bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase ib study of safety, tolerability and pharmacokinetics of simotinib in patients with advanced non-small cell lung cancer.
Authors: Hu Xingsheng , Han Xiaohong , Zhang Li , Ding Yanhua , Wang Hanping , Mu Hua , Sun Yan , Shi Yuankai
Published: September 2018

e20642

Background: Simotinib is a novel small molecule agent specifically inhibits EGFR and its downstream signaling pathway. Phase Ia study in healthy volunteers demonstrated that simotinib was well-tolerated at doses up to 500 mg. Here, we report a phase Ib study in NSCLC patients with EGFR sensitive mutations to investigate the safety, tolerability and pharmacokinetics of simotinib (ClinicalTrials.gov identifier: NCT01772732). Methods: Patients with histologically confirmed advanced or metastatic NSCLC with EGFR sensitive mutations, relapsed after first-line platinum-contained chemotherapies were eligible. Patients were orally administered with simotinib twice daily continuously, with assessment of dose-limiting toxicities (DLTs) during the first cycle (28 days). Dose escalation was carried out to determine maximum tolerated dose (MTD) using a 3+3 design and 100 mg as starting dose. Pharmacokinetics of simotinib was assessed on Days 1 and 15, respectively. Tumor response was assessed on Day 29 and every 8 weeks afterwards. Results: Fourty-one patients were enrolled and 40 patients were evaluable for response. Simotinib was well tolerated without DLTs, and MTD was not reached up to dose 650 mg. Thirty-nine (95.1%) patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequent AEs. Within the doses examined, simotinib was rapidly absorbed (Tmax ranged 1-4 hours), and the elimination T1/2 ranged 6.2-13.0 hours. Exposure to simotinib was approximately proportional with a single dose from 200 mg to 650 mg, but was less than dose proportional after multiple doses. Sixteen (40%) patients achieved partial response (PR). Median progress free survival (PFS) and overall survival (OS) were 9.9 months and 14.6 months, respectively. Notably, 5 of 8 (62.5%) patients with brain metastasis (BM) in dose cohorts of 500 mg and 650 mg achieved PR. Conclusions: Simotinib was well tolerated, with encouraging efficacy observed in NSCLC patients with EGFR sensitive mutations, particularly in those with BM. Further study of simotinib in treatment of NSCLC patients with BM is warranted and on-going. Clinical trial information: NCT01772732.
Prognostic benefit of statin with or without metformin in elderly patients with advanced non-small cell lung cancer: A nationwide population-based outcome study.
Authors: Lee Yun-Gyoo , Lee Ju Hyun , Jang Joung Soon , Kim Jee Hyun
Published: September 2018

e20661

Background: Taking statin or metformin potentially decreases chronic inflammation, which may reduce cancer mortality as well as incidence. We aimed to clarify the prognostic impact of either use of metformin or statin in elderly patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients ≥ 70 years with advanced NSCLC incident from 2007 to 2012 were identified using reimbursement claims from Korea’s National Health Insurance Service Database, and exposure to metformin and/or statin documented. Median overall survival (OS) was assessed by using Kaplan-Meier methods. Cox proportional-hazards regression model was used to examine the use of metformin and/or statin on mortality. Propensity score matching method adjusted for confounding. Results: Excluding 976 patients treated by upfront EGFR tyrosine kinase inhibitor, 7298 patients receiving palliative chemotherapy were included: 949 (13.0%) had a history of statin use, 1010 (13.8%) used metformin, 255 (3.5%) used both, and 5594 (76.6%) used neither. Median OS of statin + / metformin +, statin + / metformin –, statin - / metformin +, and statin - / metformin – users was 14.5, 12.9, 11.4 and 9.9 months respectively. By multivariate analyses, metformin use was not statistically significantly associated with improved survival in statin non-user (HR 0.99; 95% CI 0.91-1.08; p= 0.819) and statin user (HR 0.99; 95% CI 0.85-1.16; p= 0.898) group. However, use of statin, regardless of metformin, was associated with improved OS (HR 0.80; 95% CI 0.74-0.86; p< 0.001). In propensity-matched cohort, survival benefit was noted not by the use of metformin (HR 0.97; 95%CI 0.85-1.11; p= 0.661) but by the use of statin (HR 0.83; 95%CI 0.73-0.95; p= 0.007). Conclusions: Our findings did not suggest the survival benefit of metformin use in elderly patients with advanced NSCLC receiving palliative chemotherapy. Use of statin may provide a survival improvement in outcomes of elderly NSCLC.
Clinical outcome of EGFR-mutant NSCLC patients continuing TKIs beyond progression in combination with local ablative radiotherapy.
Authors: Rossi Sabrina , Finocchiaro Giovanna , D'Argento Ettore , Di Noia Vincenzo Pio , Cassano Alessandra , Bonomi Maria , Cerchiaro Eleonora , Ceresoli Giovanni Luca , Beretta Giordano D. , Barone Carlo , Santoro Armando , Toschi Luca
Published: September 2018

e20662

Background: Continuation of EGFR TKIs with or without local ablative treatments in patients with metastatic EGFR-mutant NSCLC experiencing disease progression under TKIs is feasible and may be associated with improved outcomes. Methods: The retrospective analysis includes 130 patients with advanced EGFR-mutant NSCLC experiencing RECIST disease progression under first-line gefitinib or afatinib, treated in 3 Italian centers between 2011 and 2016. In group 1 (n = 99, 76.2%) patients stopped TKI treatment at first RECIST-confirmed progression while in group 2 (n = 31, 23.8%) TKIs were continued and sites of progression were irradiated. The primary endpoint was overall survival (OS). Progression-free survival (PFS) and time to treatment failure (TTF) were calculated from the start of first-line TKIs. Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate outcome endpoints. Median follow-up time was 40 months. Results: Median OS, PFS and TTF in the whole cohort were 22.4, 11.1 and 13.0 months, respectively. The two groups resulted well balanced in terms of patients’ characteristics and TKI administered. Median OS was significantly longer in group 2 (37.3 vs 15.6 months; HR 0.33; 95%CI 0.22-0.50; p < 0.0001), as well as median PFS (13.8 vs 8.9 months; HR 0.60; 95%CI 0.42-0.86; p = 0.01) and median TTF (29.3 vs 10.4 months; HR 0.30; 95%CI 0.21-0.44; p < 0.0001). Ten out of 31 (32.3%) patients underwent radiotherapy in ≥2 sites of progressive disease; the most frequently irradiated site was bone (n = 16), followed by brain (n = 9), lung (n = 8) and lymph nodes (n = 6). On multivariate analysis including age, sex, smoking history, mutant exon, presence of brain metastases, TKI administered and treatment strategy at progression, only TKI continuation with radiotherapy was independently associated with all outcome endpoints (OS: p = 0.0007, PFS: p = 0.004; TTF: p < 0.0001). Conclusions: In EGFR-mutant NSCLC progressing under first-line TKIs continuation of TKI in association with local ablative radiotherapy is associated with prolonged OS, PFS and TTF. Whether the improved outcome is a result of treatment strategy or more indolent disease remains unclear.
Sequence of stereotactic ablative radiotherapy and immune checkpoint blockade in the treatment of metastatic lung cancer.
Authors: Pinnamaneni Ramya , Hegde Aparna Madhukeshwar , Cherukuri Sulochana Devi , Arastu Hyder Husain , Bowling Mark , Leinweber Clinton , Stroud Chipman Robert Geoffrey , Cherry Cynthia R. , Walker Paul R.
Published: September 2018

e20665

Background: Monoclonal antibodies targeting immune checkpoint proteins have recently been shown to elicit robust and durable responses in patients with advanced lung cancer. However, with response rates ranging from 15-20%, immunomodulatory strategies are needed to improve outcomes. Stereotactic ablative radiotherapy (SABR) may be a promising immunomodulatory strategy given its synergistic effects without added toxicity. Several pre-clinical trials combining SABR and immunotherapy have shown improvement in progression free and overall survival. Given this, it has been our multidisciplinary programmatic approach to bring in SABR in patients receiving immunotherapy for a potential immune boost. Methods: This is a retrospective study evaluating the overall survival (OS) of all lung cancer patients who received Nivolumab with SABR at our institution. We included lung cancer patients of all pathologic subtypes who received Nivolumab. We identified patients who received SABR, to sites of symptomatic metastatic disease, within 30 days preceding (Before) or during (Sandwich) Nivolumab treatment. Results: Out of 76 lung cancer patients treated with Nivolumab, 22 received RT- 10 Before and 12 Sandwich. At a median follow up time of 10.6 months (mo), median OS for patients with no RT was 4.8 mo, Before was 5.2 mo and Sandwich was not reached (NR) (p = 0.06). The 1 year OS for the Sandwich arm was 52.1%. When compared to no RT, the Before arm had a statistically insignificant reduction in mortality (HR 0.59, 95% CI 0.25 – 1.41, p = 0.24). The Sandwich arm had a statistically significant reduction in mortality (HR 0.37, 95% CI 0.14 – 0.94, p = 0.04). Conclusions: There is an improvement in OS when SABR is administered as a Sandwich approach during Nivolumab treatment, likely due to SABR-induced neoantigen release, increased PDL1 expression and subsequent abscopal effect. Further prospective studies are needed to evaluate optimal sequencing, dose and site of RT with immunotherapy. [Table: see text]
Treatment outcomes with tyrosine kinase inhibitors in patients with uncommon EGFR mutations in non-small cell lung cancer: A multi-centre retrospective analysis.
Authors: Hunter Sarah , Nickless Guillermina , El-Shakankery Karim , Yousaf Nadia , Smith Daniel , Brand Gillian , Nicolson Marianne , Neat Michael , Newsom-Davies Tom , Spicer James F. , Montes Ana , Karapanagiotou Eleni
Published: September 2018

e20678

Background: The clinical significance of common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions and exon 21 L858 mutations) in non-small cell lung cancer is well known1. However, 2-8% of NSCLC patients harbour an uncommon EGFR mutation2. Prognosis and response to tyrosine kinase inhibitors (TKIs) is unclear in this subgroup. The most frequent uncommon EGFR mutations are exon 18 G719 and exon 21 L861. Although not frequently reported, these appear to have favourable outcomes with TKIs3. Methods: We conducted a retrospective review of all patients with uncommon EGFR mutations identified at laboratories in 4 UK centres, between 2012 and 2016. Patient’s not treated with a TKI were excluded. Techniques including cold PCR were in use at contributing laboratories. The T790M resistance mutation was excluded from our study. For patients with uncommon EGFR mutations, patient characteristics and response to TKIs were analysed. Results: 29 patients with uncommon EGFR mutations, with both rare point mutations (86%) and deletions (14%), were identified. All patients were treated with a TKI. Age ranged from 37 to 85 (median 67). The majority (86%) of patients were performance status 1. TKIs used were afatinib (31%), gefitinib (24%) and erlotinib (45%). 19 patients (66%) benefitted from TKI treatment (38% partial response (PR), 28% stable disease (SD). 10 patients (34%) did not respond, including all four with exon 20 mutations. 15 mutations were exon 18 G719 mutations: 40% had a PR and 40% stable disease with TKI therapy. There were two L861 mutations, both responded with a PR. 13 patients remained on TKI treatment at data cut off. The median progression free survival at this time was 8.1months. Tabulated details of response according to mutation will be presented. Conclusions: The majority (66%) of NSCLC patients with uncommon EGFR mutations benefitted from TKI therapy in this series. These high clinical benefit rates, typified by patients with G719 mutation, are in line with the limited previous reports 1,3. Exon 20 mutations were associated with TKI resistance, in line with the literature4.
Brigatinib (BRG) in patients (pts) with ALK+ non-small cell lung cancer (NSCLC): Updates from a phase 1/2 trial.
Authors: Bazhenova Lyudmila , Gettinger Scott N. , Langer Corey J. , Salgia Ravi , Gold Kathryn A. , Rosell Rafael , Shaw Alice Tsang , Weiss Glen J. , Haney Jeff , Rivera Victor M. , Kerstein David , Camidge D. Ross
Published: September 2018

e20682

Background: The investigational next-generation ALK inhibitor BRG has shown activity in ALK+ NSCLC pts in a phase 1/2 trial; here, we provide updated data with longer follow-up. Methods: In this ongoing phase 1/2, single-arm, open-label, multicenter trial (NCT01449461), pts with advanced malignancies (including ALK+ NSCLC) received oral BRG (30–300 mg/d). Activity by RECIST v1.1 in ALK+ NSCLC pts and safety in all pts are shown. Results: 58% (79/137) pts had ALK+ NSCLC, with median age 54 y; of these, 90% (71/79) had received crizotinib (CRZ). As of May 31, 2016, 41% (32/79) ALK+ NSCLC pts continued to receive BRG; median treatment duration was 20.0 mo (1 d–47.4 mo). The table shows efficacy in CRZ-treated pts; median overall survival was 47.6 mo (95% CI 21.4–47.6 mo). All 8 CRZ-naive pts had confirmed objective responses; median duration of response and progression-free survival (PFS) were not reached. In a post hoc analysis, 53% (95% CI 27%–79%; 8/15) ALK+ NSCLC pts with measurable baseline brain metastases had confirmed intracranial objective responses (last scan date: October 8, 2015). Median intracranial PFS in 46 evaluable ALK+ NSCLC pts with baseline brain metastases was 14.6 mo (95% CI 12.7–36.8 mo). Treatment-emergent adverse events (AEs) in ≥30% of all pts, mainly grade 1/2, were nausea 53%, fatigue 45%, diarrhea 42%, headache 35%, and cough 33%; serious treatment-emergent AEs in ≥5% of pts were pneumonia 7%, dyspnea 6%, and hypoxia 5%. 10% of pts (14/137) discontinued BRG due to an AE. Conclusions: BRG yielded substantial whole-body and intracranial activity in ALK+ NSCLC pts in this trial, with acceptable safety. These data informed design of the pivotal randomized phase 2 trial of BRG (90 mg qd or 180 mg qd [with lead-in]) in CRZ-refractory ALK+ NSCLC (ALTA). Clinical trial information: NCT01449461. [Table: see text]
Clinical correlates of response to anti-PD-1 (aPD1)-based therapy in patients (pts) with metastatic melanoma (MM).
Authors: Davis Elizabeth J. , Zhao Shilin , Ye Fei , Rappazzo Katherine , Sosman Jeffrey Alan , Johnson Douglas Buckner
Published: September 2018

e21000

Background: aPD1, alone or in combination with ipilimumab (IPI), produces durable responses in a subset of MM. Tumor features that correlate with treatment response, including size, number, and location of metastases (mets) are not well defined. Methods: We collected clinical data from mm pts treated at one center who received aPD1 (n = 185) or aPD1 + IPI (n = 42). We correlated number of mets, size of largest tumor, and organ involvement with response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: Among all pts, RR was 67% for aPD1 + IPI and 41% for aPD1 alone. In univariate analyses, responders to aPD1 had lower diameter of largest tumor (4cm vs. 5.5cm; p = 0.02) whereas aPD1 + IPI had equivalent largest tumor diameters (p = 0.65). Regarding sites of mets, liver mets were associated with lower RR in aPD1 treated pts (26% vs. 46%), lower PFS (median 138 vs. 326 days, p = 0.02), and lower OS (median 334 vs. 1080 days, p < 0.01). No associations with RR, PFS, or OS were observed with liver mets in aPD1 + IPI treated pts. We also did not observe any differences between pts who did or did not have lung, lymph node, or brain mets for either aPD1 or aPD1 + IPI. Interestingly, superior RR to aPD1 + IPI was observed in pts with bone mets compared to those without bone mets (91% vs. 58%, p = 0.048). Regarding number of sites, RR to aPD1 was greater in pts with ≤10 mets compared with those with > 10 (46% vs. 28%, p = 0.02), although no consistent relationship was observed at lower cutoffs. In multivariable analyses, diameter of largest tumor (tumor bulk) was independently associated with PFS (OR, 1.11, p < 0.001) and OS (OR 1.08, p < 0.001) whereas AJCC stage, lactate dehydrogenase, liver mets, ECOG performance status, number of mets, and prior therapies were not significant. Tumor bulk and other risk factors were not associated with PFS or OS in aPD1 + IPI. Conclusions: Tumor bulk was strongly and independently associated with clinical outcomes in aPD1 but not IPI + aPD1. Other associations with disease sites (liver and bone) need further validation. In conjunction with molecular biomarkers, clinical predictors may help guide selection of aPD1 or aPD1 + IPI.
Real world treatment patterns and discontinuation of systemic combination therapies in metastatic melanoma.
Authors: Qiu Ying , Li Zhiyi , Tang Jackson , Atanasov Pavel , Mahmood Syed , Grzegorzewski Kris , Chen Lei , Chen Joyce S
Published: September 2018

e21003

Background: Guidelines for metastatic melanoma (MM) recommend targeted therapy combination (combo) for patients (pts) with BRAF mutation (BRAF+) and immunotherapy for pts irrespective of BRAF status. The study objective was to describe real world characteristics and treatment patterns among mm pts treated with either dabrafenib+trametinib (D+T) or ipilimumab+nivolumab (I+N) combo therapies. Methods: This retrospective observational study utilized Flatiron Health’s electronic health record (EHR) data. Included pts were ≥18 years and treated with either D+T or I+N (post mm diagnosis) from Jan 2013 - Jul 2016. Baseline characteristics, treatment patterns and data on therapy discontinuation were collected from structured data in patient records and unstructured data in physician notes. Non-parametric statistical tests were used in light of sample size limitations. Results: 135 D+T pts and 75 I+N pts were included. Median age was 60 for D+T pts and 64 for I+N pts. 69% of D+T pts were male vs 68% of I+N pts. Most pts were Caucasian (82% for both). Before receiving combo therapy, 100% of D+T pts vs 31% of I+N pts were BRAF+, 38% of D+T pts vs 31% of I+N pts had brain metastasis (mts) (p > .05), 25% of D+T pts vs 16% of I+N pts had high LDH levels (p = .05), and 18% of D+T pts vs 35% of I+N pts reported ECOG = 0 status (p < .01). Median follow-up time was 234 days for D+T pts vs 173 days for I+N pts (p < .01). 64% of D+T pts vs 81% of I+N pts received combo therapy as first line (1L) therapy (p = .02). The 3 and 6 month discontinuation rates were 9% and 24% for D+T 1L pts; 12% and 26% for I+N 1L pts; and 21% and 47% for the subset of I+N 1L BRAF+ pts. 13% of D+T 1L pts vs 28% of I+N 1L pts discontinued treatment over the follow-up period citing toxicity in physician notes (p = .05). Among pts with brain mts, the 3 and 6 month discontinuation rates were 3% and 20% for D+T 1L pts; 24% and 35% for I+N 1L pts; and 33% and 50% for I+N 1L BRAF+ pts. Conclusions: Prior to initiation of combo therapy, D+T pts had more advanced disease: pts were more likely to have brain mts, high LDH level, receive D+T as 2L+ therapy, and less likely to have ECOG = 0 status than I+N pts. I+N 1L pts were more likely to discontinue therapy due to toxicity than D+T 1L pts even with a shorter median follow-up time.
Phase II study of ipilimumab (IPI) in children and adolescents with unresectable stage III or IV malignant melanoma (MEL).
Authors: Pappo Alberto S. , Bergeron Christophe , Gore Lia , Sender Leonard S. , Dunkel Ira J. , Herzog Cynthia E. , Brochez Lieve , Cruz Ofelia , Nysom Karsten , Berghorn Elmer , Simsek Burcin , Shen Jun , Geoerger Birgit
Published: September 2018

e21006

Background: IPI (anti-CTLA4) is approved for treatment of advanced MEL in adults, and more information on efficacy and safety of IPI in younger patients (pts) is needed. Methods: Pts from study CA184-178 (NCT01696045) age 12 to <18 yrs with previously treated or untreated, unresectable stage III or IV malignant MEL received up to 4 doses of IPI at 3 or 10 mg/kg Q3W. Key exclusion criteria were ocular MEL, active brain metastases, or autoimmune disease. Primary endpoints were 1-yr overall survival (OS) and safety. Results: From April 2013 to June 2016, 12 pts received either IPI 3 mg/kg (n=4) or 10 mg/kg (n=8); 2 did not meet study criteria and were not treated. For the 3 and 10 mg/kg groups, median age was 13 yrs and 15 yrs, 50% and 63% were male, 25% and 13% had elevated baseline lactate dehydrogenase, and 75% and 50% had prior systemic therapy, respectively. Median number of IPI doses received was 4.0 (range: 2–4) for 3 mg/kg and 3.0 (range: 1–4) for 10 mg/kg. At 1 yr, 3/4 pts on 3 mg/kg and 5/8 pts on 10 mg/kg were alive (Table). Two pts on 10 mg/kg had partial response and 1 pt from each group had stable disease (Table). One pt had ongoing partial response >2 yrs without further treatment. Treatment-related grade 1-4 adverse events were reported in 2/4 and 7/8 pts in 3 and 10 mg/kg groups, respectively. There was 1 grade 3-4 immune-mediated adverse reaction with 3 mg/kg (hepatitis) and 5 with 10 mg/kg (hepatitis [2] and pyrexia [2] were most common). The study was stopped early due to slow accrual. Conclusions: At >1 yr of follow-up, IPI demonstrated activity in MEL pts aged 12 to <18 yrs, with a safety profile consistent with that observed in adults. Our trial highlights the difficulties of enrolling children with rare diseases in clinical trials for drugs that are approved in adults, suggesting adolescents should be included earlier in adult trials of promising new drugs. Clinical trial information: NCT01696045. [Table: see text]
Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.
Authors: Gaughan Elizabeth Mary , Petroni Gina R. , Grosh William W. , Slingluff Craig L.
Published: September 2018

e21009

Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%, 95% CI [1.3% to 33.1%]) had an objective response (CR+PR) and 9/19 patients (47.4%, 95% CI [24.5% to 71.1%]) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5% (95% CI [39.3% to 85.8%]) Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.
Selinexor, a selective inhibitor of nuclear export (SINE), in patients with unresectable melanoma.
Authors: Kendra Kari Lynn , Watson Ryan , Lesinski Gregory B
Published: September 2018

e21014

Background: Limited effective therapies exist for patients with melanoma after progression on immune- and targeted-therapies. Treatment with selinexor, a potent small molecule inhibitor of exportin-1 (CRM/XPO1), results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leads to growth arrest and apoptosis in vitro, in xenograft models (BRAF +/-), and Phase I solid tumor trial. (Yang et al PLOS One, 2014, Razak et al JCO, 2016). Methods: Objectives of this single institution trial were to determine: the safety in melanoma patients, the clinical benefit rate, and efficacy at the MTD as measured by PFS. Patients received prior immunotherapy and a BRAF inhibitor (mutation positive). Lead-in phase is completed. Median number of prior systemic therapies = 2 (2 – 4). Selinexor (50 mg/m2) was orally administered twice weekly, with 2-3 days off between doses. Toxicities were evaluated every 28-days. Tumor biopsies were collected for correlative analysis. Results: As of Jan 2017, 7 patients (0/7 BRAF mutant) were enrolled. Drug related AEs: neutropenia (grade 4) (1/7 patients), hyponatremia (grade 3) (1/7 patients), thrombocytopenia (Grade 3) (3/7 patients), anemia (Grade 3) (1/7 patients), and thromboembolic events (Grade 3) (1/7 patients). There were no DLT’s. Four patients experienced stable disease (SD); one patient had a minor response, for a disease control rate (DCR) of 71% (5/7). Mean duration of response was 207 days (70 – 335). One patient, removed from therapy due to a CNS met, continued with stable systemic disease off therapy for 177 days. Another patient, taken off therapy due to a non-drug related adverse event, remained SD for 127 days. Conclusions: These preliminary results demonstrate that selinexor is well tolerated with supportive care, is safe for melanoma patients dosed at the 50 mg/m2, and has the potential to control disease progression as a single agent in patients with prior BRAF inhibitor and immunotherapy. Patients are currently enrolling at a flat 60 mg dose. Correlative studies including evaluation of selinexor target engagement and exploratory markers of drug response are underway. Clinical trial information: NCT02120222. Clinical trial information: NCT02120222.
An observational study of patients with advanced melanoma receiving pembrolizumab in a real-world U.S. community oncology practice.
Authors: Cowey Charles Lance , Liu Frank Xiaoqing , Black-Shinn Jenny , Stevinson Kendall Lee , Boyd Marley , Patt Debra A. , Ebbinghaus Scot
Published: September 2018

e21015

Background: PD-1 monoclonal antibodies are promising immunotherapies approved for treatment of patients (pts) with advanced melanoma. As the first US FDA approved PD-1 antibody, pembrolizumab (pembro) has demonstrated efficacy and safety in clinical trial settings. However, patterns of real world utilization and pt outcomes associated with pembro are limited. Methods: Adult pts with advanced melanoma who initiated pembro between 9/1/ 2014-3/31/2016 were identified retrospectively fromelectronic health records (EHR) of McKesson Specialty Health and followed through 9/ 30/2016. Pts in clinical trials were excluded. Demographic, disease, treatment characteristics and reasons for treatment discontinuation of pembro were abstracted from structured data elements of the EHR with further supplementation of unstructured data within the patient chart (progress notes, radiology scan reports). Overall survival (OS) and physician-reported progression free survival (PFS) from pembro initiation were analyzed using Kaplan Meier analysis. Results: 182 pts, with a median follow-up of 9.9 mos (range = 0.0-25.0), were included. Median age at pembro initiation was 66.0 yrs; 30.8% had an elevated lactate dehydrogenase (LDH); 23.6% had brain metastases and 65.4% had an ECOG performance status of 0 or 1. The most common reason for pembro discontinuation was progression (45.5%) followed by treatment-related toxicity (24.4%). In the overall population, median PFS from pembro initiation was 4.2 mos (95% CI = 3.2-5.3). Median OS was 19.4 mos (14.0-NR) with 12 and 24-month survival probabilities of 61.4% (95% CI = 53.4-68.5) and 43.9% (95% CI = 31.1-55.9). In multivariable analyses, characteristics predictive of worse survival included receipt of pembro at a later line of therapy (HR = 3.36, p = 0.0013 for 3L+), presence of brain metastases (HR = 2.67, p = 0.0007) and elevated LDH (HR = 4.10, p < 0.0001). Conclusions: The study results are consistent with those from pembro clinical trials (KeyNote001) and are in support of the effectiveness of pembro in real world treatment of advanced melanoma. Presence of brain metastases, elevated LDH, and use of pembro 3L+ were associated with worse survival outcome.
Pretreatment features and risk of death from BRAF-positive metastatic melanoma patients treated with vemurafenib.
Authors: Kwapisz Dorota Malgorzata
Published: September 2018

e21028

Background: Clinicopathologic features of BRAF-positive metastatic melanoma patients were identified. No study to date has examined influence on risk of death features at baseline before starting treatment with vemurafenib. The purpose of the study is to identify demographic, clinical, biochemical, and tumor-related features at baseline before treatment with vemurafenib that are related with increase risk of death in BRAF-positive metastatic melanoma patients. Methods: 323 consecutive patients with metastatic melanoma tested for BRAF mutation were analysed. The presence of BRAF gene V600 mutation was evaluated by the cobas 4800 BRAF V600 Mutation Test. The pretreatment features were collected prospectively after inclusion patients for BRAF inhibitor treatment but before treatment was started. Results: 204 patients had a BRAF mutation. Of these, 115 were treated with vemurafenib. The median time of treatment with vemurafenib was 198 days. Death occurred more frequently among patients with: pretreatment disease symptoms (p = 0.003), ECOG PS ≥1 (p = 0.03), CNS metastases at baseline (p = 0.049) [χ2 test]. The pretreatment elevated serum LDH level (p < 0.0005), leukocytosis (p = 0.042), and hipoalbuminemia (p = 0.002) had an impact on higher incidence of death. AJCC stage 3 was reported more frequently in patients who have died (AJCC 1-2 vs. AJCC 3; p = 0.025, χ2 test). Higher incidence of death in patients with ≥4 localisations of metastases (different organs) was noted (1-3 vs 4-8; p = 0.001, χ2test). The maximum metastasis dimension was greater in the group of patients who have died (p = 0.009; Mann-Whitney test). In the analysed population, all patients whose pretreatment metastasis dimension exceeded 56 mm have died. Age, BMI, and sex were not related with higher risk of death. Conclusions: Pretreatment features may identify patients at higher risk of death. Those with features at baseline such as: disease symptoms, poor performance status, elevated LDH, leukocytosis, hipoalbuminemia, increased metastatic tumor burden, especially when brain is one of the metastatic localisation are in higher risk of death among all patients treated with vemurafenib.
A 'melanoma mortality belt' of ten U.S. states with the highest melanoma mortality rates.
Authors: Geller Alan , Berk-Krauss Juliana , Polsky David , Stein Jennifer
Published: September 2018

e21039

Background: To our knowledge, no study has looked at U.S. melanoma mortality trends by state. We sought to determine the ten states with the highest melanoma mortality rates (per white population) and those with the lowest, as well as any state-wide demographics that could account for these trends. Methods: State melanoma mortality rates were collected from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program and National Program for Cancer Registries. Data on state characteristics were collectied from the Area Health Resource File (AHRF) and the US Census Bureau. We used a regression model to determine associations between melanoma mortality and the state demographic context, such as median income, per capita income, unemployment rate, education level, and rural versus nonrural. We also examined the effect of access to health care resources by looking at density of dermatologists, density of primary care providers, and total number of hospitals. Results: We identified ten states concentrated across the central United States with the highest melanoma mortality rates. Per capita income was the only significant association for melanoma mortality rates (p = 0.0016, 95% CI 6.88 to 18.09). Median income, unemployment rate, education level, rural versus non-rural, health professional density, and unemployment rate were not associated with melanoma mortality rates by state. Conclusions: There exists a ‘melanoma mortality belt’ across the central United States made up of the ten states with the highest melanoma mortality rates. This trend could not be consistently accounted for by state demographics, even socioeconomic status traditionally thought to correlate with mortality. Only one significant association was seen between melanoma mortality rate and per capita income. Our preliminary findings highlight the multifactorial picture of geographic melanoma mortality inequalities in the U.S.
Clinico-epidemiologic characteristics and patterns of care in Merkel cell carcinoma: Data from a single-institution series.
Authors: Del Rosario Michael , Anderson Eric , Lu Yani , Farrell Stephanie , Plaxe Steven C. , Dasanu Constantin
Published: September 2018

e21049

Background: Merkel cell carcinoma (MCC) is associated with increased sun exposure. There is an average of 348 days of sunshine per year in our geographic area. Methods: With the IRB approval, we performed a retrospective chart review of all consecutive MCC patients seen at our institution between 2006-2017. Clinico-epidemiologic data such as age, gender, race, stage, tumor size, stage at presentation, and disease course were collected. Therapy and survival were analyzed. Using the surveillance, epidemiology, and end results program (SEER), we identified 4,256 patients with MCC from the years 2006-2013. We compared our data with the SEER findings . Statistical analysis: Chi-square and Fishers’ exact tests were used to assess the significance of associations in large and small populations, respectively. Survival analyses were performed using the Cox proportional hazards. Results: We identified 40 patients with MCC (n = 40) with a median age of 77. Compared to SEER data, our population was entirely Caucasian (100% vs. 95%; p = 0.11) and male predominant (75% vs. 63%; p = 0.11). The patients in our cohort were diagnosed more often with TNM stage I (50% vs. 39%; p = 0.00003) and found to have more often a primary tumor size < 2cm (58% vs. 34%; p < 0.01). Our patients were more frequently treated with lymph node dissection (70% vs. 63%, p = 0.002) and radiation therapy (60% vs. 50%; p = 0.24). Conclusions: Compared to the general population, MCC patients treated at our institution had similar mean age at diagnosis, gender and racial distribution and radiation treatment frequency (all p-values > 0.05). However, our patient population was significantly more likely to be diagnosed at stage I disease, have a primary tumor size less than 2 cm and receive lymph node dissection. Final statistical analysis, including survival analysis, and significance are to be discussed.
Serum 5-s-cysteinyldopa for identifying non-responders to nivolumab treatment of melanoma.
Authors: Omodaka Toshikazu , Minagawa Akane , Uhara Hisashi , Wakamatsu Kazumasa , Koizumi Tomonobu , Koga Hiroshi , Okuyama Ryuhei
Published: September 2018

e21068

Background: Despite considerable advances in the treatment of metastatic melanoma, reliable markers to monitor treatment response are still lacking. 5-S-cysteinyldopa (5-S-CD) is a precursor of melanin that has been established as a biomarker for melanoma progression. This study evaluated serum 5-S-CD in parallel with lactate dehydrogenase (LD) as a predictor of treatment progress in melanoma patients receiving Nivolumab (Nivo) therapy. Materials and Methods: Twenty-one patients (median age: 77 years; 10 male and 11 female) with metastatic melanoma who were treated with Nivo at Shinshu University Hospital between 2014 and 2016 were retrospectively examined. Primary lesions were in the head and neck in 5 patients, trunk and extremities in 5 patients, acral area in 5 patients, mucosa in 3 patients, and an unknown site in 3 patients. Serum 5-S-CD and LD were recorded and change ratios were calculated between the baseline and values obtained 14-90 days after the initial administration of Nivo, prior to the first imaging examination. The change ratios of each biomarker were evaluated based on the response classifications defined by the RECIST criteria (version 1.1). Results: The respective baseline median concentrations of serum 5-S-CD (normal range: 2.5–6.1 nmol/L) and LD (normal range: 120–230 IU/L) were 26.5 nmol/L and 247 IU/L in partial response (PR) patients (n = 5), 74.2 nmol/L and 428 IU/L in a stable disease (SD) patient (n = 1), and 9.9 nmol/L and 237 IU/L in progressive disease (PD) patients (n = 15). The maximum change ratios of 5-S-CD before the first imaging examination were 0.13–1.14 (median: 0.34) in PR patients and 0.30–15.38 (1.52) in PD patients, as compared with 0.73–0.98 (0.96) in PR patients and 0.63–2.23 (1.04) in PD patients for LD. The maximum change ratios of 5-S-CD were ≥1.3 in 9 of 15 (60%) PD patients but < 1.3 in all (100%) PR and SD patients. Conclusions: The maximum change ratio of serum 5-S-CD in the early phase of Nivo treatment may be a useful and more sensitive marker than that of LD to predict a non-response in metastatic melanoma.
Ratio of some fibrinolytic system components and biological aggressiveness of melanoma.
Authors: Bandovkina Valeria , Frantsiyants Elena Mikhaylovna , Kaplieva Irina V. , Trepitaki Lidia K. , Pogorelova Yulia A. , Cheryarina Natalia D. , Neskubina Irina Valerevna , Sustretov Vyacheslav A. , Maksimova Maria I. , Rozenko Ludmila , Kit Oleg I.
Published: September 2018

e21069

Background: Melanomas of early stages in a horizontal growth phase can masquerade as a melanocytic nevus or other benign skin lesions. Activation of plasmin/plasminogen system is typical of both physiologic and pathologic processes. Cell remodeling and neoangiogenesis play critical role in melanoma invasion and metastasis. The purpose of the study was comparative analysis of plasmin/plasminogen system in tissues of nevi and melanomas of different sizes and extension. Methods: Activity of plasmin and plasminogen was studied and antigen and activity assays (ELISA) were performed for uPA, tPA and PAI-1 in tissues of nevi (n = 30) and melanomas pТ1-2N0M0 (n = 17) and pТ3-4N0-1M0 (n = 23). Intact tissue (n = 15) obtained in surgical treatment of patients without cancer was used for the control. Results: Plasminogen levels were decreased by 2 times in tissues of nevi and pТ1-2N0M0 melanoma, while plasmin was unchanged. pТ1-2N0M0 melanoma significantly differed from nevi by a marked activation of uPA without PAI-1 increase. Activation of plasminogen system in both рТ1-2N0M0 melanoma and in nevi was not accompanied by plasmin accumulation. The main difference between tissues of nevi and pТ1-2N0M0 melanoma was the uPA/PAI-1 ratio reduction by more than 40 times in nevi. pТ3-4N0-1M0 melanoma was characterized by plasmin level increase by more than 19 times and uPA activity and content increase by 2.5 times, compared to pТ1-2N0M0, without an increase in PAI-1 activity. The uPA/PAI-1 ratio almost doubled. Conclusions: Normal plasmin levels in nevi and melanomas in a horizontal growth phase are probably the result of its inhibitors activity. Increased activity of fibrinolytic system, plasmin accumulation and uPA/PAI-1 increase in a vertical growth phase determine proliferative, invasive and metastatic potential of tumors.
Mohs micrographic surgery volume and payment patterns among dermatologists in the Medicare population, 2013.
Authors: Johnstone Cameron , Joiner Keith M , Krouse Robert S.
Published: September 2018

e21078

Background: Mohs Micrographic Surgery (MSS) has expanded markedly in recent years but there is limited information on volume, practice patterns, compensation or comparative effectiveness data to support preferential use. This study examines patterns of MSS utilization in the Medicare population. Methods: We obtained the Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File Calendar Year 2013dataset from CMS.gov. This contains comprehensive payment and utilization data for physician/supplier Medicare Part B Fee For Service final-action non-institutional claims in 2013. For dermatologists as a whole and the subset of dermatologist MSS surgeons, we analyzed provider service volume and reimbursement for all services as well as for malignant skin cancer procedures (destructions, excisions or MSS) in SAS 9.3. Results: Total Medicare funded MSS procedures increased 25 percent from 2009 (558,447) to 2013 (700,262). Dermatologists who performed MSS had significantly more average services per provider (5,419.4 vs. 3,627.1, r = 0.16, p < 0.0001), earned significantly more in average total procedure-related compensation ($475,883.64 vs. $144,564.74, r = 0.49, p < 0.0001) than dermatologists who did not perform MSS, and made up 71.3 percent of the top decile of dermatologists ranked by total payment received from Medicare. Total MSS service volume and compensation was concentrated among a subset of providers: the top quintile in this group (513 – 3,759 procedures) in annual procedure volume performed over 50 percent of total MSS surgeries. MSS providers with higher annual service volumes performed a greater percentage of their total MMS procedure annual totals on lesions located on the trunk, arms or legs versus the head, neck, hands, feet or genitals (r = 0.27, p < 0.001). Conclusions: Mohs Micrographic Surgery is expanding among Medicare beneficiaries. A subset of dermatologists performing MSS accounts for most services and earnings, and performs surgeries more frequently on the trunk or extremities. Further studies are needed incorporating clinical data not available in Medicare billing information to explore implications of these findings for clinical practice.
Effect of gene expression profile (GEP) testing on clinical management in 19% of consecutively treated patients with stage IB/IIA melanoma at a single institution.
Authors: Dengel Lynn Thacher , Hickman Alexandra W. , Slingluff Craig L.
Published: September 2018

e21080

Background: A 31-GEP test is predictive of metastasis in cutaneous melanoma. We hypothesized that GEP testing would “upgrade” surveillance to routine imaging in at least 16% of stage IB/IIA patients, similar to the upgrade rate from sentinel node biopsy. Methods: A GEP score was obtained for consecutive patients with Stage IB/IIA melanoma treated between 6/2014-6/2016. A retrospective review of a prospectively collected database was performed. Results: 67 patients with Stage IB/IIA melanoma met inclusion criteria. In four cases, a GEP result was not available. Of the 63 tested cases, 68% were Stage IB (N = 43), and 32% were Stage IIA (N = 20). A high-risk result was seen in 12% of stage IB (5/43) and 42% of stage IIA (8/19) patients. Insurance denied coverage of scans in 1/13 patients with a high-risk GEP result. The remaining 12 Stage IB/IIA patients with high-risk scores were “upgraded” to high-intensity surveillance. With a median follow-up of 14 months, 1/13 patients with a high-risk GEP result developed distant metastases 21 months after diagnosis of a Stage IIA melanoma. Conclusions: Results from this retrospective single institution study show that GEP testing altered patient management in 19% of Stage IB/IIA patients. Early detection in 1/13 patients with high-risk scores in this series supports further investigation into stratifying traditionally low-risk patients by GEP testing.
The use of anticoagulants in terminal cancer patients admitted in hospice center.
Authors: Shim Hyun Jeong , Kim Ka-rham , Hwang Jun Eul , Bae Woo Kyun , Cho Sang-Hee , Chung Ik-Joo
Published: September 2018

e21503

Background: Venous thromboembolism (VTE) is common in patients with cancer and the risk increases with advanced disease. However, no management guidelines exist specific to terminal cancer patients in hospice. We conducted a retrospective analysis to determine the patterns of anticoagulant use in hospice setting. Methods: We identified patients who were prescribed anticoagulants in the Hospice and Palliative Care Clinic at Jeonnam Regional Cancer Center from August 2008 to September 2016 in this study. Patient characteristics included age, gender, cancer diagnosis, length of hospice stay, type and duration of anticoagulation. Results: Of 1,494 consecutive patients who received hospice care in our center, 57 (3.8%) were prescribed ≥ 1 anticoagulants. Types of anticoagulants prescribed were; LMWH only (n = 44, 77.2%), warfarin only (n = 7, 12.3%), rivaroxaban (n = 2, 3.5%) and both LMWH and warfarin (n = 4, 7%). Indications for anticoagulation were DVT (n = 17, 29.8%), PTE (11 = 19.3%), clinical suspicion of DVT with leg swelling (n = 23, 40.4%) and atrial fibrillation (n = 6, 10.5%), respectively. The mean age was 65 years (range 28-84) and 37 (52.6%) were male. The mean age was 63.5 years in LMWH treated patients and 67 years in warfarin treated patients (p < 0.95). The median duration of hospice stay and anticoagulation use were 18.5 days and 11.2 days. The reasons for discontinuation of anticoagulants were bleeding (n = 8, 14%), no palliative benefit (n = 10, 17.5%) and clinical signs of impending death (n = 39, 68.4%). Conclusions: In this retrospective study, anticoagulants were used in highly selected patients. In the absence of specific evidence, decisions are difficult for clinicians to initiate and stop anticoagulation treatment in hospice patients with terminal cancer. Further research is needed to determine the impact of anticoagulation on outcomes, especially cost, quality of life and complications for cancer patients in hospice.