bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 2 clinical trial of regorafenib in patients with advanced pretreated melanoma (RegoMel).
Authors: Dirven Iris , Vounckx Manon , Kessels Jolien Isabel , Vanlaer Nathalie , von Kemp Berlinde , Fasolino Giuseppe , Neyns Bart 
Published: July 2024

9518 Background: A majority of advanced melanoma patients (pts) will eventually progress despite treatment with PD-(L)1/CTLA-4/LAG-3 immune checkpoint- and BRAF-/MEK-inhibitors (BRAF-/MEKi; restricted to BRAFV600-mutant pts). Retrospective case observations indicate activity of regorafenib (REGO) in this setting (1). Methods: This single center, prospective, two-stage, phase 2 clinical trial, investigates REGO 80 mg QD (continuous dosing) in pts with advanced melanoma refractory to standard of care treatment. Objective response rate (ORR, by RECIST v1.1) served as the primary endpoint. The sample size (n=16) was determined according to a Simon’s two-stage minimax statistical design; the trial is considered positive if 3 or more responses are observed. Response assessments are performed every 6 weeks (q6w) during the first 24w, and q12w thereafter. Secondary endpoints are safety, progression free survival (PFS) and overall survival (OS). REGO treatment beyond first progression was permitted if considered to be of potential clinical benefit. Database lock was on Jan 9th, 2024. Results: From Oct 2022 to Sep 2023, 16 pts were enrolled (9 male, med age 61y; AJCC stage IIIC: 1; IV-M1a: 1; -M1c: 12, -M1d: 2, ECOG PS 0-1: 100%). Oncogenic driver mutations were identified in BRAFV600: 7-, KIT: 3-, NF1: 3-, NRASQ61K: 2-, RAF fusion: 1 pt. The ORR was 31% (: 5 partial responses (PR) - 4 confirmed in 3 KIT-,and 1 BRAFV600 -mut pt; and 1 unconfirmed in a BRAFV600-mut pt). One KIT-mut pt had previously progressed on imatinib. The median duration of response (DoR) was 29.7w (range 12-44). The disease control rate (DCR) was 56%. The median time on REGO monotherapy was 12.3w [95% CI 2.3-22.3], treatment is ongoing in 3 pts. At first progression, 6 BRAFV600-mut pts continued REGO in association with BRAF-/MEKi, in 5 response evaluable pts there is an ORR of 40% (2 PR with DoR of 24w and 30w) and DCR of 80%. At database lock, 11 pts were alive with a median follow up of 48.4w (range 24-63), 13 pts have progressed on REGO monotherapy (median PFS 11.9w [95% CI 3.5-20.3]; median OS was not reached). There were no grade ≥ 4 treatment related adverse events (TRAE); 56% of pts had at least one grade 3 TRAE, including hypertension (n=3) and maculo-papular rash (n=2). There was one toxicity-related REGO discontinuation. Conclusions: This phase 2 clinical trial on REGO monotherapy in advanced pretreated melanoma patients met its primary endpoint and demonstrated significant anti-tumor activity in KIT-mutant melanoma patients. In BRAFV600-mutant melanoma, continuation of REGO in combination with BRAF-/MEK-inhibitors demonstrated promising activity in patients who previously progressed on BRAF-/MEK-inhibitors for which further prospective investigation is ongoing. 1. Dirven I. et al. ESMO Meeting 2023. Clinical trial information: NCT05370807 .
The 31-GEP to identify patients with localized cutaneous melanoma at the highest risk of metastasis to the central nervous system.
Authors: Hasanov Merve , Martin Brian , Hasanov Elshad , Wu Richard Cheng Han , Goldberg Matthew S. , Cook Robert W. , Kendra Kari Lynn , Jarell Abel 
Published: July 2024

9530 Background: Cutaneous melanoma (CM) metastasis to the central nervous system (CNS) has a poor prognosis; however, treatment of CNS metastasis while asymptomatic is associated with better outcomes. CNS imaging is not routinely recommended for patients with early-stage CM (i.e., AJCC stage I–II), yet ˜14% of patients with stage II melanoma will develop CNS metastases. The 31-gene expression profile test (31-GEP) identifies patients at a low (Class 1A), intermediate (Class 1B/2A), or high risk (Class 2B) of tumor recurrence and metastasis. We evaluated the association of CNS metastasis with the 31-GEP test result for the purpose of directing CNS-directed imaging to detect metastasis earlier and, thus, improve outcomes. Methods: A retrospective analysis of patients clinically tested with the 31-GEP from 2013-2017. Patients were included in the study if they had clinical or pathological AJCC stage I-II CM (n=1,662). Kaplan-Meier analysis was used to estimate 5-year recurrence-free survival (RFS), and the log-rank test was used to compare survival between groups. Patients with non-CNS metastasis were censored at the time of recurrence. Univariate analysis to identify predictors of CNS metastasis was performed for tumor location, mitotic rate, Breslow thickness, ulceration status, tumor-infiltrating lymphocytes, age, sex, regression, lymphovascular invasion, tumor subtype, and 31-GEP results. Only significant (p<0.01) factors in univariate analysis were included in Cox multivariable analysis. Results: Median follow-up time was 4.6 years (range: 0.02-14.5 years). Patients with a CNS metastasis tended to have thicker tumors (median 1.1 vs. 0.8, p=0.003), higher mitotic rate/mm2 (median 2.5 vs. 1.0, p<0.001) and a higher proportion of males (73% vs. 55%, p=0.03) than patients that did not develop CNS metastasis. Patients with a Class 2B result were significantly more likely to develop CNS metastasis (7.4% [15/202]) relative to patients with a Class 1B/2A (1.7% [5/291]) or Class 1A (0.9% [10/1,169], p<0.001) 31-GEP result. Patients with a Class 2B result had significantly lower 5-year RFS than patients with a Class 1B/2A or Class 1A result (91.6% vs. 98.2% vs. 99.1%, p<0.001) and had shorter times to CNS metastases (1.5 yrs. vs. 4.2 yrs. vs. 3.4 yrs. p<0.001). In multivariable analysis, only the 31-GEP Class 2B (HR=9.42, p<0.001) result was a significant predictor of CNS metastasis; mitotic rate, Breslow thickness, and ulceration were not significantly predictive. Conclusions: Under multivariable analysis, the 31-GEP was the only significant predictor of CNS metastasis, and CNS metastasis occurred early (1.5 yrs). Patients with early-stage I-II CM and a Class 2B result should be considered for CNS imaging to enable asymptomatic detection of CNS metastasis and, thus, improve survival relative to symptomatic CNS metastasis.
High dose bolus (HDB) interleukin-2 (IL2) and concurrent low dose ipilimumab followed sequentially by nivolumab in patients with advanced melanoma after failure of anti-PD1-based immunotherapy and BRAF-MEK inhibition.
Authors: Tarhini Ahmad A. , Eroglu Zeynep , Galuia Mariem , Eljilany Islam , Kalos Denise , Schell Michael J , Tetteh Leticia , Abraham Edith , Richards Allison , Brohl Andrew Scott , Khushalani Nikhil I. , Markowitz Joseph 
Published: July 2024

9543 Background: Options are limited for patients with advanced metastatic melanoma who have disease progression following anti-PD1-based immunotherapy and BRAF-MEK inhibition (if BRAF V600 mutant). Evidence supports synergism between IL2 and CTLA4 blockade in enhancing the immunogenicity of the tumor microenvironment and therapeutic susceptibility to PD1 blockade. Methods: We conducted a phase II study of HDB IL2 in combination with LD ipilimumab followed sequentially by nivolumab in patients with advanced inoperable stage III or stage IV melanoma with progression after anti-PD1-based immunotherapy and BRAF-MEK inhibitors. Treatment consisted of up to 3 courses (One cycle is 21 days and one course is 4 cycles). HDB IL2 and concurrent ipilimumab 1 mg/kg were given during week 1 of the initial 2 cycles of each course. Nivolumab was given during week one of the 3rd cycle of each course. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities (CTCAE v.5) were offered additional courses of treatment. A Simon two-stage minimax design (Simon, 1989) was followed. We report the outcomes for Stage I. Results: 12 pts (5 female, 7 male) with metastatic melanoma (2M1a, 1M1b, 6M1c, 3M1d) were treated. Median age 53 years (33 – 69), 11 cutaneous (including 1 acral) and 1 mucosal primary. Tumor mutation status: 4BRAF (V600E), 2NRAS (p.Q61K), 1NF1. The median number of prior regimens for metastatic melanoma was 3 (range 1 - 5). Eight patients previously received ipilimumab as monotherapy or in combination with anti-PD1. On study, the median number of doses of IL2 was 9 during cycle 1 and 7 during cycle 2. A median of 2 doses of ipilimumab and 1 dose of nivolumab were given as part of the combination regimen. Among the 11 evaluable patients (completed 1 course of systemic therapy), the response rate was 2/11 (18.2 %; 95% CI: 2.3% – 51.8%); 1CR, 1 PR, 5 SD, 4 PD and 1 NE as best response. After a median follow up of 39 months, both responses are ongoing (at 10+ and 37+ months), median progression free survival (PFS) was 3 months and median overall survival (OS) was 18.8 months. One-year PFS and OS were 17% (95% CI: 4.7% - 59%) and 83% (95% CI: 65% - 100%), respectively. The adverse event profile was consistent with the expected toxicity profile for each agent with no increase in frequency with the combination. Conclusions: Our combination regimen was relatively safe and well tolerated and demonstrated promising efficacy in a heavily pretreated patient population passing the prespecified efficacy criteria for Simon Stage I. The study has moved into Stage II testing. Clinical trial information: NCT04562129 .
Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An updated indirect treatment comparison (ITC).
Authors: Schadendorf Dirk , Tawbi Hussein A. , Lipson Evan J. , Hodi F. Stephen , Ascierto Paolo Antonio , Larkin James , Lao Christopher D. , Grob Jean-Jacques , Ejzykowicz Flavia , Palaia Jennell , Horton Viviana Garcia , Zhou Zheng-Yi , Christensen Dana , Rosenblatt Lisa , McDonald Laura , Ratto Barbara , Salvatore Anthony , Patel Divya , Sakkal Leon A. , Long Georgina V. 
Published: July 2024

9557 Background: An ITC comparing NIVO + RELA and NIVO + IPI, approved dual immunotherapy treatment options for patients with advanced melanoma, was previously conducted using pt-level data from the pivotal RELATIVITY-047 (RELA-047; NIVO + RELA vs NIVO) and CheckMate 067 (CM-067; NIVO + IPI or NIVO vs IPI) trials (Schadendorf 2023). Here we present results using updated, 3-year follow-up data from RELA-047. Methods: Inverse probability of treatment weighting was used to adjust for cross-trial imbalances in baseline characteristics. Database locks were selected to best align follow-up length in RELA-047 (median 34 mo) and CM-067 (median 38 mo). Progression-free survival (PFS) per investigator, confirmed objective response rates (ORRs) per investigator, overall survival (OS), melanoma-specific survival (MSS), treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation (DC) were analyzed. PFS, OS, and ORR were evaluated across key subgroups. PFS, OS, and MSS were compared using Kaplan–Meier curves and hazard ratios (HRs); ORRs were compared using odds ratios (ORs). The weighted NIVO arm from each trial was compared for internal validation. Results: After weighting, key baseline characteristics were balanced for NIVO + RELA (n=339) and NIVO + IPI (n=297). Efficacy outcomes after weighting were similar between NIVO + RELA and NIVO + IPI and between NIVO arms (table). Similar outcomes between the NIVO arms validate the ITC methodology. Across subgroups, efficacy appeared similar between treatments, although trends favoring NIVO + IPI were observed for ORR among pts with BRAF MT disease or lactate dehydrogenase > 2x the upper limit of normal. TRAEs were less common with NIVO + RELA (23%) compared to NIVO + IPI (61%); any-grade TRAEs leading to DC occurred in 17% and 41% of pts, respectively. Conclusions: Consistent with previous results, this updated ITC suggests that 1L treatment with NIVO + RELA may have comparable efficacy to, and lower toxicity than, NIVO + IPI in pts with advanced melanoma. Results should be interpreted with caution given differences in study designs and changes in treatment landscape. Research is ongoing to determine which pts respond best with each combination. [Table: see text]
Metabolic factors affecting response to adjuvant anti-PD1 therapy for melanoma.
Authors: Bruno Sabrina , Knight Andrew David , Wang Hong , Sander Cindy , Karapetyan Lilit , Kirkwood John M. 
Published: July 2024

9589 Background: Given the intersection between metabolism and the immune system, and with the increasing use of immune checkpoint inhibitors (ICIs) in the treatment of solid tumors, it is important to determine whether metabolic factors are associated with outcomes for patients treated with ICIs. Obesity is often associated with improved response to immunotherapy for patients with melanoma. However, the impact of other metabolic disorders, such as type 2 diabetes (T2DM), hypertension (HTN), and hyperlipidemia (HLD), on immunotherapy response is not as well understood. The purpose of this study is to determine the impact of these metabolic disorders on immunotherapy treatment. Methods: Patients with stage II or III melanoma who were treated with adjuvant anti-PD-1 therapy and consented to the University of Pittsburgh Melanoma Center repository were included in this study. A retrospective chart review was conducted of the eligible 281 patients. Results: HTN, T2DM, HLD, and body mass index (BMI) > 35 were analyzed together in two multivariate Cox proportional hazard models, one considering overall survival (OS) and the other recurrence free survival (RFS). T2DM (n=49) was significantly associated with both a decreased OS (HR=2.51, 95% CI 1.14-5.52; p=0.0219) and RFS (HR=1.92, 95% CI 1.16-3.164; p=0.011). No significant differences were observed for patients with HTN (n=156) in OS (HR=1.45, 95% CI 0.73-2.87; p=0.29) or RFS (HR=1.22, 95% CI 0.80-1.86; p=0.35), HLD (n=140) in OS (HR=0.62, 95% CI 0.30-1.29; p=0.20) or RFS (HR=0.69, 95% CI 0.44-1.07; p=0.098), or BMI > 35 in OS (HR=1.01, 95% CI 0.48-2.13; p=0.99) or RFS (HR=0.78, 95% CI 0.47-1.29; p=0.34). After adjusting for common pre-treatment comorbidities (coronary artery disease, chronic kidney disease, and smoking), age, and sex, T2DM was no longer significantly associated with reduced OS (HR=1.78, 95% CI 0.83-3.8; p=0.14), but the association with RFS remained significant (HR=1.69, 95% CI 1.04-2.76; p=0.034). In patients with T2DM alone, metformin use (n=24) during immunotherapy treatment was associated with improved OS in univariate (HR=0.28, 95% CI 0.08-0.9; p=0.0385) and multivariate (HR=0.18, 95% CI 0.05-0.7; p=0.0098) analyses controlling for age, sex, and the comorbidities listed above. It was also near significant for increased RFS in a univariate (HR=0.46, 95% CI 0.20-1.06; p=0.067) and multivariate (HR=0.42, 95% CI 0.17-1.06; p=0.065) model. Baseline A1C (n=15) values were not significantly associated with OS (HR=0.18, 95% CI 0.001-24.7; p=0.49) or RFS (HR=0.60, 95% CI 0.21-1.76; p=0.35) in univariate models. Conclusions: T2DM is associated with decreased RFS for patients with melanoma treated with adjuvant anti-PD-1 therapy. Within the T2DM cohort, metformin use was associated with significantly improved RFS and OS. A1C did not correlate with either OS or RFS, suggesting that the effects of both T2DM and metformin may be independent of glycemic control.
Germline pathogenic variants in a large convenience cohort of multiple melanoma subtypes.
Authors: Lochrin Sarah E. , Kemel Yelena , Stuart Jessica , Smithy James William , Mandelker Diana , Momtaz Parisa , Chatila Walid Khaled , Schultz Nikolaus , Postow Michael A. , Stadler Zsofia Kinga , Shoushtari Alexander Noor 
Published: July 2024

9595 Background: A heritable component accounts for approximately 10% of melanomas. These estimates derive from populations deemed high risk for a germline pathogenic variant (gPV). The prevalence and clinical features of a broader melanoma patient population are unknown. Methods: Using the MSKCC IMPACT dataset, we identified a convenience cohort of all pts with melanoma who had undergone targeted tumor-normal sequencing (NCT01775072) for gPV in 76-90 genes. gPV were categorized by association with cancer predisposition and penetrance. Results: 701 pts with melanoma and germline sequencing demonstrated 105 pathogenic variants in 29 genes (Table). 14% of pts (n=99) harbored a gPV in a cancer susceptibility gene (gPV+); 49% high/moderately pathogenic, 32% low/recessive, and 19% uncertain. 6% of gPV+ pts had 2 gPVs. 77% of gPVs were involved in DNA damage repair pathways. The genes known to be associated with melanoma risk accounted for 9% of gPVs, inclusive of CDKN2A (2%), CDK 4 (1%), MITF (4%), and BRCA2 (2%). A further 15% were in genes with suggested, as yet undefined, susceptibility for melanoma; BRCA1 (6%), ATM (5%), BAP1 (2%) and PALB2 (2%). gPV+ frequency varied by melanoma subtype: unknown primary (19%, n=18), cutaneous (15%, n=64), mucosal (13%, n=13), acral (7%, n=2) and uveal (4%, n=2) (p=0.039). No significant difference in age, sex, race, stage at diagnosis, personal history of other cancer, or family history (FHx) of melanoma was seen between gPV+ and gPV-, on univariate analysis. 47% of gPV+ pts had either >1 primary melanoma, age<45 years or a FHx of melanoma (n=47), of which 14 pts had >1 risk factor. The presence of >1 melanoma and FHx of melanoma was associated with gPV+ (p=0.016). There was no significant difference in somatic TMB and MAPK pathway alterations between gPV+ and gPV-. In this cohort selected for high-risk melanomas, melanoma was the first presenting cancer for 83% of patients with gPV+. Assessment of biallelic loss to clarify if gPVs may be driving melanoma carcinogenesis is ongoing. Conclusions: This represents the largest cohort of sequenced matched germline and somatic analysis in melanoma. There is a 14% overall gPV prevalence that varies by melanoma subtype. The association of >1 primary melanoma, young age and a family history of melanoma with gPV+ is consistent with prior studies, however, would not capture 53% of gPV+ in this cohort. Melanoma represents the index cancer for the majority of gPVs, informing the need to expand germline testing in patients with melanoma. [Table: see text]
Arthralgia and myalgias associated with aromatase inhibitors: Frequency and characterization in real-life patients.
Authors: Camejo Natalia , Castillo Cecilia , Santana Diego , Argenzio Lucia , Amarillo Dahiana , Herrera Guadalupe , Guerrina Maria , Krygier Gabriel David 
Published: July 2024

e12504 Background: Adjuvant treatment with aromatase inhibitors (AI) in estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer (BC) has been shown to increase overall survival (OS). However, arthralgias and myalgias are common adverse effects in patients treated with AI. Objective: To evaluate the frequency and characteristics of arthralgias and myalgias in patients with early BC, treated adjuvantly with AI at the Mastology Unit of the Oncology Service of the Hospital de Clínicas and the Soriano Departmental Hospital. Methods: A prospective, cross-sectional, descriptive study was conducted. A questionnaire was administered to the patients to assess the presence and characteristics of arthralgias and myalgias associated with AI. Statistical analysis: "Age" was described using measures of central tendency and dispersion. Qualitative variables were presented in absolute and relative frequencies. Logistic models were used to assess the association between patient, tumor, and treatment characteristics and the presence of pain. Results: Results were presented using Odds Ratio and p-value, using R software (version 4.1.2) with a significance threshold of 5%. 83 patients were included, with a median age of 69 years. 75.9% presented treatment-related arthralgias and/or myalgias, with an average intensity of 5 to 7. 80.9% received NSAIDs, achieving satisfactory analgesia. The presence of arthralgias and myalgias was significantly associated with age and time since last menstruation, being more frequent in patients over 50 years old and those with more than 5 years since the last menstruation. Conclusions: Approximately 70% of the patients presented arthralgias or myalgias. These findings suggest a possible role of estrogen withdrawal in their development mechanism. It is crucial to carry out multidisciplinary and translational research to evaluate the etiology and therapeutic options for patients with AI-related arthralgia.
Reconstructive plastic surgery in combined treatment of breast cancer: Predictive risk factors of complications and reconstruction failure.
Authors: Ulrikh Daria , Krivorotko Petr , Zhanna Bryantseva , Novikov Sergey , Mortada Viktoriia , Pesotskiy Roman , Bondarchuk Yana , Amirov Nikolay , Emelyanov Alexander , Enaldieva Diana , Levchenko Valerii , Zhiltsova Elena , Tabagua Tengiz , Zernov Konstantin , Semiglazov Vladimir 
Published: July 2024

e12594 Background: Breast reconstruction after mastectomy must consider potential complications from surgical techniques as well as additional complications of oncologic treatment such as radiation or systemic therapy. But the consensus is lacking regarding the optimal reconstruction plan for patients requiring adjuvant radiation therapy. Objective: To determine the impact of risk factors on the development complications of breast reconstruction for postmastectomy radiotherapy. Methods: This study included patients diagnosed with breast cancer who received combination treatment from 2016 to 2021 at the FSBI “N.N. Petrov National Medical Research Center of Oncology” of the Russian Ministry of Health. The patients were divided into 3 groups: immediate reconstruction (158 people), immediate-delayed (210 people) and delayed (98 people). Results: Every fourth patient (24.0%, 112/466) may encounter a complication after mastectomy with reconstruction and adjuvant radiation therapy. According to the analyzed data, there was no correlation between potential risk factors depending on the general status of patients (age, obesity, diabetes mellitus, hypertension, history of smoking) and the occurrence of complications after combination treatment. Conclusions: The analysis of complications and reconstructive failures showed that immediate breast reconstruction at the FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Health of Russia is the safest method of reconstruction in the combined treatment of breast cancer with the lowest incidence of severe complications (9.5%, 15/158, z>1.96), which plays a key role in the development of reconstructive failures (Pearson Correlation=0.861, p<0.001). However, these surgeries are associated with a significant number of capsular contractures (15.2%, 24/158, z>1.96, Pearson Correlation=0.230, p<0.001), which requires finding ways to minimize these risks to optimize treatment in each individual case in short and long term results.