bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence of low incidence of myelodysplastic syndrome (MDS) in patients exposed to bendamustine treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Authors: Burke John M. , Bibeau Kristen , Kahl Brad , Carson Kenneth R. , Zelenetz Andrew D. , Brander Danielle M. , Maddocks Kami J. , Gerecitano John F. , Pathak Ashutosh K. , Cheson Bruce D.
Published: September 2018

e19008

Background: CLL/SLL is a treatable malignancy, which is responsive to therapies that include bendamustine. However, as with many alkylating agents, there is concern for the development of secondary malignancies and MDS after exposure to bendamustine. We evaluated the risk of MDS using electronic medical records from a geographically diverse cohort of cancer patients (pts). Methods: Pathologically confirmedCLL/SLL pts with any exposure to bendamustine were identified in the Flatiron Health database (FHD, Flatiron Health, New York [122016]). This is a longitudinal US-based cohort with > 1.5 million cancer pts drawn from over 250 cancer clinics. Pts with bendamustine exposure and no history of MDS or other malignancy were included. Pts were followed longitudinally to identify incident cases of secondary malignancies or MDS. Results: Of 3140 CLL/SLL pts in the analytic cohort, 1022 met inclusion criteria. Median follow-up after bendamustine exposure was 1.7 years. Overall, 8% received bendamustine monotherapy, 84% received combination therapy, and 8% received cycles of bendamustine monotherapy and combination therapy. Of the 1022 pts, 205 (20%) had prior antineoplastic exposure, a risk factor for MDS. During the follow-up period, five pts developed MDS (0.48% of the bendamustine-exposed cohort), one of whom had prior antineoplastic exposure. Conclusions: This real-world study demonstrated that pts received bendamustine overwhelmingly as combination therapy, and 20% had prior antineoplastic exposure. MDS related to alkylators and purine analogs can have a latency of > 3 years; in this study a minority (~20%) of pts had > 3 years of follow-up. Thus, longer follow-up is required to draw definitive conclusions regarding the risk. Nevertheless, the FHD provides a source of oncology data for studying long-term outcomes of cancer pts, which have historically been difficult to capture in epidemiological studies. At a median of 1.7 years after exposure, the current study identified a low risk of MDS after controlling for potential confounders.
Clinical outcomes of DLBCL, follicular lymphoma (FL) and Richter transformation (RT) patients treated with ibrutinib: A real-world experience of off-label ibrutinib use.
Authors: Isaac Krista , Kennard Kaitlin , Landsburg Daniel Jeffrey , Hughes Mitchell E. , Svoboda Jakub , Nasta Sunita , Latorre Tanya , Surkis William , Fanning Molly J , Chatburn Elizabeth , Dorsey Colleen , Daniel Catherine , Timlin Colleen , Gill Jennifer , Schuster Stephen J. , Mato Anthony R.
Published: September 2018

e19043

Background: Ibrutinib (IBR), a BTK inhibitor, is FDA approved for CLL, Waldenstrom macroglobulinemia, marginal zone lymphoma and mantle cell lymphoma. Despite limited data, IBR is being utilized as a therapy for patients (pts) with relapsed/refractory (RR) DLBCL and FL. In an effort to further characterize the efficacy of IBR in these settings, we conducted a retrospective cohort study of IBR-treated pts with DLBCL, RT or FL. Methods: A retrospective cohort study of DLBCL, RT and FL pts treated with IBR was completed. Data collected included demographics, stage, IPI, prior treatments, IBR dose/duration, reasons for discontinuation, and response. PFS and OS were estimated using the Kaplan Meier method. Results: 44 pts were identified (DLBCL: n = 24, 55%; FL: n = 12, 27%; RT: n = 8, 18%). Baseline characteristics: age (range 19 – 80), 61% male, 95% ECOG 0 - 1, 71% stage IV, 62% elevated LDH, 48% R-IPI ≥ 4. DLBCL subtypes (Hans criteria) were 46% non-GC (n = 11), 29% GC (n = 7), 25% unclassifiable (n = 6). In FL, 8% were grade 1, 59% grade 2, and 33% grade 3a. Med number of prior therapies was 5 (range 1-11). Most common reasons for IBR discontinuation were progression (35%), toxicity (20%), bridge to CAR-T (10%). PFS and OS data are shown in the table below. In DLBCL, cell of origin (Hans) did not impact outcomes (p = .97, LR test). PFS was superior in RT as compared to DLBCL (p = .03, LR test). Conclusions: In the largest single-center, real-world experience of IBR use in DLBCL, RT and FL, we validate findings reported in clinical trials. In FL, responses appear to be durable (median PFS > 10 months). Outcomes are poor in DLBCL and use of IBR as monotherapy is not recommended. Perhaps IBR is best used as a short-term bridge to more definitive therapies. Cell of origin (Hans) may not predict PFS and should not be used to select pts for IBR. Pts with RT appear to have more durable responses (vs. DLBCL) suggesting differing dependence on BTK signaling. [Table: see text]
Differences in health care costs and utilization: BR vs RCHOP in patients with follicular lymphoma.
Authors: Zhou Jifang , Pathak Ashutosh K. , Brander Danielle M. , Gabriel Susan
Published: September 2018

e19049

Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL) with an incidence of more than 1500 cases annually and comprising 35% of all iNHL cases in North America. Combination chemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) or bendamustine plus rituximab (BR) are both category 1–approved first-line therapies. This analysis examined differences in healthcare costs and utilization between two cohorts of newly diagnosed FL patients undergoing BR or RCHOP therapy. Methods: Newly diagnosed FL patients from 1/1/2006 to 7/31/2016 treated with first-line RCHOP or BR were identified in the Truven Health MarketScan Research Databases. Inclusion criteria were age ≥18 years and continuous enrollment from 3 months before to 1 month after the index date (eg, first prescription for RCHOP/BR). Healthcare utilization and costs were calculated on a per month basis from the index date to 6 months post-index date. Costs included all payments made by insurance providers except for pharmacy claims. Healthcare utilization variables included number of outpatient visits, emergency room (ER) visits (yes/no), and hospitalizations (yes/no). Logistic regression and general linear models were used to test for differences. Results: Of the 6460 FL patients (male = 55%; mean age = 60.46 years, SD = 12.56) identified, 2360 were in the BR cohort and 4100 patients were in the RCHOP cohort. At baseline, the BR cohort was significantly older; had more comorbid conditions, lower costs, and fewer outpatient visits; and was less likely to have an ER visit or hospitalization relative to RCHOP patients. Over the first 6 months of therapy, controlling for baseline differences, the BR group experienced significantly lower costs and fewer outpatient visits. The BR cohort was also significantly less likely to be admitted to the ER or experience a hospitalization. Conclusions: The results of this analysis suggest that, in general, the healthcare costs and utilization of FL patients receiving BR is significantly lower than for RCHOP patients. These results support the emerging prominence of BR as an effective and safe first-line treatment option for FL patients.
Fluoroquinolone prophylaxis for the prevention of central line-associated bloodstream infection in autologous stem cell transplant.
Authors: Ziegler Matthew , Gilmar Cheryl , Landsburg Daniel Jeffrey , Pegues David , Kucharczuk Colleen , Gorman Theresa , Bink Kristen , Moore Amy , Fitzpatrick Rebecca , Stadtmauer Edward A. , Mangan Patricia , Kraus Kelly , Han Jennifer
Published: September 2018

e19508

Background: Patients (Pts) undergoing stem cell transplant (SCT) for the treatment of hematologic malignancy are at increased risk for central line-associated bloodstream infection (CLABSI). Use of prophylactic antibiotics to prevent CLABSI in autologous SCT (autoSCT) is of unclear benefit. We aimed to evaluate the impact of levofloxacin prophylaxis on reducing CLABSI in autoSCT. Methods: Pts undergoing autoSCT at the University of Pennsylvania received levofloxacin prophylaxis during a 6-month intervention period from 1/13/2016 - 7/12/2016. Levofloxacin was administered from autoSCT until day 13, absolute neutrophil count > 500/mm3, or febrile neutropenia. Outcomes were compared to a retrospective cohort who underwent autoSCT, but did not receive routine antibacterial prophylaxis during the previous year (1/13/2015 – 1/12/2016). The primary endpoint was incidence of CLABSI assessed using Cox proportional hazards regression. Results: A total of 243 pts underwent autoSCT, with 69 receiving levofloxacin prophylaxis during the intervention period. Median age was 59 yrs, 74% had multiple myeloma, and 58% received melphalan 200mg/m2. Median duration of neutropenia was 6 days. CLABSI rate was reduced from 18.4% during the baseline period to 7.3% during the intervention period ( P= 0.03). There were no significant differences in characteristics between the baseline and intervention groups except for liver disease (1% versus 5%, P= 0.03). On multivariable analysis, levofloxacin prophylaxis was associated with a significant reduction in CLABSI incidence (HR 0.33; 95% CI 0.12-0.88; P= 0.02), as was underlying multiple myeloma (HR 0.38; 95% CI 0.20-0.74; P= 0.004) and liver disease (HR 4.31; 95% CI 0.99-18.8; P= 0.05). There was also a reduction in neutropenic (NTP) fever (OR 0.21; 95% CI 0.11-0.38; P< 0.001) and a trend toward reduction in ICU transfer for sepsis (OR 0.13; 95% CI 0.01-1.39; P= 0.08) in patients receiving levofloxacin prophylaxis. There were no significant differences in rates of secondary BSIs, C. difficileinfection, or mortality. Conclusions: Levofloxacin prophylaxis was effective in reducing CLABSI and NTP fever in patients undergoing autoSCT.
The use of proteasome inhibitors among patients with POEMS syndrome.
Authors: Kourelis Taxiarchis , Kapoor Prashant , Dingli David , Stewart A. Keith , Buadi Francis , Gertz Morie A. , Lacy Martha , Kumar Shaji , Gonsalves Wilson I. , Go Ronald S. , Lust John Anthony , Hayman Suzanne R. , Warsame Rahma M. , Rajkumar S.Vincent , Zeldenrust Steven R. , Russell Stephen J. , Hwa Lisa , Kyle Robert A. , Dispenzieri Angela
Published: September 2018

e19530

Background: Neuropathy is a universal symptom of patients with POEMS syndrome, which makes the use of bortezomib less appealing. However, proteasome inhibitors (PIs) can provide rapid and deep hematologic responses in plasma cell disorders. Because there is very little data regarding the use PIs in POEMS syndrome, we performed a study of patients with POEMS syndrome treated with PIs. Methods: Among the 167 patients with POEMS syndrome seen at our institution between 2001-2016, we identified 12 patients who received a PI. One patient receiving < 1 cycle of bortezomib because of worsening neuropathy was included but was excluded from response analyses. One patient received 2 different PIs at separate points during the disease course and each course was considered separately. Four response categories were considered: hematologic, PET, VEGF and clinical as previously described (Dispenzieri et. al AJH 2015). Results: Among the 12 patients who received 13 courses of therapy, the median age at PI initiation was 59; 8 patients were male. Median number of prior therapies was 1 (0-4) and median time from diagnosis to initiation of PI was 75 months. Excluding steroids, regimens were as follows: bortezomib, n=3; bortezomib and cyclophosphamide, n=4; carfilzomib, n=1; and ixazomib, n=1. With a median follow-up from PI initiation of 18 months, the median duration of treatment was 7 months (1-18). Three patients achieved a hematologic CR. Of 6 patients with an abnormal baseline VEGF, 3 achieved normalization VEGF levels. Of 5 patients with an abnormal baseline PET, 2 achieved normalization of their PET. Two patients had improvement of their neuropathy, with the rest having stable symptoms. Of 9 patients with fluid overload, 8 improved. Only 2 patients stopped therapy due to worsening neuropathy related to PIs. Median PFS and OS from initiation of PI were 50 months and 53 months, respectively. Conclusions: We show that PI use in patients with POEMS syndrome can be safe and effective. Nearly 75% of patients treated with bortezomib had no exacerbation of their neuropathy. Clinical improvement in severe fluid overload symptoms (edema, ascites, pleural effusions) is almost universal, making PI-based therapy an attractive potential option in these patients.
Three-year survival after combined treatment with induction chemoimmunotherapy in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Lazutin Yuriy N. , Pyltsin Sergey P. , Kharitonova Anna Pavlovna , Ayrapetova Tamara G. , Leyman Igor A. , Chubaryan Anna V. , Anistratov Pavel A. , Shogenov A. S. , Gappoeva M. A. , Afaunov M. Kh.
Published: September 2018

e20064

Background: Induction chemotherapy (iCT) for NSCLC has potential advantages over adjuvant CT, high therapeutic compliance, the ability to influence the primary tumor and metastatic disease. Standard approaches to iCT improving are largely exhausted. However, the development of iCIT techniques using recombinant cytokines and assessment of the effectiveness of its clinical application remains poorly understood. Methods: Clinical trial included 65 pts. with stage IIB, IIIA (N2), IIIB (T4 ipsi. nod.) NSCLC, randomized in main (n = 33) and control (n = 32) groups with comparable clinical and pathological characteristics: m 23 (69.7) vs. 23 (71.8%), W 10 (30,3%) vs. 9 (28.2%); stage IIB - 8 (24.4%) vs. 9 (28.6%), IIIA - 22 (66.6%) vs. 19 (59.4%), IIIB - 3 (9%) vs. 4 (12.5%); 40-49 years 5 (15,5%) vs. 5 (15,6%), 50-59 14 (42,4%) vs.15 (46,8%), 60 years and older 14 (42,4%) vs. 12 (37,8%). Pts. of the control group received 2 iCT cycles: cisplatin 75 mg / m2 i.v. 1 day and gemcitabine 1000 mg / m2 i. v. 1 and 8 days; pts. of the main group additionally received recombinant tumor necrosis factor coupled with thymosin (TNF-T Farmaclon Russia) 50. 000 ED / m2i.v. 3, 5 and 7 days of the cycle. The direct results were evaluated 3 weeks after completion of induction. Pts. who underwent radical surgery received 2 cycles of platinum-based adjuvant CT. DFS was studied by the method of Kaplan-Meier. Results: 3-year DFS in the main group was 72% vs. 48% in the control group (p = 0.10603). Conclusions: Clinical trial of the effectiveness of iCIT with using immune drug TNF-T demonstrated a tendency to improve 3-year DFS by 24%, which favors further studies on a larger number of pts.
A new nodal classification based on log odds and location of involved lymph nodes in lung cancer.
Authors: Zhou Rui , Zhang Jingwen , Sun Huiying , Zeng Dongqiang , Liao Wangjun
Published: September 2018

e20069

Background: To explore the prognostic effect of log odds of positive lymph nodes (LODDS) in node-positive non-small cell lung cancer (NSCLC) patients, and evaluate whether a model incorporates the pN and LODDS is a more reliable prognostic determinant in these patients. Methods: Data of 9557 NSCLC patients (pT1-pT3, pN1-pN2, M0) with lymphadenectomy recorded in the Surveillance Epidemiology and End Results database between 2004 and 2009 were retrospectively studied. Results: In adjusted analyses, LODDS value was an independent prognostic factor for patients with node-positive NSCLC, as well as pN classification and MLN count. However, the LNR value lost its significance in multivariate regression model. Next, we established the pN-LODDS (N-L) classification model and observed that it had better discriminatory ability, monotonicity, and homogeneity for prognostic stratification, as well as more accurate time point OS prediction than either of pN, MLN and LODDS classifications alone. Moreover, besides the pN classification, the N-L model could serve as a referential indicator designing postoperative treatment in node-positive NSCLC patients. Analyses stratified by the N-L classification showed that postoperative radiotherapy was independently linked to prolonged survival in patients with N-L 3 classification, N-L 5 classification, and in pN2 subgroup of N-L 4 classification. Conclusions: Our findings indicated that the N-L classification model could serve as the optimal scheme for prognostic assessment in patients with node-positive NSCLC. Incorporating N-L classification into the staging system will enable clinicians to more accurately predict the prognosis and to guide the decision of regional therapy regiment.
Automated brightfield multiplex immunohistochemistry to quantify biomarkers related to immune senescence: Relationships with survival in non-small cell lung cancer patients.
Authors: Hofman Paul , Beaulande Mélanie , Ben Hadj Saima , Erb Gilles , Pomerol Jean-François , Lassalle Sandra , Butori Catherine , Long Elodie , Washetine Kevin , Guerin Olivier , Guigay Joel , Mouroux Jerome , Leroy Sylvie , Marquette Charles Hugo , Hofman Veronique , Ilie Marius
Published: September 2018

e20500

Background: Elderly patients have an eroded immune characterized by a progressive decline in immune surveillance that favors infection and cancer development. Tumor cells can escape immune surveillance by upregulating inhibitory immune checkpoint such as PD-L1. High expression of PD-L1 was reported in association with CD8+T-cell exhaustion and increased levels of CD33+ myeloid-derived suppressor cells. Although low CD4/CD8 ratio is associated with increased mortality, the status of the CD4+T-cells as a clinical marker of immunosenescence is less well characterized in the field of aging. The aim of this study was to determine the presence of immunosenescence biomarkers according to age in non-small cell lung cancer (NSCLC) patients and to evaluate them as predictive biomarkers of patients’ outcome. Methods: One hundred NSCLC patients, matched by age (50 patients < 70 years, 50 patients ≥70 years) were included. An automated 4-Plex optical IHC assay was developed on the Discovery ULTRA automated stainer using monoclonal antibodies PD-L1 (SP263), CD4, CD8, and CD33. The stained slides were scanned with Nanozoomer HT 2.0 Scanner, and analyzed with Calopix software. Results: The CD4/CD8 ratio and PD-L1 expression in tumor and immune cells were significantly lower in elderly NSCLC patients ≥70 years than in age-paired patients, while absolute count of CD33+ was increased. Patients with CD4/CD8 ratio higher than two, high PD-L1 density and low CD33+ frequency achieved increase in median disease-free survival. Conclusions: Distribution of PD-L1, CD4, CD8, and CD33 cells was influenced by age in NSCLC patients. The proportion of CD8 + CD28- T cells, CD4+ T cells and CD4/CD8 ratio may be used as predictive biomarkers of anti-PD-L1 therapy efficacy in NSCLC patients. The automated 4-Plex IHC assay together with its respective digital analysis could serve as a tool for further characterizing tumors and their microenvironment and provide a better understanding of which patients may benefit from immunotherapy.
Population pharmacokinetic and pharmacodynamic analysis of osimertinib.
Authors: Johnson Martin , Schmidt Henning , Sunnaker Mikael , Nash Anthony F , Nayak Suman , Tomkinson Helen , Vishwanathan Karthick
Published: September 2018

e20536

Background: Osimertinib is an oral, potent, irreversible, CNS active EGFR-TKI, selective for sensitizing (EGFRm) and T790M resistance mutations, indicated for the treatment of patients with T790M positive advanced non-small cell lung cancer who have progressed on or after EGFR-TKI therapy. Osimertinib pharmacokinetics (PK) were evaluated using a population approach and pharmacodynamic (PD) relationships using appropriate modeling approaches. Methods: To understand the impact of covariates on osimertinib PK, a population PK analysis was performed using data from patients who received osimertinib (20–240 mg) during the AURA studies. Exposure metrics were derived from a PK model and used to assess the exposure-response (safety/efficacy) relationship. Efficacy analysis included patients who were T790M positive (n = 710) and safety analysis included all dosed patients (n = 1088). The impact of covariates on exposure-response was assessed. Models accounting for rare safety events were applied to quantify the association between events and exposure. Results: Population PK analyses supported dose- and time-independent PK of osimertinib with no clinically meaningful covariates identified. Patients in the highest exposure quartile (Q4) had a numerically shorter median progression-free survival (8.3 months [95% CI 6.9, 10.5]) compared with patients in Q1, Q2 and Q3 (all 11.2 months [95% CIs 9.7, 12.7; 8.5, 15.6 and 8.7, 13.7, respectively]). A model-based analysis indicated that this effect is likely due to a larger number of patients in Q4 with poor prognostic features, i.e. worse performance status (WHO 1 or 2) and lower baseline serum albumin compared with Q1, Q2 and Q3, rather than to osimertinib exposure. Model-predicted probability of a relationship between osimertinib exposure and LVEF changes was not evident. Model-based analysis predicted that, compared with the median probability (0.03), the probability of a patient experiencing interstitial lung disease may increase with increasing osimertinib exposure (Q1 probability 0.01 [steady-state AUC 6361 nM*h] vs Q4 0.06 [24460 nM*h]) at the 80 mg dose. Conclusions: Population PK and PK-PD analysis is supportive of 80 mg as an appropriate dose for osimertinib. Clinical trial information: NCT01802632; NCT01802632; NCT02094261; NCT02151981.
Epidemiology of PD-L1 and ALK expression and EGFR mutational status in Argentinian patients with lung cancer.
Authors: Salanova Ruben , Calderazzo Pereyra Julio C , Leguina Laura , Bena Asuncion , Barberis Mariana , Vargas Rosana , Jimenez del Toro Rocio , Kreimberg Kevin , Powazniak Yanina
Published: September 2018

e20565

Background: Until now, the results of the correlation between PD-L1, ALK expression and EGFR mutations remain controversial. We prospectively evaluated patterns among EGFR mutant, ALK positive and PD-L1 positive lung cancer patients. Methods: PD-L1 and ALK expression was evaluated in 342 adenocarcinomas (AD) of the lung using inmunohistochemestry (anti-PD-L1 22C3, anti-ALK D5F3), and EGFR mutations using real time PCR (therascreen EGFR RGQ PCR Kit version 2). PD-L1 was also evaluated in 36 squamous (SQ) cell carcinomas. Results: 181 of 342 patients with AD were positive for PD-L1. 108 were positive with a TPS value between 1 and 49, and 73 were positive with a TPS value higher than 50 (p = 0.002). 25 of 36 patients with SQ were positive for PD-L1. 17 were positive with a TPS value between 1 and 49, and 8 were positive with a TPS value higher than 50. 133 samples with AD PD-L1 positive and 97 PD-L1 negative were tested for EGFR and ALK, 33 and 14 respectively were positive for EGFR mutations (p = 0.15), with 45% for exon 19 deletions (p = 0.003), 5 and 0 respectively were positive for ALK translocations (p = 0.053). 210 of 342 patients were men and 132 were women, 117 and 64 were positive for PD-L1 expression respectively (p > 0.1). Conclusions: NSCLC with EGFR mutation showed a trend for higher frequency of positive PD-L1 expression and NSCLC harboring ALK rearrangement was significantly associated with PD-L1 expression. These findings might contribute to the understanding of the regulation of PD-L1 expression in lung cancer and its relation to ALK expression and EGFR mutation.
Efficacy and safety of endostar in the treatment of advanced lung squamous cell carcinoma.
Authors: Hu Weiheng , Fang Jian , Nie Jun , Dai Ling , Zhang Jie , Chen Xiaoling , Ma Xiangjuan , Tian Guangming , Wu Di , Han Jindi , Han Sen , Wang Yang , Long Jieran
Published: September 2018

e20574

Background: From the early 2000s, many advances in non-small cell lung cancer (NSCLC) have been made with the emergence of targeted therapies. However, because of safety concerns and a lower prevalence of relevant therapeutic targets, patients with squamous NSCLC have been excluded from many of these breakthroughs. Endostar is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. This study is to explore the clinical efficacy and safety of endostar in advanced squamous NSCLC patients. Methods: We performed a retrospective analysis of 259 newly diagnosed advanced squamous NSCLC patients who had received platinum-based doublet chemotherapy (PBDC) between September 2009 and March 2016. Of these patients, 116 received Endostar combined with PBDC, and 143 received PBDC only. Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and analyzed. Results: After a median follow-up of 13.5 months, a improvement in PFS was observed in the Endostar group, the median PFS was7.7 months compared with 5.4 months in the control group (HR, 0.745; P= 0.034). The median OS was 19.0 months in the Endostar group versus 14.3 months in the control group, but the difference was not significant (HR, 0.780; P= 0.094). Multivariate analysis demonstrated that in patients with advanced squamous NSCLC, anti-angiogenesis therapy with Endostar, radiotherapy of primary tumor and Ⅲb stage were significant and independent predictors of improved PFS ( P< 0.05). For both arms, hematologic and gastrointestinal toxicities were the most common adverse events. Patients treated with Endostar had slightly higher rates of cardiac disorder and thromboembolic event, as compared with the control patients, but there were no statistically significant differences in toxicities overall between the 2 treatment groups. Conclusions: The current study indicates that Endostar as an anti-angiogenesis therapy combined with PBDC is able to provide further survival benefits with satisfactory toxicity in previously untreated squamous NSCLC patients, which merits further evaluation in randomized trials.
The efficacy and toxicity of osimertinib in T790M-positive NSCLC with acquired resistance to EGFR-TKI in clinical practice.
Authors: Sonoda Tomoaki , Yanagitani Noriko , Saiki Masafumi , Ariyasu Ryo , Koyama Junji , Takano Natsuki , Kawashima Yosuke , Oguri Tomoyo , Nishikawa Shingo , Kitazono Satoru , Ohyanagi Fumiyoshi , Horiike Atsushi , Nishio Makoto
Published: September 2018

e20575

Background: A Phase III study (AURA3) demonstrated that osimertinib prolonged PFS compared to platinum doublet in patients with T790M-positive non-small-cell lung cancer (NSCLC) exhibiting acquired resistance to epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI). Although the patients in the study had good PS and only one prior EGFR-TKI treatment, most practical patients had multiple prior EGFR-TKI and poor PS. Moreover, several patients exhibited symptomatic central nervous system (CNS) metastasis in clinical practice. In this study, we evaluated the efficacy and toxicity of osimertinib in clinical practice. Methods: We retrospectively analyzed 30 patients who were treated with osimertinib at our hospital from April 11th 2016 to September 30th 2016. The efficacy and toxicity was compared between the patients with matched and unmatched AURA3 eligibility criteria. Efficacy was evaluated according to RECIST ver.1.1 and toxicity was evaluated using CTCAE ver.4.0. Results: A total of 9 out of 30 patients matched the AURA3 eligibility criteria (PS ≤ 1 and one prior EGFT-TKI) and 21 patients were unmatched (PS ≥ 2 or two or more EGFR-TKI or symptomatic CNS metastasis). The overall response rate(ORR) of osimertinib was 78% and 67% for the matched and unmatched patients, respectively. The disease control rate (DCR) was 100% and 90% for the matched and unmatched patients, respectively. In addition, the response rate of symptomatic CNS metastasis was 67%. Regarding toxicity, grade 3/4 toxicities were observed in 22% of the matched patients and 33% of the unmatched patients. In the matched patients, the most frequent AE was a rash (89%) and the frequent grade 3/4 toxicities were a rash (22%) and pneumonitis (11%). In unmatched patients, the most frequent AE was also a rash (57%), but the frequent grade 3/4 toxicities were pneumonitis (14%), rash (10%), and neutropenia (10%). Conclusions: Both the ORR and DCR in the unmatched patients were slightly lower than the matched patients; however, osimertinib was still found to be beneficial in clinical practice.
Impact of EGFR mutation status on clinical outcome of nintedanib plus docetaxel in patients with previously treated non-small cell lung cancer (NSCLC): Retrospective analysis of Korean nintedanib named-patient usage (NPU) program in NSCLC (KCSG LU14-2).
Authors: Hong Sook-hee , An Ho Jung , Lee Yun-Gyoo , Kim Hoon-Kyo , Lee Seung-Sei , Kang Jin Hyoung
Published: September 2018

e20638

Background: Anti-angiogenic agents have been reported to have clinical activity for NSCLC harboring EGFR mutation (mutEGFR) with/without EGFR Tyrosine kinase inhibitor (TKI). We report clinical outcomes of nintedanib plus docetaxel for refractory NSCLC patients conducted by virtue of Korean NPU program. Methods: Patients with NSCLC were eligible if they failed at least one prior systemic treatment. Docetaxel was administered with 75 or 60mg/m2 on D1 or 37.5mg/m2 on D1, D8 every 3 weeks plus nintedanib 200mg orally twice daily. Nintedanib treatment was continued until disease progression or unacceptable toxicity after 4-6 cycles of combination therapy. Results: Of 62 patients enrolled, 23 patients had activating EGFR mutations (14 in exon19 deletion, 7 exon21 L858R/L861Q, 1 exon20 duplication, and 1 in both exon19 deletion and exon20 T790M) and progressed during prior EGFR-TKI treatment. Of 23 patients, 22 had progressed during or after platinum doublet chemotherapy. Only for 2 patients, EGFR mutation status was unknown. The majority of patients were heavily pretreated, with 43.7% received nintedanib plus docetaxel as ≥ 4th line therapy. 4 patients had prior bevacizumab treatment. Objective response rate (ORR) was 22.9%. Median PFS and OS were 3.9 months (95% CI 3.1-4.6) and 9.5 months (95% CI 5.3-13.7), respectively. Depending on EGFR mutation status, ORR in mutEGFR group was higher than wtEGFR group (30.4% vs 20%, p= 0.50) and median PFS in mutEGFR group was significantly longer than wtEGFR group (6.1 vs 3.3 months, p= 0.008). No treatment related death was reported. Common grade 3/4 adverse events were neutropenia (58.3%) and reversible elevated liver enzyme (18.8%). Conclusions: Taken together, nintedanib plus docetaxel showed meaningful clinical activity with good tolerability for refractory NSCLC patients. Our data suggest that this combination may be a recommendable regimen for EGFR-TKI-resistant mutEGFR NSCLC.
Molecular analysis of cell-free DNA to identify distinct molecular mutational burden and its effect on first-line chemotherapy in patients with NSCLC from a phase III trial.
Authors: Zhou Caicun , Li Xuefei , Jiang Tao , Ren Shengxiang , Su ChunXia , Zhao Chao , Han Wenbo , Wang Jianfei , Zhang Henghui , Du Bo
Published: September 2018

e20660

Background: To investigate the predictive significance of molecular mutational burden via genetic analysis of circulating cell-free DNA (cfDNA) in NSCLC patients treated with first-line platinum-based chemotherapy. Methods: Eligible patients were enrolled in a phase III trial (NCT01560195). Blood samples were collected at baseline, every two cycles of chemotherapy and at disease progression. Both cfDNA fragment and genomic DNA were isolated and subjected to enrichment for a 1.15M size panel covering exon regions from 1,086 genes. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: Forty-eight patients were enrolled. 17 genes alterations were frequently found from 15 patients (training set). Patients with partial response (PR, n = 3) had significantly lower total mutational burden of these genes than that with stable disease (SD, n = 9) and progression disease (PD, n = 3) (P < 0.05). Based on these results, we further developed a predictive model including 6 genes ( PIK3CA, KIF5B, CD74, XRCC1, MTHFR and KRAS) in the validation set (n = 33). The results showed that the mutational burden of 6-genes panel had the promising predictive yield in patients with PR (n = 7) vs. SD+PD (n = 25) (AUC = 0.962, P = 0.000), PR vs. SD (n = 18) (AUC = 0.960, P = 0.000) and SD vs. PD (n = 8) (AUC = 0.964, P = 0.003). Notably, there was no significant difference in the baseline cfDNA concentration among patients with PR, SD and PD (P > 0.05). Patients with PR experienced a reduction of molecular mutational burden of cfDNA while patients with SD or PD experienced no change or increased molecular mutational burden of cfDNA after two or four cycles of chemotherapy. However, it did not reach the statistically significant difference. Conclusions: The current study demonstrated that molecular characteristics of cfDNA was significantly associated with the effect of first-line platinum-based chemotherapy in patients with NSCLC. The mutational burden of six-genes panel had the promising predictive value in NSCLC patients treated with first-line chemotherapy.
The changing paradigm of management in melanoma brain metastases.
Authors: Ladwa Rahul , Atkinson Victoria
Published: September 2018

e21027

Background: Brain metastases (BM) are a frequent complication in patients with metastatic melanoma (MM). We aimed to explore the outcome of these patient with modern therapeutic options. Methods: We retrospectively analysed 142 patients diagnosed with BM at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 57(17-82) years, presence of seizures (N = 18), dexamethasone use (N = 106) and BRAF mutant mm (N = 117). BM were categorised as solitary (N = 45), 2-6 (N = 65), more than 6 (N = 28) and leptomeningeal only (N = 4). BM were found on systemic treatment in 62 patients. Tyrosine kinase inhibitor (TKI) was used after the diagnosis of BM (N = 50). Management of BM included surgical resection (N = 39), Stereotactic radiosurgery (SRS) (N = 33) and Whole Brain Radiotherapy (N = 45). Immunotherapy with Ipilimumab (N = 35), Pembrolizumab (N = 36) and Nivolumab (N = 21) was used. With a median follow up of 8 months, 115 patients had died, 112 from MM. Death occurred due to progressive disease in the brain (N = 66), systemically (N = 13) or both (N = 33). The number of patients dying of mm were statistically higher on dexamethasone, increasing number of BM, BRAF mutants, absence of surgical resection or SRS and absence of immunotherapy use. Statistically Improved OS were found with solitary BM, treatment naive patients and surgical management of BM. In BRAF mutant patients who were TKI naïve at diagnosis of BM the mean OS was 14.7 versus 6.5 months in patients on TKI treatment (P < 0.05). In BRAF wild type patients mean OS was 11.7 months with PD1 use versus 8.3 months without PD1 use (Not Significant). Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BM remains poor. Solitary BM amenable to resection or ablation provides optimal treatment. The use of TKIs in BRAF mutant mm post BM diagnosis and the use of immunotherapy are effective treatment options.
NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.
Authors: Kirchberger Michael Constantin , Ugurel Selma , Mangana Joanna , Heppt Markus , Eigentler Thomas , Berking Carola , Schadendorf Dirk , Schuler Gerold , Dummer Reinhard , Heinzerling Lucie
Published: September 2018

e21035

Background: About 20% of metastatic melanomas harbor NRAS mutations which constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis. The response of patients with NRAS-mutated melanoma to checkpoint inhibitor therapy is so far unknown. A previous study suggested a higher response rate of NRAS-mutated melanoma to anti-PD-1/anti-PD-L1 with an objective response in 7 out of 11 (64%) patients compared to 35% and 21% in BRAF wildtype or BRAF V600-mutated melanoma, respectively. Methods: In total, 224 patients with NRAS-mutated melanoma were analyzed. Of these, 180 patients received ipilimumab, 98 anti-PD1 monotherapy, and one patient combined ipilimumab and anti-PD1 therapy. We evaluated overall response rate (ORR), disease control rate, progression-free survival (PFS) and overall survival to checkpoint inhibitor therapy in these patients. Results: In this patient cohort with NRAS-mutated melanoma, 27% had brain metastases, 62% an elevated LDH and 22% an ECOG > = 1. ORR was 15% for treatment with ipilimumab and 34% for anti-PD1 therapy. Disease control rates were 27% for ipilimumab and 52% for anti-PD1 therapy. PFS was 4.5 months for ipilimumab and 11.4 months for anti-PD1 therapy. Overall survival of all patients was 29 months. Conclusions: The efficacy data of ipilimumab or anti-PD1 therapy in NRAS-mutated melanoma patients were similar to the known response rates of NRAS wildtype melanoma patients.
Mutation of the DNA damage gene signature to predict for better outcome in malignant melanoma.
Authors: Iddawela Mahesh Y. , Azad Arun , Risbridger Gail
Published: September 2018

e21036

Background: DNA damage response is a fundamental cellular pathway with an important role in maintaining genomic integrity. As Malignant Melanoma (MM) is associated with high mutation rates, and we postulated that mm is likely to have abnormal DNA repair pathway aberrations that could have prognostic and/or therapeutic significance. Methods: We conducted an unbiased assessment of genes involved in the DNA damage response through a comprehensive survey of established public data repositories and published literature and abstracts in all cancers. This survey was used to generate a 6-gene DNA Damage Signature (DDS). The DDS was then applied to 287 mm samples in The Cancer Genome Atlas. Results: The DDS was altered in 25% (72/287) of patients with mutations being present in all 6 genes including ATM (6%), TP53BP1 (7%), MDC1 (7%), BRCA1 (5%), PRKDC (8%) and RAD50 (1.4%). The DDS was more commonly altered in mm harboring alterations in BRAF (78%, 112/143), NRAS (89%, 73/82) or NF1 (75%, 5/20) than in triple wild type tumors (60%,19/32). The correlation between alteration in BRAF/NRAS/NF1 and DDS (p = 0.02) reached significance, as did the tendency for DDS and NF1 altered subtype to co-occur (p < 0.05). Importantly, alteration in the DDS was associated with significantly longer disease free (88 vs. 44 months, p = 0.02) and overall survival (152 vs. 66 months, P = 0.02). The mutations in ATM and BRCA1, shown to be targets in other cancers for PARP inhibition were seen in these patients as well as other oncogenic or hot-spot mutations. Conclusions: The improved survival associated with alteration of the DDS implicate DNA damage response signaling as favorably modulating the immune system, and propose a possible role for PARP inhibition as a therapeutic strategy in melanoma.
Prognostic relevance of neutrophil to lymphocyte ratio (NLR) before anti-PD1 therapy in metastatic melanoma patients.
Authors: Araujo Daniel Vilarim , de Moraes Rafael Vanin , Ramos Sousa Victor Aurelio , Donadio Mauro Daniel Spina , Fares Aline Fusco , Freitas Helano C. , Lima Vladmir C. , Barros Milton Jose
Published: September 2018

e21045

Background: Biomarkers to select the patients most likely to benefit from checkpoint inhibitors are urged. NLR is a simple way of measuring systemic inflammation and is an independent predictor of survival before Anti-CTLA4 therapy. We hypothesized if NLR is also a predictor of survival before Anti-PD1 therapy. Methods: We performed a retrospective review of the medical records of all consecutive metastatic melanoma patients who received Nivolumab treatment from January/2014 – February/2017, including 53 patients prospectively collected from an Expanded Access Program. Of 86 patients, 83 patients were included for demographic and efficacy analysis, and 74 had information about baseline pre-treatment NLR. We analyzed NLR as a continuous variable and categorised ≥ 5 vs. < 5. Kaplan-Meier method was used for survival analysis. Long-rank test compared categories and Cox proportional hazards regression model was used to assess the prognostic significance of baseline NLR in univariate and multivariable analysis. Results: Median PFS for the entire population was 6,407 months (3,28 – 9,52) and median OS was not reached (NR) with a median FU of 10,74 months. The median NLR ratio was 3,11 (0,87 – 19). 18 patients (24,3%) had a ≥ 5 NLR vs. 56 (75,7%) < 5. Median PFS for NLR ≥ 5 was: 2,3 (1,75 – 2,84) vs. 12,02 (5,11 – 18,93) for < 5 (HR = 3,11; IC95% 1,52 – 6,27; p = 0,001). Median OS ≥ 5: 3,05 (2,06 – 4,04) vs. NR for < 5 (HR = 5,88; IC95% 2,60 – 13,29; p = 0,001). NLR categorised remained statistically significant in multivariate analysis for PFS and NLR as a continuous variable remained statistically significant for both PFS and OS in multivariate analysis (Table 1). Conclusions: Baseline NLR is a rapid, simple, and cost-free predictor of survival before Anti-PD1 therapy. These results should be validated in a larger cohort of patients. [Table: see text]
Different patterns of non immediate allergic reaction to BRAF inhibitor in two patients with metastatic melanoma.
Authors: Berciano-Guerrero Miguel-Angel , Lavado Rocío , Montesa Álvaro , Alvarez Martina , Santonja Angela , de Luque Vanessa , Robles Cynthia , Gómez Marta , Alonso-Carrión Lorenzo , Salas María
Published: September 2018

e21052

Background: Non immediate allergic reactions (niAR) related with oncology drugs are a rare entity. Usually, it is called Drug Reaction with eosinophilia and sistemic symptoms (“DRESS”), occurring at first ten days of treatment.Recently, the treatment of metastatic melanoma (MM) has included new drugs in patients wtih BRAF V600E mutation. Despite skin reactions are usual, niAR to these drugs have not been reported. We present 2 clinical cases with mm treated with BRAFi, developing such niAR. Methods: Patient 1: 47yo female with lymph node relapse and multiple subcutaneous skin metastases (previously pT1N0M0 melanoma) that received nivolumab in adjuvant setting. BRAF-mutated. She starts with Vemurafenib-Cobimetinib (V-C). At 8 days, niAR (maculo-papular exantema G4, fever G2). After discontinuation of this treatment (3 weeks), it is changed to Dabrafenib(50%)-Trametinib (D-T). With only 1 dose, skin niAR (G3) is newly developed. Biopsy are taken at the beginning (T0), during (T1) and after desentizitation (T2). Patient 2: 60 yo female, lung and lymph node relapse of melanoma (previously pT2bN0M0) after IFN-alpha adjuvant 2 years before. BRAF-mutated. Start with V-C. At 9 days, skin niAR (G4), with fever (G1). Discontinuation of treatment. Biopsys and blood test are taken (T0, T1 and T2). Gene expression was performed with PanCancer Immune Profiling Panel Nanostring™ in this points. Results: Different lymphocytic subpopulations in blood and biopsy at acute phase are showed in table 1. Immune gene expression profiling found decreased expression of 5 genes: UBC, IL8, IL32, NFKB1A and FOS, increasing IFNGR1 (pt 1). In both of pts, desensitizitation protocol by Allergologists was made succesfully, with incremental oncology drugs and steroid reduction protocol. Both of pts had a maior partial response (RECIST), even the scarce of the drug received. Conclusions: D and V develop important “of class” skin niAR. Different immunologic patterns are related with this niAR. Previous exposition to IFN or anti-PD1 therapy might modulate such response. Immune gene expression profiling could be used as a method to identify biomarkers. Desensitization with BRAFi has enough efficacy and tolerance.
Natural killer cells as a predictive biomarker for response to anti-PD-1 therapy in patients with advanced solid tumors.
Authors: Tang Bixia , Chi Zhihong , Sheng Xinan , Si Lu , Cui Chuanliang , Kong Yan , Li Si Ming , Yan Xieqiao , Mao Li Li , Lian Bin , Bai Xue , Wang Xuan , Zhou Li , Li Dan , Yu Jiayi , Guo Jun
Published: September 2018

e21055

Background: Assessment of PD-L1 expression in tumor biopsy has been widely used for predicting anti-PD-1 therapy. Several factors, including tumor heterogeneity, false negative staining and unavailability of biopsy samples limit the application. Natural killer (NK) cells exert cytotoxicity against cancer cells. Therefore, we explored using NK cells percentage in peripheral blood (PB) as a biomarker to identify pts who are more likely to benefit from anti-PD-1 therapy. Methods: Pts treated with anti-PD-1 antibody (JS001) 1 mg/kg, 3mg/kg or 10mg/kg every 2 weeks in a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT02836795) had PB collected at baseline and at time of radiographic evaluation performed every 8 wks. Disease status (shrinking stable disease, growing stable disease, partial response, complete response, or progressive disease) was characterized using RECIST v1.1 and immune-related response criteria. Frequencies of NK cells (CD3-CD16+CD56+) were measured by flow cytometry. Results: Thirty-six patients were enrolled in this trial, including 22 melanoma, 9 urothelial carcinoma and 5 renal cell carcinoma. As of 1/27/2017, median treatment duration: 3.92 months. Radiographic tumor evaluation has been performed in 32 pts: 1/32 CR, 6/32 PR, 6/ 32 shrinking SD, 4/32 growing SD and 15/32 PD. Pts with high NK cells at baseline observed 60% (6/10) Clinical Benefit Rate (CR/PR/ shrinking SD) versus 40% (13/32) in overall pts. Patients with clinical benefit had higher frequency of NK cells at baseline compared to pts with radiographic growing SD and PD (mean 24.3% vs. 17.9%, P = 0.076). Furthermore, pts with NK cell level consistently above UN or increasing above UN during treatment are more likely to get clinical benefit than those under UN (7/10 vs 3/22, P = 0.013). Conclusions: Baseline high NK cells frequency may predict a favorable response to anti-PD-1 therapy, which provides a non-invasive way to monitor response to PD-1 blockade. These results are being validated in a phase II trial. Clinical trial information: NCT02836795.