bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world evaluation of the association between baseline metastatic patterns and clinical outcomes among patients with BRAF-positive metastatic melanoma.
Authors: Eroglu Zeynep , Chandra Sunandana , Buchbinder Elizabeth Iannotti , Ling You-Li , Tang Jackson , Shah Rohan , Truong Thach-Giao 
Published: June 2022

9532 Background: While immunotherapy (IO) and BRAF-targeted therapy (TT) have benefit in BRAFV600 mutant (BRAF+) metastatic melanoma (MM), there is a paucity of real-world data on the impact of systemic therapy choice on outcomes based on key characteristics such as site and number of baseline metastases. Patients with >1 baseline site and certain sites of metastases are also underrepresented or excluded in clinical trials. The aim of this study was to evaluate the association between these characteristics and survival among BRAF+ MM patients. Methods: This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) dataset – harmonized customized data from Flatiron and ConcertAI. It included patients ≥18 years, who received treatment with a first-line (1L) IO (anti-PD-1 mono or combination therapy ipilimumab + nivolumab) or TT (any BRAF/MEK-inhibitors) after 1/1/2014. Progression free survival (PFS) and overall survival (OS) for IO and TT were analyzed according to number (1, 2, 3+ sites) and location (brain, lung, liver, bone) of baseline metastasis. Treatment sequence from 1L to 2L (i.e. IO/TT vs TT/IO) were also compared for PFS and OS outcomes. Results: A total of 1,961 patients were included, with 620 patients (32%) on IO monotherapy, 501 patients (26%) on IO combo therapy, and 840 patients (43%) on TT in the 1L. When adjusted for sex, age, ECOG, and Charlson Comorbidity Index, there was no difference in PFS or OS between 1L IO mono, IO combo and TT therapies in patients who had 1, 2, or 3+ baseline metastases. For patients who had either baseline brain, liver, lung, or bone metastasis, there was no difference in PFS and OS between IO mono, IO combo, and TT combo therapies. Of the 521 patients included in the sequencing analysis (only patients who received 2L therapy), 239 patients (46%) had 1L IO/2L TT. There was no difference in PFS or OS between treatment sequences for patients with any number or location of baseline metastasis. Conclusions: In this real-world retrospective cohort study, there is no difference in survival between 1L TT and IO for BRAF+ MM patients. Outcomes are comparable regardless of number and location of metastases, including brain metastasis. Whether switching from 1L TT to IO before progression may account for differences compared to trial data will be explored further.[Table: see text]
The prognostic impact of immune-related adverse events in real-world patients with metastatic melanoma treated with single-agent and combination immune checkpoint blockade.
Authors: Watson Alexander , Goutam Siddhartha , Stukalin Igor , Ewanchuk Benjamin , Sander Michael , Meyers Daniel E. , Pabani Aliyah , Cheung Winson Y. , Heng Daniel Yick Chin , Cheng Tina , Monzon Jose Gerard , Navani Vishal 
Published: June 2022

9542 Background: Immune checkpoint blockade (ICB) has revolutionized the treatment of metastatic melanoma (MM). Immune-related Adverse Events (irAEs) associated with ICB have been shown to correlate positively with survival outcomes across solid tumours. In MM, conclusions on the impact of irAE severity have been conflicting, and combination ICB therapy experience is limited to smaller cohorts. We sought to clarify these relationships using the Alberta Immunotherapy Database (AID). Methods: The AID provides a multi-centre, province-wide observational cohort comprising consecutive patients treated with ICB. We included adult patients with MM, treated with ICB (single agent nivolumab or pembrolizumab, or combination ipilimumab and nivolumab) at any line of therapy, agnostic to site of origin, from August 2013 to May 2020, with analysis in December 2021. The primary endpoint of interest was the identification of a relationship between development of irAEs and subsequent overall survival (OS, defined from time of ICB initiation). To minimize immortal time bias from poor prognosis patients who may have died prior to the development of irAEs, patients who died before 12 weeks were excluded from OS and time-to-next-treatment (TTNT) analysis. Adjusted Cox regression analyses were performed to determine the association of variables with OS. Results: Of 492 MM patients receiving ICB, 124 received combination ICB, 198 developed an irAE and 67 required hospitalization for an irAE. irAEs were more common in patients < 50 years old (p = 0.02), with ECOG 0 (p < 0.001) and normal albumin (p = 0.002). Median time to irAE development (2.6 months) and frequency of individual irAEs were consistent with the published literature. In the overall population, patients who experienced an irAE had longer median OS (56.3 vs 18.5mo, p < 0.0001), and TTNT (49.6 vs 12.9mo, p < 0.0001). This remained consistent in combination ICB-treated patients (median OS 56.3 vs 19mo, p < 0.0001). Patients hospitalized for an irAE had improved OS and TTNT over patients requiring only outpatient treatment (median OS NR vs 27.9mo, p = 0.0039), while ICB re-challenge after an irAE also improved OS (56.3 vs 31.5mo, p = 0.0093). Development of an irAE retained independent association with OS after adjusted multivariable regression (HR 0.376, p < 0.001). Conclusions: These data support the association of irAEs and improved survival outcomes in MM, including those patients treated with combination ICB. Among patients with irAE, hospitalization for irAE, and ICB re-challenge post-irAE, were further associated with improved outcomes.
Metabolic complete responses (mCR) in patients with metastatic uveal melanoma (mUM) treated with image-guided injection (IGI) of PV-10.
Authors: McVay Krysta , Sheth Rahul , Murthy Ravi , Gombos Dan S. , Carter Brett W. , Bhosale Priya , Tahon Nourel hoda , Balmes Gener C , Coz Ysabell M , Washington Edwina , Rodrigues Dominic , Wachter Eric Andrew , Patel Sapna Pradyuman 
Published: June 2022

9543 Background: Traditional CT imaging can underestimate the degree of anti-cancer treatment effect due to reliance on morphological changes of visualized tumors. In contrast, PET imaging offers information on metabolic activity using a positron emitting radiolabeled agent (e.g. FDG) but is less sensitive to changes in tumor size. FDG-PET images acquired, co-registered, and superimposed on CT images (PET-CT) allow spatial detection of anti-cancer activity. Moreoever, FDG-PET-CT can provide information regarding anti-tumor immune responses in patients receiving immunotherapy. Rose bengal (PV-10) is a small molecule autolytic immunotherapy in development for metastatic disease. When administered by intralesional injection, PV-10 can produce immunogenic cell death and a T-cell mediated immune response against treatment-refractory and immunologically-cold tumors. Herein, we report the FDG-PET-CT imaging responses of 7 metastatic uveal melanoma (mUM) patients who received percutaneous image-guided injection (IGI) of PV-10 into hepatic tumors. Methods: The Phase 1 study is evaluating safety, tolerability, and efficacy of intralesional PV-10 in hepatic tumors. PV-10 is administered percutaneously via IGI into designated tumors ≤4.9 cm in diameter. Response is assessed at Day 28, then every 3 months, using CT/MRI or PET-CT. Patients with multiple tumors may receive further IGI of PV-10 after Day 28. Results: To date, 25 mUM patients with liver metastases have been treated; 16 patients received standard of care immune checkpoint inhibitor (ICI) during or post PV-10 treatment. Seven subjects had FDG-PET-CT imaging during the study (baseline 1, follow-up 6). Two follow-up FDG-PET-CTs were performed 1 and 3 years after PV-10 injection with intervening ICI, and another was 1.5 years after PV-10, without any follow-on treatment. Four patients experienced mCR in all metastatic sites, including extrahepatic metastasis. Conclusions: FDG-PET-CT shows that PV-10 is capable of inducing mCR in injected (adscopal) and non-injected (abscopal) lesions. This pattern of response is suggestive of immunogenic cell death in mUM patients with liver metastases. Clinical trial information: NCT00986661.
Better (a little) late than never: The impact of steroidal treatment initiation timing on the outcome of patients with melanoma treated with immunotherapy.
Authors: Asher Nethanel , Bar-Hai Neta , Ben-betzalel Guy , Stoff Ronen , Grynberg Shirly , Schachter Jacob , Shapira-Frommer Ronnie 
Published: June 2022

9544 Background: The immune-system manipulation by immune-checkpoint inhibitors (ICI) has led to unprecedented clinical advances in melanoma. The management of the consequent immune-related adverse events (irAEs) is based mostly on steroids and other immune-modulators. Methods: A real world single-site cohort of metastatic melanoma patients who were treated with immunotherapy as first line between 2014 and 2020. This study explores the effect of dose, timing, and duration of steroid exposure on treatment efficacy. Results: Four hundred and forty patients were treated with either anti PD-1 (n = 285, 65%) or combination of anti PD-1 and ipilimumab ICI (n = 112, 25%), or ipilimumab alone (n = 43, 10%). The median age was 68 years [12-99y], and 57% were male. Any-grade irAEs were seen in 71% of the patients, and 49% were exposed to steroids. The median steroid dose was 0.75mg/kg prednisolone equivalent [0.03- 80mg/kg], the median duration of steroidal treatment was 11.2 weeks [0.1-316w] and the median time to onset of steroids was 7.6 weeks [0-193w]. Both experiencing irAEs, and the associated steroid exposure were associated with a significant progression free survival (PFS) benefit [HR 0.47, p < 0.001; 95%CI 0.39-0.6 and HR 0.77, p = 0.026; 95%CI 0.60-0.97, respectively], regardless of dose and duration. Notably, within those who were exposed to steroids, an earlier onset of < 4 weeks from immunotherapy initiation was significantly associated with a shorter PFS [HR = 3.5, p < 0.001 (95%CI 2.32-5.45)]. This observation resulted significant also on multivariable analysis including other prognostic variables – ECOG PS, M-stage, LDH and protocol. Conclusions: Steroidal treatment during the immunotherapy priming phase (first 4 weeks) might have a deleterious effect on its’ efficacy and should be explored in larger prospective cohorts.
Glycoproteomics as a powerful liquid biopsy-based predictor of checkpoint inhibitor treatment benefit in metastatic malignant melanoma.
Authors: Lindpaintner Klaus , Mitchell Alan , Pickering Chad , Xu Gege , Vigal Kimberly , Axenfeld Bianca , Rice Rachel , Cong Xin , Frederick Dennie T. , Michaud William , Boland Genevieve Marie , Serie Danie 
Published: June 2022

9545 Background: Protein glycosylation is the most abundant and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein glycosylation as biomarkers has so far been limited by the technical complexity of generating and interpreting this information. We have recently established a novel, powerful platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine that allows, for the first time highly scalable interrogation of the glycoproteome. Methods: Using this platform, we interrogated 526 glycopeptide (GP) signatures derived from 75 serum proteins in pretreatment blood samples from a cohort of 205 individuals (66 females, 139 males, age range 24 to 97 years) with metastatic malignant melanoma treated either with nivolumab plus ipilimumab (95 patients) or pembrolizumab (110 patients) immune-checkpoint inhibitor (ICI) therapy. Results: In an optimized assay containing 27 glycopeptides and 20 non-glycosylated peptides, we identified 14 GPs with abundance differences at FDR q≤0.05 with regard to PFS. Using 40% of the cohort as a training set and selecting 12 glycopeptide and non-glycosylated peptide biomarker features of the 47 total by LASSO shrinkage, we created a multivariable-model-based classifier for PFS that yielded a hazard ratio (HR) for prediction of likely ICI benefit of 7.5 at p < 0.0001. This classifier was validated in the test set comprised of the held-out 60% of patients, yielding a HR of 4.7 at a similar p-value for separating patients likely benefiting from ICI therapy and those likely not benefiting from ICI therapy (50% PFS of 18 months vs. 3 months based on classifier score above/below cutoff). This classifier has a sensitivity of > 99% to predict likely ICI benefit, while still performing at a specificity of 26%, thus helping to safely reduce ultimately unnecessary and non-beneficial exposure to these agents of one in four who otherwise would unnecessarily be exposed to them. Conclusions: Our results indicate that glycoproteomics holds a strong promise as a predictor for checkpoint inhibitor treatment benefit that appears to significantly outperform other currently pursued biomarker approaches in this context.
Clinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting.
Authors: Kahn Adriana Matutino , Perry Curtis , Etts Katrina , Kluger Harriet M. , Sznol Mario 
Published: June 2022

9555 Background: Patients with advanced BRAFV600-mutated melanoma are typically treated with immunotherapy in the first-line setting, followed by BRAF/MEKi upon disease progression based on an absolute 20% improvement in 2-year overall survival over initial treatment with BRAF/MEKi in the DREAMseq trial. Our goal was to identify clinical predictors of longer survival for patients treated in our institution with this approach. Methods: We identified 40 patients with BRAFV600-mutated metastatic melanoma treated at our institution from 2011 to 2020 with immunotherapy followed by BRAF/MEKi upon progression. Clinical data were collected and analyzed by Cox regression and Kaplan-Meier methods. Favorable outcome was defined as survival > 2 years (y) after starting BRAF/MEKis. Results: Median follow up was 33 months (m, 3 – 172 m). Median age was 54 y (20 - 83). Most patients were female (n = 24, %). Most patients were initially treated with ipilimumab plus nivolumab (n = 34, 85%), with 13 of these patients (38%) tolerating all 4 cycles of initial ipilimumab. Adverse events of any grade were seen in 28 (70%) patients after first-line immunotherapy, with the most common being hepatitis, colitis, hypothyroidism, rash, and fatigue. Median duration of first-line immunotherapy was 3.5 m (.75 - 42.5 m). Most common sites of progression on immunotherapy were lymph nodes (n = 14, 35%), liver (n = 12, 30%), bone (n = 10, 25%) and brain (n = 10, 25%). Prior to BRAF/MEKis, median ECOG-PS was 1 (0-4) and median LDH was 268 mg/dL (151 - 11,300). Most common BRAF/MEKi regimen was dabrafenib plus trametinib (n = 34, 85%). Adverse events of any grade were seen in 30 (75%) patients, with the most common being fever, fatigue, nausea, and vomiting. Best response to BRAF/MEKi was CR (n = 4, 10%), PR (n = 26, 65%), SD (n = 4, 10%) and PD (n = 6, 15%), and at the data cutoff, 35 (87.5%) patients progressed on BRAF/MEKi. Median duration of BRAF/MEK inhibition was 7 m (0.5 – 106 m). Median survival since starting BRAF/MEKi was 19.2 m (1.7 – 106 m). On multivariable analyses assessing predictors of survival, presence of bone metastases after disease progression on first-line immunotherapy was associated with worse 2-year survival after initiation of BRAF/MEKi (OR 2.5, 95% CI, 0.51-5.6, p = 0.0121). Other factors, such as ECOG-PS 0-2, normal LDH prior to BRAF/MEKi, and age at metastatic diagnosis < 60 years were not significantly associated with longer survival after initiation of BRAF/MEKi. Conclusions: We showed that the presence of bone metastases upon progression on first-line immunotherapy was associated with worse 2-y survival on salvage BRAF/MEKi for patients with BRAFV600-mutated metastatic melanoma. Predictive and prognostic biomarkers for long-term response to both immunotherapy and BRAF/MEKi are needed to optimize treatment strategies and patient outcomes.
Adjuvant dabrafenib plus trametinib (D + T) versus placebo in patients with resected stage III BRAFV600-mutant melanoma: Updated 5-year distant metastases-free survival (DMFS) analysis of COMBI-AD.
Authors: Schadendorf Dirk , Hauschild Axel , Mandalà Mario , Kirkwood John M. , Robert Caroline , Grob Jean-Jacques , Nathan Paul D. , Davies Michael A. , Banerjee Hiya , Shah Rohan , Lau Mike R. , Dummer Reinhard , Long Georgina V. 
Published: June 2022

9563 Background: DMFS is an important endpoint for patients with stage III cutaneous melanoma, as delaying or preventing systemic disease is associated with improved clinical and patient-reported outcomes. Prior results from the phase 3 COMBI-AD trial (NCT01682083) showed 5-year DMFS rates of 65% with adjuvant D + T vs 54% with placebo (PBO; hazard ratio [HR] = 0.55; 95% CI: 0.44-0.70). An analysis of DMFS by AJCC-7 stages IIIA-C suggested a similar benefit of D + T vs PBO regardless of stage (Dummer R et al. N Engl J Med. 2020). Here, we report 5-year DMFS rates by AJCC-8 stages IIIA-D, other prognostic subgroups, and results of a regression tree analysis with DMFS. Methods: Patients with resected AJCC-7 stage III BRAFV600E/K-mutant melanoma were randomized to either D (150 mg twice daily) + T (2 mg once daily) or 2 matched PBOs for 12 months. Primary endpoint was relapse-free survival (RFS); DMFS was a secondary endpoint. Kaplan-Meier survival analyses were performed to assess the long-term benefits for DMFS rates with D + T vs PBO. The regression tree analysis (data cutoff: 5 years) for all patients (N = 870) evaluated potential prognostic/predictive factors of long-term DMFS including baseline age, sex, region, BRAF mutation type, body mass index, lactate dehydrogenase levels, ECOG, T and N categories, histology, primary tumor ulceration, treatment type, number of lymph nodes with metastases, tumor mutational burden, and interferon-gamma gene expression signature (IFN-γ GES). Results: At 5 years, DMFS rates were higher for patients with AJCC-8 stages IIIB-D disease receiving adjuvant D + T vs PBO (table). Five-year DMFS rates also favored D + T vs PBO in subgroups of patients with microscopic or macroscopic lymph node involvement (table) and those with or without primary tumor ulceration and/or in-transit metastases. A regression tree revealed T and N stage, treatment type, and IFN-γ GES as important variables defining 5-year DMFS subgroups. Conclusions: In this retrospective analysis, adjuvant D + T provided long-term DMFS benefit vs PBO in stage IIIB-D patients with resected BRAFV600E/K-mutant melanoma. Key clinical and patient factors impacting DMFS were similar to prior RFS findings (ESMO 2021; Robert C et al. Ann Oncol. 2021) and included T and N stage, treatment type, and IFN-γ GES. These results further validate the robust long-term clinical benefit of adjuvant D + T for patients with melanoma. Clinical trial information: NCT01682083. [Table: see text]
Body composition changes in a 12-week exercise intervention for breast cancer patients.
Authors: Asato Chloe , Vance Alanna , Cheng Shirley , Lim Shannon , Yamada Paulette , Teranishi-Hashimoto Cheri , Shepherd John , Fukui Jami Aya 
Published: June 2022

e12500 Background: Evidence has linked weight gain and obesity to increased breast cancer risk, poorer outcomes, decreased survivorship, and increased risk of recurrence. Adjuvant therapies can increase weight gain, making tailored exercise interventions beneficial in maintaining a healthy weight. In this study, body composition changes were examined after a 12-week exercise program in a cohort of breast cancer survivors. Methods: The Breast Cancer Exercise Rehabilitation Research Study recruited breast cancer survivors to undergo a 12-week exercise program (NCT04013568) and examine body composition changes. Measurements taken included anthropometry (waist circumference, waist-to-hip ratio, BMI), DXA body composition measurements (fat mass-visceral and subcutaneous, trunk to limb, muscle mass-appendicular, and whole body), and BIA (Bio-electrical Impedance Analysis-muscle, fat, and water). 34 participants completed the exercise program and baseline and post-12-week measurements were obtained. Descriptive statistics and a paired t-test analysis was done to analyze changes in body composition using SAS onDemand. A correlation analysis between measurements simple to do in clinic and DXA measurements were run to determine proxy use for DXA. Results: After a 12-week exercise program, reductions in body fat via DXA scan, BIA, and InBody (whole body fat, whole body fat %, trunk fat, leg fat, body fat %, hip width at maximum girth, body fat mass, and percent body fat) were observed. Additionally, increases in lean mass (Appendicular Lean Mass (ALM)/height2, Appendicular Lean/height2, ALM index, and lean body mass), whole body mass measured by DXA, basal metabolic rate, water retention (extracellular water and total body water), and skeletal muscle mass were observed. Correlation analysis revealed BMI can be used as a surrogate measure for whole body mass measured by DXA (r=0.91, p<0.001) and can be utilized to measure change over time. Skinfold sum showed moderate correlation for measuring subcutaneous fat mass by DXA (r=0.45, p=0.0096). Conclusions: In our population of breast cancer survivors, a 12-week exercise program did show various changes in body composition according to InBody, DXA, and BIA measurements. DXA and InBody measurements were feasible, making it readily available for patients. Additionally, simple measures such as BMI and skinfold sum showed moderate to strong correlation with DXA measurements, validating use of these measurements in routine practice. Clinical trial information: NCT04013568. [Table: see text]