bluuebunny/crossref_metadata_2025_split huggingface dataset:
STREAM: A randomized discontinuation, blinded, placebo-controlled phase II study of sorafenib (S) treatment of chemonaïve patients (pts) with metastatic uveal melanoma (MUM).
Authors: Scheulen Max E. , Kaempgen Eckhart , Keilholz Ulrich , Heinzerling Lucie , Ochsenreither Sebastian , Abendroth Annalena , Hilger Ralf A. , Grubert Matthias , Wetter Axel , Guberina Nika , Bauer Sebastian , Schuler Gerold , Bornfeld Norbert , Schuler Martin H. , Richly Heike 
Published: September 2018

9511 Background: There is no established systemic treatment for pts with MUM. The STREAM study evaluated the efficacy of the oral multikinase inhibitor S in chemonaïve pts with MUM with the primary endpoint progression-free survival (PFS). Methods: During the initial 56d run-in period all pts received oral S 400 mg bid with concomitant monitoring by magnetic resonance imaging including diffusion weighted imaging (DWI-MRI). Pts with partial remission (PR) on d56 according to RECIST 1.1 were further treated with open-label S and monitored, pts with progressive disease (PD) were taken off study, and pts with stable disease (SD) were randomly assigned to blinded S or placebo (P) and were further monitored every 8 wks and unblinded in case of PD. Pts on S were taken off study and pts on P were offered S with further monitoring. Results: Altogether, 118 (79.2%) of 149 pts entering the run-in period were evaluable for response on d56. Two pts had PR (1.7%), 78 pts had SD (66.1%) and 38 pts had PD (32.2%), respectively. Median PFS from randomization was significantly longer with S (5.5 mths) than P (1.9 mths, HR = 0.527, p = 0.0079). S was readministered to 23 pts with PD under P (59.0%) with a median PFS of 2.0 mths (range 1.2-15.7 mths). Overall survival (OS) was not different between the S group (median 14.8 mths, range 3.7-38.3 mths) and the P group (median 14.4, range 3.3-37.3 mths). During the entire study there were 43 NCI-CTCAE grade 3 and 9 grade 4 adverse events requiring dose reduction of S to 200 mg bid or treatment discontinuation, respectively. No pt died from toxicity. The evaluation of the apparent diffusion coefficient (ADC) ratio derived from DWI-MRI in 47 pts of the run-in period showed a significant difference between pts with SD and pts with PD (p < 0.05). Conclusions: The primary endpoint of STREAM was reached. S is clinically active and tolerable in first-line treatment of pts with MUM with an increase of median PFS from 1.9 mths for P to 5.5 mths for S (p = 0.0079). The median OS of 14.8 mths compares favorably with previous findings in pts with MUM. Besides morphological MRI features, ADC ratio may be used as an additional functional response criterion. Clinical trial information: NCT01377025.
Incidence, features and management of radionecrosis (RN) in melanoma patients (pts) treated with cerebral radiotherapy (RT) and anti-PD-1 antibodies (PD1).
Authors: Pires Da Silva Ines Esteves Domingues , Johnpulle Romany Anne Nilanthi , Banks Patricia Diana , Grass G. Daniel , Smith Jess Louise , Everett Ashlyn S. , Goldinger Simone M. , Roberts-Thomson Rachel , Millward Michael , Glitza Isabella Claudia , Haydu Lauren Elaine , Atkinson Victoria , Wang Tim , Eroglu Zeynep , Conry Robert Martin , Shackleton Mark J. , Hong Angela , Long Georgina V. , Johnson Douglas Buckner , Menzies Alexander M. 
Published: September 2018

9513 Background: Melanoma brain metastases confer poor prognosis, with various treatments used including RT and PD1. While RT and PD1 may have a synergistic effect to improve efficacy, RN may complicate RT, and whether PD1 potentiates this is unknown. We examined the incidence and features of RN and other neurotoxicities in melanoma pts treated with PD1 and whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS). Methods: Pts treated with PD1 who received WBRT/SRS during or within 1 year (y) of PD1 who survived > 1y were examined for short and long term neurotoxicity. 2 cohorts were included: (A) consecutive pts fulfilling eligibility criteria from 8 melanoma centers, (B) additional cases of RN from 3 centers. Pt demographics, disease features, treatment details, neurotoxicity, and outcome data were collected. Results: Cohort A included 118 pts, with median follow-up of 24.3 months (mo). Median age was 56yo, 51% had mutant BRAF, 41% elevated LDH and 65% were ECOG 1-2 at PD1 start. 58% had prior ipilimumab and 43% prior MAPK inhibitors. 85% were treated with pembrolizumab, 10% nivolumab and 5% combination ipilimumab/nivolumab. Most pts (82, 69%) had SRS, 22 (19%) had WBRT alone and 14 pts (12%) had both. Median PFS was 24mo and OS was 45.8mo. 21 pts (18%) developed RN, (14/82) 17% after SRS, (2/22) 9% after WBRT and (5/14) 36% after both. With 13 further cases from cohort B (total 34), all had radiological signs on MRI, 78% had neurological symptoms and 56% had pathological confirmation of RN. Median time to symptom onset and to first radiological sign was 9.8mo and 10.8mo, respectively. 52% were treated with steroids and 30% had bevacizumab, with clinical improvement in 64% and 100%, respectively. Updated analysis including clinical variables associated with RN development will be presented, including RT dose and schedule. Conclusions: RN is a significant toxicity in melanoma pts with brain metastases treated with RT and PD1, particularly in long term survivors. Further research to identify those at risk of RN, those who do not require RT, and studies exploring RT and PD1 schedules are required.
Incidence, patterns of progression and outcomes of melanoma brain metastasis (MBM) during programmed-death 1 inhibitor (PD1i) therapy.
Authors: Schvartsman Gustavo , Ma Junsheng , Bassett Roland L. , Haydu Lauren Elaine , Amaria Rodabe Navroze , Hwu Patrick , Hwu Wen-Jen , Diab Adi , Patel Sapna Pradyuman , Davies Michael A. , Tawbi Hussein Abdul-Hassan , Glitza Isabella Claudia 
Published: September 2018

9532 Background: MBM are common in patients (pts) with metastatic melanoma (MM) and represent a frequent site of treatment failure with current therapies. Little is known, however, about the incidence, patterns of progression and outcomes of MBM pts treated with PD1i and in conjunction with central nervous system (CNS) focused therapy. Methods: Outcomes of mm pts treated with PD1i at MD Anderson from 01/12 to 07/16 were reviewed. The association between clinical variables and development of MBM and overall survival (OS) were assessed using logistic regression and Cox regression analyses. Results: We identified 324 mm pts, including 77 pts (24%) who had MBM prior to first dose of PD1i. Median follow-up from start of therapy was 16.3 months, median OS for pts without MBM at the start of PD1i 3.37 years, as compared to 2.85 years in pts with prior MBM (p = 0.268). Of the 247 pts without prior MBM, 64 (26%) developed MBM after exposure to PD1i. Of those, 21 pts (8.5%) developed MBM during therapy or within 30 days of discontinuation, with 12 (4.5%) having CNS-only progression, while 9 (3.6%) had both systemic and CNS progression. Pts with MBM prior to PD1i (n = 77) had CNS-only progression in 22 pts (28.6%) during therapy. Progression occurred in systemic and systemic plus CNS in 12 pts (15.6%) and 19 pts (24.7%), respectively. 24 pts (31.2%) had stable disease (SD). On multivariate analysis, pts with lung metastases (OR, 2.16; 95% CI, 1.25 - 3.78; p = 0.006) and NRAS-mutated tumors (OR, 2.17; 95% CI, 1.14 - 4.18; p = 0.02) were more likely to develop MBM; pts who had liver metastases at the start of PD1i (HR, 1.77; 95% CI, 1.09 - 2.87; p = 0.002) and those who developed MBM during PD1i (HR, 4.81; 95% CI, 3.00 - 7.71; p < 0.0001) had increased risk of death. Conclusions: We found a 26% incidence of MBM after PD1i exposure. Pts that develop MBM are still at higher risk of death despite advances in systemic and local CNS therapy. CNS-only progression was substantially higher in patients with MBM prior to PD1i, supporting a change in the natural history of the disease after PD1i. These findings support the use of CNS imaging to monitor disease during PD1i therapy.
Safety of resuming anti-PD-1 (aPD1) in patients (pts) with immune-related adverse events (irAEs) during combined anti-CTLA-4 (aCTLA4) and aPD1 in metastatic melanoma (MM).
Authors: Pollack Megan , Betof Allison Shayna , Rappazzo Katherine , Valentine Ian , Eroglu Zeynep , Johnson Douglas Buckner , Shoushtari Alexander Noor 
Published: September 2018

9544 Background: Combination aPD1 and aCTLA4 has demonstrated greater response rates (RR) than aPD1 alone in MM. However, aPD1 + aCTLA4 also leads to more frequent and severe irAEs compared to aPD1. The safety of resuming aPD1 following these irAEs is not known. We characterized the safety and efficacy of resuming aPD1 following severe irAEs during aPD1 + aCTLA4 in pts with MM. Methods: We retrospectively reviewed mm pts from 3 academic centers who had a severe irAE with aPD1 + aCTLA4 (defined as CTCAE v4.03 G3-4 or leading to early discontinuation of aPD1 + aCTLA4) and who resumed aPD1 thereafter. We assessed for frequency, timing, and spectrum of irAEs as well as RR, progression free survival (PFS) and overall survival (OS). Results: We identified 64 pts who received aPD1 + aCTLA4 for a median of 2 doses (range, 1-4). The most frequent irAEs that led to aPD1 + aCTLA4 discontinuation were: colitis (36%), hepatitis (23%), hypophysitis (8%), pneumonitis (5%), nephritis (3%), neurologic complications (3%), and pancreatitis (3%); eight pts (13%) had > 1 concurrent severe irAEs. aPD1 was resumed at a median of 55 days after last dose of aCTLA4 + aPD1 (range, 17-289); 23% experienced recurrence of the same irAE with aPD1 monotherapy, 16% experienced a distinct irAE, and 60% did not experience any severe irAE after resuming aPD1. Hepatitis recurred in 6 of 18 pts, pancreatitis in 2 of 2, dermatitis in 1 of 4, nephritis in 1 of 2, pneumonitis in 1 of 3, hypophysitis in 1 of 5, and colitis in 1 of 27; the grade of these recurrent irAEs was: 46% grade 1-2, 33% grade 3, 13% grade 4, and 7% grade 5 (n = 1). One death from irAEs occurred related to Toxic Epidermal Necrolysis (TEN). No difference was observed in time prior to resuming aPD1 in those that had recurrent irAEs vs. those without (median 56 days each). The RR in this cohort was 73% (30% CR; 44% PR); median PFS (range, 2.2-not reached (NR)) and OS (range, 2.4-NR) were not reached. Conclusions: In our experience, pts who resume aPD1 following irAEs with aPD1 + aCTLA4 exhibit variable toxicity profiles with most experiencing no irAEs, but a minority experiencing severe or life-threatening irAEs. We observed excellent efficacy in this cohort.
Safety and results of anti-PD1 combined with radiosurgery for the treatment of melanoma brain metastases.
Authors: Gaudy Marqueste Caroline , Carron Romain , Amatore Florent , Malissen Nausicaa , Muracciole Xavier , Loundou Anderson , Troin Laura , Monestier Sandrine , Mallet Stéphanie , Richard Marie-Aleth , Regis Jean , Grob Jean Jacques 
Published: September 2018

9552 Background: Anti-PD1 are now pivotal in the treatment of metastatic melanoma (MM). Some concerns have emerged regarding the risk/benefit ratio of their combination with stereotactic radiosurgery. Methods: Retrospective assessment of the interaction between Gamma-Knife radiosurgery (GKRS) and anti-PD1 in terms of toxicity and OS in mm patients (pts) with BM. Patients were included if they were under anti-PD1 (PRE) at time of GKRS, or if they had started anti-PD1 concomitantly with GKRS (CO), or had received anti-PD1 within 3 months after GKRS (POST). Results: Among 47 pts who received GKRS and anti-PD1 during their disease course, 35 fulfilled PRE or CO or POST criteria (anti PD1 1st line therapy in 10 pts and 2d or more in 25 pts). One pt died before radiological evaluation. GKRS targeted a single BM in 10 pts and multiple BMs in 24 (max 19 BMs). Out of the 128 BMs treated, 6 cases of increase of preexisting edema (4.7%) and 8 hemorrhages (6.25%) occurred in 12 pts, but only 5 events (5%) were regarded as Adverse Radiation effects (ARE), being symptomatic in 3 pts (8% of pts). One BM had to be resected because of the occurrence of a symptomatic hemorrhage with hemiparesis 9 month after treatment. Median follow- up from GKRS was 13.7 mths. Median overall survival (OS) from GKRS and 1st BM were 14.8 and 26.5 mths respectively, with 6 and 12 mths 0S rates from GKRS of 65.7% and 57%, respectively. Local failure was observed in 5 pt. Median time to new BM was 12.6 mths. There was no significant difference in outcomes in pts, depending on PRE, CO and POST conditions. Conclusions: In this series, the largest to date of pts with BMs treated by GKRS and anti-PD1,ARE were within the expected range and survival rates appear promising. Given the natural propensity of MM-BMs for bleeding and edema our data do not support an increased risk with the combination of GKRS and anti-PD1. Regarding the timing between anti-PD1 administration and GKRS our data do not support a higher efficacy or higher toxicity among the 3 following potential mechanisms: immuno- sensitization to radiation (PRE), immuno-radio direct synergy (CO) or radiosensitization to immunotherapy (POST).
A phase Ib study of napabucasin plus weekly paclitaxel in patients with advanced melanoma.
Authors: Edenfield William Jeffery , Becerra Carlos , Braiteh Fadi S. , Spira Alexander I. , Sullivan Ryan J. , Panella Timothy J. , Li Wei , Huang Janet , Li Youzhi , Flaherty Keith , Hitron Matthew , Li Chiang 
Published: September 2018

9553 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity with paclitaxel was observed in pre-clinical testing, and a favorable clinical safety profile was established in a phase I/II trial in patients (pts) with advanced solid tumors. A phase 1b trial was established to evaluate the safety and preliminary signs of anti-cancer activity of the combination regimen in pts with advanced melanoma. Methods: Pts with melanoma were enrolled after failure of standard therapies for advanced disease. Napabucasin 480 or 500 mg orally twice daily was administered with paclitaxel 80 mg/m2 IV weekly for 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks and evaluated per RECIST 1.1 criteria. Results: A total of 12 pts with advanced melanoma were enrolled after a median 3 prior lines of therapy (including immune checkpoint inhibitors, BRAF-inhibitor if presence of BRAF V600E mutation). Protocol therapy was well tolerated with grade 3 AEs including diarrhea (n = 3), abdominal pain (n = 1), and fatigue (n = 1). Partial response (PR) was observed in 1 pt. Stable disease of at least 24 weeks or more was achieved by 33% of patients (n = 4) and the median progression-free survival (mPFS) was 3.7 months. Prolonged survival of 1 year or more was achieved by 33% of pts (n = 4), with a median overall survival (mOS) of 10.4 months. Conclusions: Napabucasin plus weekly paclitaxel has shown clinical safety and encouraging anti-tumor activity in a cohort of pts with previously treated advanced melanoma. The RP2D in combination with weekly paclitaxel was established to 480 mg orally bid. The data suggest that targeting stemness pathways with napabucasin may be a novel therapeutic strategy for melanoma. Clinical trial information: NCT01325441.
Evaluation of the Melanoma Tumor Burden Score (MTBS) in a real-world setting.
Authors: Weichenthal Michael , Senel Gamze , Both Marcus , Senkpiehl Ilka , Lekic Dragana , Kähler Katharina C. , Ugurel Selma , Leiter Ulrike M. , Mohr Peter , Hauschild Axel , Schadendorf Dirk 
Published: September 2018

9565 Background: Clinical cancer registration is increasingly important for healthcare delivery and outcome research in oncology. As compared to clinical trial data, information from clinical routine is often limited regarding the granularity and quality of measures for individual tumor load and distribution. Methods: In an effort to implement a robust and useful measure of tumor burden for patients with metastatic melanoma in a German national skin cancer registry (ADOReg) we evaluated the melanoma tumor burden score (MTBS), originally developed for analyzing chemotherapy data in melanoma patients. The MTBS contains a simple categorization of size, number an distribution of metastatic lesions in individual patients. It is aimed at being used on routine radiologic report allowing for a certain level of uncertainty and imprecise quantification of metastatic lesions. Basically, the lesions are categorized per affected organ with respect to number (solitary, few, multiple) and size (≤1cm, >1- 5cm, >5cm). For evaluation of prognostic significance the summary score was calculated and included in univariate and multivariate survival analysis. We performed extensive sensitivity analyses for a variety of different model settings. Results: In the primary analysis set we re-evaluated 898 radiologic reports in a total of 235 various chemotherapies in n=128 stage IV melanoma patients. The confirmatory data sets consisted of n=384 stage IV melanoma patients with various treatments including chemotherapy, BRAF inhibitor treatment, and immune checkpoint blockade. MTBS categorization could be applied on routine radiologic reports in the majority of cases (95.7 %). In a multivariate model MTBS remained significantly correlated with outcome when adjusted for age, sex, LDH, and number of metastatic sites. Moreover, change in MTBS correlated to a formal response evaluation according to RECIST. Conclusions: The MTBS appears to be a promising tool for meaninful quantification of metastatic tumor load in metastatic melanoma for real life data collection like in clinical cancer registries. [Table: see text]
Exploratory analysis of multiprotein serum predictors at baseline of progression-free survival of ipilimumab or ipilimumab and nivolumab in the Checkmate-069 study.
Authors: Homicsko Krisztian , Cuendet Michel A. , Mlynska Agata , Moura Bianca , Horak Christine , Hanahan Douglas , Michielin Olivier 
Published: September 2018

9571 Background: Checkpoint inhibitors have revolutionized the treatment of stage IV melanoma patients. Selection of patients for PD-1 monotherapy or CTLA4/PD1 combination remains an important challenge. We set out to perform a discovery study of pretreatment serum protein biomarkers to identify predictors of progression free survival (PFS) for ipilimumab (IPI) or ipilimumab/nivolumab (IPI/NIVO). Methods: We performed an exploratory analysis of baseline serum samples from 135 treatment-naive patients with metastatic melanoma included in the randomized phase II clinical trial, CheckMate 069 (NCT01927419). We used the RayBiotech 440 human cytokine array and evaluated the relationship of serum protein levels with 44 clinical parameters. R, Prism 7.0 and TensorFlow were used for analyses. Results: We focused on correlation of serum protein markers with PFS as a predictor of long-term benefit. In the IPI arm (n = 46), high FGF4 correlated with worse PFS outcome (p = 0.0012). However, FGF4 levels alone were unable to select responsive vs. non-responsive patients. In contrast, a set of three markers consisting of FGF4 ( < 760pg/ml), CCL15 ( > 2.7 ng/ml), and TACE ( > 600pg/ml) separated non-progressing versus progressing patients. Moreover a small group of FGF4-high patients who were concomitantly TIM-3-low also had longer PFS (combined of both: p = 0.0004, HRlogrank: 0.07, 95% CI: 0.03279 to 0.1533). The same markers did not discriminate between IPI/NIVO patients (p = 0.467, HR: 15). In the IPI/NIVO arm, three different markers could select patients. Patients either with low CCL2 ( < 72 pg/ml) or alternatively with high CCL2 combined with high PDGF-AA ( > 8.2 ng/ml) and low GASP-1 ( < 1.3 ng/ml) had longer PFS (p < 0.0001, HR: 0.115, 95% CI: 0.03848 to 0.3408). Conversely, these markers did not predict benefit for IPI-monotherapy. Conclusions: In this study we identified protein signatures in baseline serum that correlate with PFS for therapies with IPI or IPI/NIVO. The markers were exclusive for IPI or IPI/NIVO but not for both. Additional research is warranted to substantiate these results and evaluate the possibility of incorporating into clinical practice.
Performance of a prognostic 31-gene expression profile test in stage III cutaneous melanoma subjects.
Authors: Fleming Martin D. , Middlebrook Brooke , Covington Kyle R. , Gerami Pedram , Wayne Jeffrey D. , Zager Jonathan S. 
Published: September 2018

9578 Background: The management of stage III cutaneous melanoma (CM) patients has changed significantly with the introduction of contemporary therapies. A 31-gene expression profile (GEP) test that provides a prediction of low or high risk of melanoma metastasis has been validated as an independent prognosticator of distant metastasis-free (DMFS) and melanoma-specific survival (MSS). We examine the prognostic accuracy of the test in a cohort of stage III, and particularly stage IIIA, subjects from a multicenter validation study. Methods: 207 primary CM tumors from 16 centers were analyzed as part of an IRB-approved study. Quantitative RT-PCR and predictive modeling were performed to classify metastasis and survival risk as Class 1 (low risk) or Class 2 (high risk). Results for Kaplan-Meier and Cox regression survival analysis are reported. Results: Of the 207 subjects with stage III melanoma, 76 were stage IIIA. The table shows 5-year DMFS and MSS rates for all stage III and stage IIIA groups. Patients with Class 2 GEP had significantly worse outcomes compared to Class 1. In univariate analyses, GEP was a significant predictor of DMFS and MSS with a hazard ratio for DMFS of 2.8 (95%-CI; 1.7-4.6) and for MSS of 4.0 (95%-CI; 1.7-9.4) for all stage III, while HR of 2.2 for DMFS (95%-CI; 1.0-4.7) and 4.3 for MSS (95%-CI; 1.2-15.2) were observed for the stage IIIA group. For all stage III cases, Breslow thickness and GEP were significant predictors of DMFS and MSS in multivariate models including ulceration and mitotic rate (p < 0.05). Conclusions: The results support the capability of the GEP to accurately predict stage III distant metastasis and survival, and that the test complements existing prognostic factors. GEP testing may be useful in identifying stage IIIA patients who are appropriate for adjuvant therapies and/or enrollment in clinical trials. [Table: see text]