bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycemic disorders in melanoma patients treated with anti-PD1.
Authors: Magis Quentin , Gaudy Marqueste Caroline , Monestier Sandrine , Loundou Anderson , Richard Marie-Aleth , Malissen Nausicaa , Beliard Sophie , Grob Jean-Jacques 
Published: September 2018

9525 Background: Anti-PD1 are now the backbone of immunotherapy (IT) of metastatic melanoma (MM). Although they are overall well- tolerated, a number of severe immune-related adverse events (IRAE) have been described, among which type 1 diabetes. We observed 3 cases of fulminant diabetes (FD) in our center, and also had the impression that diabetics patients became more difficult to manage when receiving anti-PD1. Methods: Retrospective analysis of blood glucose samples collected before, during and after anti-PD1 treatment (trt ) in all mm patients (pts) receiving anti-PD1 in our department over a 36-month period. Study of FD cases observed. Results: A total of 163 pts were treated with 1920 cures of anti-PD1 including 27 treated within clinical trials. Anti-PD1 was the 1st line of IT in 70% of cases. As a whole, 1470 glycaemia were available. There was no significant difference between the median pre and post-trt glycaemia (5.37 +/-1.6 vs 5.6 +/-1.3 mmol/L (p = 0.033)). In the 28 pts with a type I (n = 0) or II (n = 28) diabetes prior to trt, there was very slight drift toward an increase of glycaemia along with the successive trt infusions (+0.05mmol/L/Cure, p = 0.004 with linear regression tendency test) .Three pts (1.84%) developed a FD revealed by a severe episode of ketosis with acute polyuria polydipsia, hyperglycaemia until 50mmol/L and weight loss. Two additional cases of FD were observed in pts treated within clinical trial comparing anti-PD1 with anti-CTLA4 in adjuvant and metastatic situation (imputability of anti-PD1 likely but uncertain until unblinding). None of these pts had any glucose increase in weeks prior to FD diagnosis. Four out of 5 FD cases had an HLA group at risk for type 1 diabetes development (HLA DRB3/4), a rare group in general population (1%). Conclusions: We could not document any systematic tendency to glycemic disorder in mm pts treated by anti-PD1. In diabetic pts prior to trt, a slight drift toward increase of glycaemia may be explained by other interfering factors (diet, metastatic disease itself, corticosteroids, anxiety etc). FD is not exceptional (2% of patients in our series) and does not seem to be announced by any minor preliminary glycemic disorder. Despite apparently stochastic onset, FD may be associated with HLA DRB3/4 subgroup.
PD-L1 and CD8 expression and association with outcomes in patients (pts) with BRAF V600E/K-mutant metastatic melanoma (MM) who received dabrafenib + trametinib (D+T) in the randomized phase 3 COMBI-v study.
Authors: Schadendorf Dirk , Long Georgina V. , Grob Jean Jacques , Nathan Paul D. , Ribas Antoni , Davies Michael A. , Flaherty Keith T. , Squires Matthew , Jaeger Savina , Powell William , Tan Puay , Robert Caroline 
Published: September 2018

9527 Background: The phase 3 COMBI-v study (NCT01597908) showed that D+T significantly improved outcomes vs vemurafenib in pts with BRAFV600E/K–mutant MM. Checkpoint inhibitors also provide clinical benefit in some pts with MM. To date, characterization of markers associated with response to anti–PD-1 therapy has identified positive associations with PD-L1 expression and immune cell infiltration. Here we describe expression of PD-L1 and the T-cell marker CD8 in tumor samples from pts randomized to receive D+T in COMBI-v and associations with clinical outcomes. Methods: Biopsies from 74 of 352 D+T pts (21%) in COMBI-v were assessed for expression of PD-L1 (PD-L1 IHC 22C3 pharmDx assay; Dako) and CD8 (anti-CD8 antibody, clone C8/144B; Dako). PD-L1 positivity was determined as a percentage of stained tumor cells and MEL score (staining on both tumor and mononuclear inflammatory cells; 0 or 1 [negative]: < 1% staining; 2-5 [positive]: ≥ 1% staining; Daud et al. J Clin Oncol. 2016). Results: Of 74 pts analyzed, 54 (73%) had PD-L1–positive tumors, and the largest MEL score subgroup was 2 (45%). A significant association ( P < .0001) was observed between PD-L1 and CD8 expression. Overall response rate, tumor shrinkage, progression-free survival, overall survival (OS), and duration of response with D+T were not associated with PD-L1 (MEL score of ≥ 2) or CD8 positivity. However, a significant association ( P = .04) with improved OS was observed in tumors with high PD-L1 expression (≥ 20% of cells PD-L1 positive), and a trend ( P = .06) was seen in pts with a MEL score of ≥ 3. Among PD-L1–negative pts, improved OS was seen in those with high CD8 positivity ( P = .03), particularly in the stromal compartment. Conclusions: These data, representing PD-L1 and CD8 expression profiles for a BRAF-mutant mm population in the context of outcomes following D+T, showed that clinical benefit was maintained regardless of immune phenotype. The results also suggest that an immune component has an impact on outcomes following targeted therapy. Clinical trial information: NCT01597908.
First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.
Authors: D'Angelo Sandra P. , Russell Jeffrey , Hassel Jessica Cecile , Lebbe Celeste , Chmielowski Bartosz , Rabinowits Guilherme , Terheyden Patrick , Brownell Isaac , Zwiener Isabella , Bajars Marcis , Hennessy Meliessa , Kaufman Howard 
Published: September 2018

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.
Micro- and macro-metastatic disease kinetics: Results from the French cohort Melbase.
Authors: Vallet Anais , Dalle Stéphane , Mortier Laurent , Dutriaux Caroline , Leccia Marie Thérèse , Dalac-Rat Sophie , Saiag Philippe , Guillot Bernard , Lacour Jean Philippe , Lesimple Thierry , Arnault Jean-Philippe , Legoupil Delphine , Aubin Francois , De Quatrebarbes Julie , Maubec Eve , Descamps Vincent , Granel Brocard Florence , Stoebner Pierre-Emmanuel , Oriano Bastien , Lebbe Celeste 
Published: September 2018

9538 Background: In the past decade, the prognosis of advanced melanoma has been greatly improved by new therapeutic agents such as immune and targeted therapies, which are now being evaluated as adjuvant therapies. Although the kinetic of metastatic disease is correlated to patient survival, the unfolding of the dormant disease remains hardly predictable and data from the literature on the topic is controversial (Karakousis, Francken). We hypothesized that the course of the advanced disease could be predicted from time to distant recurrence. Methods: Melbase is a French multicentric cohort dedicated to the prospective follow-up of adults with unresectable stage III or IV melanoma. Date of primary excision, time to recurrence, progression free survival (PFS) and overall survival (OS) of 298 patients treated in first line by immune therapies (IT, n = 148), targeted therapies (TT, n = 68) or within clinical trials (n = 73) were collected on September 5th, 2016. Patients with unknown primary or de novo metastatic melanoma were not included. Time to distant recurrence was analyzed as a continuous variable and as a categorical variable ( < 12 months; 12 to 24 months; ≥ 24 months). Results: Patients’ characteristics at baseline are: mean age 62 years, PS 0-1 84%, elevated LDH 32%, BRAF mutated 39%, brain metastases 18%. Time to recurrence studied as a continuous variable was not correlated to PFS (HR = 0.96; 95%CI: 0.85-1.07) or OS (HR = 0.89; 95%CI: 0.77-1.03). These results remained insignificant after stratification upon treatment or even when time to recurrence was analyzed as a categorized variable. Conclusions: Our data showed no correlation between the time from primary to distant recurrence and PFS or OS in patients treated with TT or IT. Therefore, kinetics of advanced disease cannot be predicted by the history of dormant disease. Dormancy and metastasis proliferation are thus probably driven by different molecular and cellular mechanisms.
Real life outcome of advanced melanoma patients who discontinue pembrolizumab (PEMBRO) in the absence of disease progression.
Authors: Jansen Yanina , Rozeman Elisa A. , Foppen Marnix Geukes , Bastholt Lars , Schmidt Henrik , Van Thienen Johannes V. , Haanen John B. A. G. , Tiainen Leena , Svane Inge Marie , Mäkelä Siru Päivikki , Arance Ana , Hoejberg Lise , Nyakas Marta , Straume Oddbjorn , Blank Christian U. , Neyns Bart 
Published: September 2018

9539 Background: PEMBRO improves survival of patients (pts) with advanced melanoma. Optimal duration of treatment in responding pts hasn’t been established. Methods: 12 European hospitals collected data from 509 pts treated with PEMBRO outside an interventional clinical trial. Outcome was evaluated for pts who discontinued PEMBRO in the absence of progressive disease [PD]. Results: After a median follow up of 56 wks [range 1-135], median PFS was 22 wks [95% CI 18-26] and median OS was 70 wks [95% CI 59-81] for the total population. PEMBRO is ongoing in 66 [13%] pts, 344 [68%] pts stopped PEMBRO because of PD, and 99 [19%] pts discontinued PEMBRO without evidence of PD (of which 65 [13%] pts upon pt/MD decision, 26 [5%] pts due to a PEMBRO-related AE of grade < 4 and 8 [2%] pts due to a grade 5 PEMBRO-unrelated AE). Pts discontinuing PEMBRO without PD had a significant [ P <.005] better ECOG PS, less advanced tumor stage, less frequent brain metastases and more often a normal LDH at baseline. There was no significant difference between pts stopping due to AE or upon pt/MD decision. The median time on treatment for the 65 pts who stopped PEMBRO upon pt/MD decision was 55 wks [range 9-112].Their best objective response rate [BORR] was 80% [31 [48%] CR, 21 [32%] PR, 12 [18%]SD, 1[2%]NE]. After a median follow-up of 26 wks [range 1-75] after the last PEMBRO dose, 3 [5%] pts progressed (after 9, 14 and 15 wks). PEMBRO was reintroduced in 1 patient resulting in a CR. The median time on treatment of the 26 pts who stopped PEMBRO due to an AE in the absence of PD was 27 wks [range 1-103]. Their BORR was 77% [9 [35%] CR, 11 [42%] PR, 5 [19%] SD, 1 [4 %] NE]. After a median follow-up of 50 wks [range 12-109] following the last PEMBRO dose, 9 [35 %] pts progressed. Median time to PD was 26 wks [range 7-108]. PD was not correlated with BOR. PEMBRO was reintroduced in 4 pts resulting in 1 CR, 1 PD, 1 SD and 1 NE. Conclusions: In this real life experience, advanced melanoma pts who discontinue PEMBRO treatment upon pt/MD decision, in the absence of PD or AE, were at low risk for short-term recurrence. Pts stopping PEMBRO due to an AE in the absence of PD (having a shorter exposure to PEMBRO and longer FU after discontinuing treatment) seem to have a higher risk for subsequent PD.
A randomized phase II study of ipilimumab at 3 (ipi3) or 10 mg/kg (ipi10) alone or in combination with high dose interferon-alfa (HDI) in advanced melanoma (E3611).
Authors: Tarhini Ahmad A. , Lee Sandra J. , Rao Uma N. M. , Nagarajan Arun , Albertini Mark R. , Mitchell Jerry W , Wong Stuart J. , Taylor Mark A. , Laudi Noel , Truong Phu Van , Conry Robert Martin , Kirkwood John M. 
Published: September 2018

9542 Background: Interferon-α (IFN) favors a Th1 shift in immunity. Combining CTLA4 blockade with IFN may downregulate CTLA4 suppressive elements. Prior data from a phase II of tremelimumab and HDI showed promising efficacy supporting the current study. Methods: E3611 had a 2x2 factorial design (A: ipi10 + HDI; B: ipi10; C: ipi3 + HDI; D: ipi3) to evaluate (i) no HDI vs. HDI (across ipi doses) and (ii) ipi3 vs. ipi10 (across HDI status). We hypothesized that median progression free survival (PFS) would improve from 3 to 6 months (mos) with HDI vs. no HDI and with ipi10 vs. ipi3. Based on the log-rank test for 80 patients (pts) these comparisons would have 82% power at 2-sided type I error of 0.10. Results: Median follow up 26.4 mos. PFS and overall survival (OS) (eligible and treated pts; N = 80: 18 III/M1a, 24 M1b, 38 M1c) are shown in Table 1. There were no significant differences in PFS or OS when evaluating HDI vs. no HDI or ipi10 vs. ipi3 (Table 1). Response (RECIST) among response evaluable pts (and 4 pts with early death) (N = 76) is shown in Table 1. Stable disease (SD) in 7 (A), 6 (B), 8 (C) and 6 (D). Adverse events (AEs) were consistent with the toxicity profiles of ipi and HDI and included 3 grade 5 AEs considered at least possibly related: 1 in A (suicide), 1 in B (lung infection and hemorrhage) and 1 in C (adult respiratory distress syndrome). One patient in B died of gastrointestinal bleed and cardiac arrest while on corticosteroids to treat temporal arteritis and vision loss. Conclusions: Within the limitations of the sample size, there were no significant differences in PFS with HDI vs. no HDI or ipi10 vs. ipi3. Response and PFS with ipi10 were superior to historical controls and similar to the combination. Correlative studies are ongoing. Clinical trial information: NCT01708941. [Table: see text]
Impact of gene expression profiles on clinical predictors of survival in patients (pts) with BRAFV600-mutated metastatic melanoma (mM).
Authors: Larkin James M. G. , Lewis Karl D. , Ribas Antoni , Flaherty Keith , Ascierto Paolo Antonio , Dréno Brigitte , Mckenna Edward Francis , Zhu Qian , Mun Yong , Hauschild Axel , McArthur Grant A. 
Published: September 2018

9556 Background: Treatment of BRAFV600-mutated mm with V and C+V has clinical benefit. Prior analyses established PFS/OS prognostic models in pts with mm based on clinical variables. This exploratory analysis evaluated the impact of immune and cell cycle gene signatures (GS) from baseline mm (Wongchenko et al, Pigment Cell Melanoma Res2015;28:822) on survival outcomes and associated prognostic models. Methods: Data from all eligible pts with GS data in the BRIM-2, -3, -7, and coBRIM studies were pooled for analysis. The independent effect of GS on PFS/OS outcomes was tested by multivariate Cox proportional hazards models. Recursive partitioning (RP) for censored response variables in a conditional inference framework was performed in the pooled dataset to model relationships between prespecified covariates, GS, and PFS/OS. Prognostic subgroups identified by the model for all pooled pts were applied to pooled treatment cohorts (dacarbazine [D], V, and C+V). Results: GS data were available for 608 pts across pooled studies. Immune GS was associated with improved survival vs cell cycle for PFS (HR = 0.75, 95% CI 0.62–0.89, P= 0.0015) and OS (HR = 0.74, 95% CI 0.61–0.90, P= 0.0024) in multivariate models. HR point estimates were consistent across treatment cohorts. PFS RP models identified baseline LDH, tumor size, and GS as prognostic factors, giving 4 groups with distinct outcomes. GS was not identified as a prognostic factor in OS RP models. C+V improved PFS/OS outcomes vs V across prognostic subgroups. Immune GS was significantly (one-sided Cochran-Armitage trend test) more prevalent in the favorable prognostic groups previously defined for PFS and OS for the V ( P< 0.0001 for both) and C+V cohorts ( P= 0.0240 and P= 0.0269, respectively), but not the D cohort. Conclusions: PFS/OS was significantly improved for pts with immune GS. RP modeling confirmed the importance of GS as an independent prognostic factor for PFS but not OS. The preferential association of immune GS with favorable prognostic subgroups in the C+V and V but not D cohorts and known effects of MAPK signaling on immune response merit further exploration in prospective studies.
Predictive biomarkers of ipilimumab toxicity in metastatic melanoma.
Authors: Gowen Michael , Tchack Jeremy , Zhou Hua , Giles Keith Michael , Paschke Scott , Moran Una , Fenyo David , Tsirigos Aristotelis , Pacold Michael , Pavlick Anna C. , Krogsgaard Michelle , Osman Iman 
Published: September 2018

9559 Background: There are no predictive biomarkers of ipilimumab (IPI) toxicity. Of metastatic melanoma (MM) patients (pts) receiving IPI (3mg/kg), 35% require systemic therapies to treat immune-related adverse events (irAEs) and 20% must terminate treatment (Horvat et al., JCO 2015). Here we tested the hypothesis that a pre-existing autoantibody (autoAb) profile is predictive of IPI irAEs. Methods: We measured autoAb levels in pre- and post-treatment sera from mm pts who received IPI (3mg/kg) monotherapy on a proteome microarray containing ~20,000 unique full-length human proteins (HuProt array, CDI Laboratories). Clinical data were prospectively collected with protocol-driven follow-up. IrAEs were categorized by CTCAE guidelines as none (grade 0), mild (grade 1-2), or severe (grade 3-4). AutoAb levels were standardized using median quantile normalization and considered positive hits if > 2-SD above the peak array signal and differed by ≥2 fold with p < 0.05 between toxicity groups (Non-parametric Analysis/Wilcox test). Results: Seventy-eight sera from 37 mm pts were analyzed. Antibodies against CTLA-4 were significantly elevated post IPI treatment (p < 0.0001), validating the assay. The pre-treatment levels of 190 IgG autoAbs were significantly different in pts who experienced irAEs (n = 28) compared to those with no irAEs (n = 9). Comparison of severe irAE (n = 9) and no irAE (n = 9) groups revealed 129 IgG autoAbs that significantly differed in pre-treatment sera. Localization and pathway analysis (UniProt, KEGG, Reactome) showed 81/190 (43%) of the autoAbs targeted nuclear and mitochondrial antigens and were enriched in metabolic pathways (p = 0.015). AutoAbs associated with irAEs did not correlate with treatment response. Conclusions: AutoAbs to antigens enriched in metabolic pathways prior to treatment may predict IPI-induced toxicity in MM. The subcellular localization of targeted antigens could explain the autoimmune toxicities associated with IPI. Studies in larger cohorts and in pts receiving other checkpoint inhibitors and/or combination therapies are essential to determine the validity of the data. If validated, our results would support the discovery of the first toxicity predictor in cancer immunotherapy.
Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.
Authors: Braune Jan , von Bubnoff Dagmar , Follo Marie , Graf Erika , Philipp Ulrike , Glaser Laura , Pfeifer Dietmar , Hahn Felix , Duyster Justus , Meiss Frank , Von Bubnoff Nikolas 
Published: September 2018

9564 Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS (hazard ratio [HR] 1.487, 95% CI 0.34-6.45). A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS (hazard ratio [HR] 0.230, 95% CI 0.04-1.20) with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS (hazard ratio [HR] 2.02, 95% CI 0.39-10.53). Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 (r = 0.73) and LDH (r = 0.52). Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. Clinical trial information: DRKS00009507.