-L group, frequencies of CDKN2A (39% vs 19%, p= 0.005), LRP1B (45% vs 8%, p< 0.001) and KMT2D (27% vs 8%, p= 0.002) were higher in TMB-H group. Conclusions: In summary, we characterized the genomic alteration profile of Chinese LUSC pts. Consistent with previous reports, high mutation rates of TP53, PIK3CA and CDKN2A are the most important genomic features of LUSC. However, the proportion of PIK3CA and CDKN2A mutations in Chinese LUSC pts is higher than that of Western populations. In addition, we also found targetable pathways (including PI3K/mTOR) along with gene related variations and high TMB in many pts, providing potential targeted therapy and immunotherapy options for LUSC pts.
Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC).
Authors: Akamatsu Hiroaki , Udagawa Hibiki , Tanaka Kentaro , Takeda Masayuki , Kanda Shintaro , Kirita Keisuke , Teraoka Shunsuke , Nakagawa Kazuhiko , Fujiwara Yutaka , Yasuda Ikuko , Okubo Sumiko , Shintani Masayuki , Leibman Rachel S , Scripture Charity D. , Tamura Tomohide , Okamoto Isamu 
Published: March 2020

8557 Background: SCLC rapidly recurs after first-line platinum therapy, and while several agents are approved in the relapsed/refractory setting, there is no approved agent or existing standard of care for third-line in Japan. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not in normal tissue. This was the first study evaluating safety, PK, and preliminary anti-tumor activity of Rova-T in Japanese pts. Methods: This was an open label Phase 1, 3+3 dose-escalation study of Rova-T in Japanese pts with advanced recurrent SCLC (NCT03086239). Eligibility: progressive disease after ≥2 prior systemic regimens incl. ≥1 platinum-based regimen; ECOG 0-1. Pts received 0.2 or 0.3 mg/kg Rova-T IV on Day 1 of a 6-week cycle for 2 cycles. Objective was to evaluate safety, tolerability, PK, and preliminary efficacy and expression of DLL3. Antitumor activity was measured by RECISTv1.1, and DOR, PFS, OS were evaluated. Results: 29 pts were treated with Rova-T (6 at 0.2mg/kg, 23 at 0.3 mg/kg). Median age 68 yrs; 76% male; 64% DLL3 high (≥75% expression); 86% DLL3 positive (≥25%). 20 pts (69%) had received ≥3 prior lines of therapy. Similar PK and AEs were seen compared to previous studies in non-Japanese pts. The most frequently reported study drug-related AEs were platelet count decreased, pleural effusion, oedema peripheral, and aspartate aminotransferase increased, the majority Grade 1/2. No DLTs occurred, and both dose levels were tolerated. Three pts previously treated with ≥3 prior lines of therapy had confirmed partial response by investigator (10% of all pts; 17% of DLL3 high pts). For DLL3 high pts, mDOR was 3.0 mos (95% CI: 2.9, 4.1), mPFS was 2.9 mos (1.2-3.6), and mOS was 7.4 mos (4.1-11.9). Individual responses were analyzed in detail and radiographic data with tumor shrinkage will be shown. Conclusions: Rova-T demonstrated a manageable safety profile with promising preliminary efficacy in Japanese SCLC pts, in particular pts with DLL3 high expression. These data support further exploration of Rova-T treatment in Japanese pts with SCLC in global Phase 3 studies. Clinical trial information: NCT03086239.
Phase II study of S-1 in patients (pts) with previously treated Invasive thymoma (IT) and thymic carcinoma (TC): North Japan Lung Cancer Study Group Trial 1203.
Authors: Tsurumi Kyoji , Sugawara Shunichi , Kuyama Shoichi , Nakagawa Taku , Harada Daijiro , Tsukita Yoko , Tanaka Hisashi , Watanabe Kana , Mori Yoshiaki , Harada Toshiyuki , Hino Toshihiko , Fujii Masanori , Inoue Akira 
Published: March 2020

8564 Background: Invasive thymoma and thymic carcinoma are rare epithelial neoplasms arise in the anterior mediastinum. Platinum-based chemotherapies are widely used for the first-line treatment for unresectable IT and TC. Although no standard treatment has been established for previously treated IT and TC, S-1 has demonstrated promising efficacy in some retrospective studies. Thus we conducted the first prospective multicenter phase II trial to evaluate the efficacy of S-1 for previously treated pts with advanced IT and TC. Methods: Eligible pts were aged 20 years or older with: advanced IT or TC not feasible to potentially curative treatments; disease progression after at least one regimen of platinum-based chemotherapy; Eastern Cooperative Oncology Group performance status 0-2; adequate organ function; written informed consent. Pts received S-1 orally, at a dose based on body surface area for 2 weeks in 3 weeks cycle until tumor progression or unacceptable toxicities. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profile. Assuming that ORR of 25% in eligible pts would indicate potential usefulness while ORR of 10% would be the lower limit of interest, with alpha = 0.05 and beta = 0.2 according to a Simon’s two-stage design, the estimated accrual was 40 pts. Results: Between June 2012 and August 2018, 40 pts were enrolled and all pts were eligible (IT, n = 20; TC, n = 20). Median age was 64.5 years (range, 40-82), 75% (30/40) were male. Median treatment cycle was 5.5 (range, 1-82). ORR was 17.5% (95% CI: 7.3-32.8; IT, 10%, TC, 25%), and disease control rate was 85% (IT, 95%, TC, 75%). With a median follow-up of 51.9 months, median PFS was 7.0 months (IT, 11.3 months; TC, 5.4 months), and median OS was 40.3 months (IT, 58.5 months; TC, 22.7 months). The major grade 3-4 toxicities were anorexia (10%) and pneumonitis (5%). No treatment-related death was observed. Conclusions: Although the primary endpoint was unmet, S-1 monotherapy showed the moderate effects and could be available option especially for previously treated advanced TC. Clinical trial information: 000008174.