bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term follow up for adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma: Final results of the COMBI-AD study.
Authors: Hauschild Axel , Dummer Reinhard , Santinami Mario , Atkinson Victoria , Mandala Mario , Merelli Barbara , Chiarion-Sileni Vanna , Haydon Andrew Mark , Schachter Jacob , Schadendorf Dirk , Lesimple Thierry , Plummer Elizabeth Ruth , Larkin James , Tan Monique , Adnaik Sachin Bajirao , Burgess Paul , Jandoo Tarveen , Long Georgina V. 
Published: July 2024

9500 Background: Dabrafenib plus trametinib, a standard-of care adjuvant treatment for patients with BRAF-mutated AJCC-stage III melanoma, has significantly improved the primary endpoint, relapse-free survival (RFS). Further to published interim assessments, we present updated and final results for RFS, distant-metastasis-free survival (DMFS) and overall survival (OS). Methods: In the COMBI-AD phase 3 study, patients received dabrafenib (150 mg BD) plus trametinib (2 mg OD; n=438) or matching placebos (n=432). Treatment continued for up to 12 months or until disease relapse, unacceptable toxicity, withdrawal of consent, or death. OS, RFS, and DMFS were summarized using Kaplan–Meier estimates. OS was compared between study arms using stratified log-rank test. Hazard ratio (HR) was calculated using Pike estimator. Safety data were summarized descriptively. Results: At final analysis, median duration of follow up was 100.0 months in the treatment arm and 82.5 months in the placebo arm. Median OS was not attained in the two arms (HR: 0.80; 95% CI: 0.62, 1.01; P=0.063). Consistent OS benefits were seen across most prespecified subgroups including patients with BRAFV600E mutation (n=397; HR: 0.75; 95% CI: 0.58, 0.96). Estimated RFS (HR: 0.52; 95% CI: 0.43, 0.63) and DMFS (HR: 0.56; 95% CI: 0.44, 0.71) favored the dabrafenib plus trametinib arm. In both arms, patients received salvage immunotherapies (29% each) and targeted therapy (21% vs. 37% for treatment and placebo arms, respectively). Safety profile was consistent with previous reports. Conclusions: COMBI-AD presents the longest follow-up data (over 10 years) in adjuvant treatment of stage III melanoma in the modern era. OS was improved with dabrafenib plus trametinib over placebo for adjuvant treatment of stage III melanoma with a 20% risk reduction for death. However, this difference was not statistically significant. Consistent with published results at 3 and 5 years, RFS and DMFS were more favorable in the treatment vs. placebo arm. Clinical trial information: NCT01682083 . [Table: see text]
FDG-PET associations with pathological response and survival with neoadjuvant immunotherapy for melanoma.
Authors: Zhou Li , Hsiao Edward , Lo Serigne N , Carlino Matteo S. , Au-Yeung George , Gonzalez Maria , Spillane Andrew John , Pennington Thomas , Howle Julie R. , Shannon Kerwin Frank , Kapoor Rony , Stretch Jonathan , Gyorki David E. , Saw Robyn P.M. , Ch'ng Sydney , Scolyer Richard A , Long Georgina V. , Menzies Alexander M. 
Published: July 2024

9523 Background: This study sought to describe the changes seen with FDG-PET following neoadjuvant immunotherapy in melanoma patients (pts), and explore associations with pathological response and recurrence-free survival (RFS). Methods: Two prospective clinical trial cohorts of stage III pts with RECIST measurable nodal melanoma were included; 1) NeoTrio, 13 pts received 2 doses of preoperative pembrolizumab alone, and 2) NeoPele, 20 pts received 2 doses of pembrolizumab and 5 weeks of lenvatinib preoperatively. All pts underwent baseline and week 6 (preoperative) FDG-PET assessments and all had surgery. PET responses were evaluated based on the modified EORTC criteria. In addition to the standard categories Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), Stable Metabolic Disease (SMD), and Progressive Metabolic Disease (PMD), a novel category was established, near-CMR, where the maximum standardized uptake value (SUVmax) decreased by more than 90%. PET responses were determined while blinded to the outcome data. Pathological response was determined as per INMC criteria. Results: 33 pts were included, 67% male, median age 65 years, 48% BRAF mutant. Pathological response, PET response and correlations are shown in the Table. All 8 (24%) pts achieving CMR or near-CMR obtained major pathologic response (MPR), while the 14 pts (42%) with PMR had variable pathological outcomes (57% MPR, 21% pPR, 21% pNR). For the 6 pts with PMD, 5 (83%) had pNR and the one pts who achieved pCR recurred with brain metastases. After a median 29.9 mo follow-up (95% CI 27.0-33.1), PET response associated with RFS; those with CMR/near CMR had 100% 24mo RFS (nil recurrences to date) while those with PMR or SMD had inferior survival (79% and 80% 24mo RFS), and those with PMD the worst outcomes (17% 24mo RFS, all pts except one have recurred) (p=0.0029). The predictive value of PET and pathology for RFS was assessed using the Cox Proportional Hazards model. 12- and 24-month RFS AUCs of PET and pathology response were similar at 81.5% (95% CI: 67.7-95.3) vs. 80.9% (95% CI: 67.8-93.9), and 83.3% (95% CI: 69.1-97.5%) vs. 80.8% (95% CI: 66.6-94.9), respectively. Conclusions: FDG-PET demonstrates utility in predicting pathological response and survival with neoadjuvant immunotherapy in melanoma. PET may identify pts who are not going to be pathological responders and who have the worst survival outcomes, enabling a potential switch of neoadjuvant systemic therapy. [Table: see text]
Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years.
Authors: Tawbi Hussein A. , Hodi F. Stephen , Lipson Evan J. , Schadendorf Dirk , Ascierto Paolo Antonio , Matamala Luis , Gutiérrez Erika Castillo , Rutkowski Piotr , Gogas Helen , Lao Christopher D. , Menezes Juliana , Dalle Stéphane , Arance Ana Maria , Grob Jean-Jacques , Ratto Barbara , Rodriguez Saima , Mazzei Antonella , Dolfi Sonia , Long Georgina V. 
Published: July 2024

9524 Background: NIVO + RELA as a fixed-dose combination (FDC) demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922), with a clinically meaningful, but not statistically significant, improvement in OS and a numerically higher objective response rate (ORR), resulting in regulatory approval of the FDC. Here we report updated descriptive analyses with 3 years of follow-up. Methods: Patients (pts) were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg Q4W. PFS per RECIST v1.1 was assessed by blinded independent central review (BICR); secondary endpoints included OS and ORR per BICR. Exploratory analyses included MSS (death due to melanoma, with censoring of deaths due to other causes), CNS metastasis-free survival in specified populations, and efficacy on subsequent systemic therapy. Results: At database lock (19 Oct 2023), median follow-up was 33.8 months (mo; range, 0.3–64.2). NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS (Table). NIVO + RELA was also favored over NIVO across the majority of key subgroups. Subsequent systemic therapy was received by 135 pts (38%) on NIVO + RELA and 141 pts (39%) on NIVO. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 78 pts (22%) on NIVO + RELA and 43 pts (12%) on NIVO; TRAEs (any grade) led to treatment discontinuation in 63 pts (18%) and 35 pts (10%), respectively. No new treatment-related deaths were reported since the last analysis. Conclusions: At 3 years of follow-up, NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS. OS and MSS demonstrated sustained improvement, with the OS HR 95% CI upper bound < 1. Efficacy results also continued to favor NIVO + RELA vs NIVO across the majority of prespecified subgroups. Safety of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. CNS metastasis-free survival and efficacy outcomes on subsequent systemic therapy will be presented. Clinical trial information: NCT03470922 . [Table: see text]
First-line treatment preferences for advanced melanoma among oncologists and patients in the US: A discrete choice experiment.
Authors: Postow Michael A. , Burgos Gabriela , DeCongelio Marc , Palaia Jennell , Ejzykowicz Flavia , Patel Divya , Rosenblatt Lisa , Modi Kushal , Pittman Zander , Honomichl Ryan , Paudel Neelanzana , Barnett Cody , Hay Jennifer L. 
Published: July 2024

9539 Background: NCCN guidelines recommend nivolumab + ipilimumab, nivolumab + relatlimab, and anti-PD-1 monotherapy as category 1 preferred first-line (1L) treatments (txs) for advanced melanoma. These immunotherapies (IOs) however differ in administration, efficacy, and safety. Given these differences, this study examines oncologists (oncs) and patients (pts) preferences when choosing 1L tx. Methods: Pts with self-reported unresectable or metastatic melanoma and oncs completed an online cross-sectional survey. A discrete choice experiment assessed preferences for three efficacy attributes, three safety attributes, and dosing schedule. Attributes (shown in table) were identified via literature and qualitative research. Each attribute had two or three levels based on clinical trial data of recommended IOs. Participants completed 12 tasks; each task showed two tx options with varying levels for each attribute. Hierarchical Bayesian modeling was used to estimate preference weights for each level and relative importance estimates, based on the range between levels, were computed. Results: 75 oncs (male 76%; mean age 46 years; community-based 51%) and 62 pts (male 68%; mean age 43 years) were analyzed (pt recruitment ongoing; target n = 75). For both oncs and pts, improvements in safety attributes was more important than improvements in efficacy attributes (pts: 50.3 vs. 33.9; oncs: 48.6 vs. 40.9). For safety, a decrease in risk of discontinuation due to treatment-related adverse events (TRAEs) was most important in oncs (24.7); while for pts, lower risk of grade 3/4 TRAEs was most important (22.6). For efficacy, an increase in overall survival (OS) was most influential for oncs (21.0); pts had similar estimates within efficacy. Dosing schedule was third most important for pts (15.8), while it was among the least important for oncs. Conclusions: Oncs and pts prioritize minimizing the risk of serious AEs when efficacy differences are minimal in 1L advanced melanoma tx choice. These findings highlight that oncs and pts value an IO with an efficacy benefit while ensuring a favorable risk-benefit profile. This information can inform tx counseling and selection discussions among oncs and pts. [Table: see text]
Overall survival and efficacy subgroup analysis of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.
Authors: Wei Xiaoting , Zou Zhengyun , Zhang Weizhen , Fang Meiyu , Zhang Xiaoshi , Luo Zhiguo , Chen Jing , Huang Gang , Zhang Peng , Cheng Ying , Liu Jiwei , Liu Jiyan , Zhang Junping , Wu Di , Chen Yu , Ma Xiaobiao , Tian Hongqi , Jia Zhongwei , Guo Jun , Si Lu 
Published: July 2024

9545 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we report the updated efficacy results. Methods: This is a multicenter, single-arm, phase II, pivotal registrational study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors, version 1.1 assessed by independent radiology review committee (IRRC). Results: A total of 100 pts were enrolled and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (October 31, 2023), median follow-up was 24.4 months (95% CI: 21.9, 27.9). The confirmed ORR was 35.8% (95%CI: 26.3%, 46.3%). Median progression-free survival (mPFS) was 4.2 months (95%CI: 3.5, 5.6). The median overall survival (mOS) was immature during last year's ASCO annual meeting, and the present mOS was 13.7 months (95% CI of 10.3–18.0). The IRRC-assessed ORRs by melanoma subtype were 42.9% (95% CI of 29.7–56.8) in acral melanoma, 25.0% (95% CI of 7.3–52.4) in mucosal melanoma. ORRs by NRASmutation site were 41.3% (95% CI of 30.1–53.3), 13.3% (95% CI of 1.7–40.5) and 20.0% (95% CI of 0.5–71.6) for Q61, G12, and G13, respectively. ORR in patients who had been treated with immunotherapy was 40.6% (95% CI of 28.5–53.6), while in those without immunotherapy, ORR was 25.8% (95% CI of 11.9–44.6). The difference in PFS was not statistically significant across subgroups, regardless of melanoma type, NRAS mutation site, line of previous treatment, type of previous treatment and previous treatment with immunotherapy. The safety profile is similar with last year's ASCO annual meeting. The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, facial oedema, peripheral oedema, and increased aspartate aminotransferase. No treatment-related death was reported. Conclusions: Tunlametinib demonstrated an encouraging treatment response rate in patients with advanced NRAS-mutant melanoma with a manageable safety profile. These results suggest that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those who had previously received immunotherapy. Clinical trial information: NCT05217303 .
Immune phenotype profiling based on anatomic origin of melanoma and impact on clinical outcomes of immune checkpoint inhibitor treatment.
Authors: Hwang Soohyun , Ryu Hyang Joo , Kim Youhyun , Cho Soo Ick , Oum Chiyoon , Valero Puche Aaron , Lee Jinhee , Kim Kyoo Hyun , Chung Kee Yang , Shin Sang Joon , Ock Chan-Young , Jung Minkyu , Shen Jeanne 
Published: July 2024

9569 Background: The inflamed immune phenotype is associated with a favorable response to immunotherapy in metastatic malignant melanoma. Although variations in molecular features across melanoma subtypes and differing ethnic distributions have been well reported, studies investigating immune phenotypes across multiple institutions within the context of different melanoma subtypes are scarce. We examined the association of immune phenotypes with outcomes after immunotherapy, based on subtypes of malignant melanoma. Methods: Two institutional advanced melanoma cohortsrepresenting Asian and Western populations (YUHS, n = 123; Stanford University, n = 102) were included. H&E-stained tumor slides were assessed using Lunit SCOPE IO, an AI-powered whole slide image analyzer, to define the inflamed score (IS, % of inflamed area) and the inflamed phenotype (>33.3% IS). Clinical outcomes after immune checkpoint inhibitor (anti-PD-1/PD-L1) treatment, including progression-free survival (PFS) and overall-survival (OS), were assessed. Results: In the overall cohort (n = 225), the inflamed phenotype was associated with prolonged PFS (HR = 0.634, 95% CI: 0.453 – 0.887, p = 0.007) and OS (HR = 0.655, 95% CI: 0.432 – 0.992, p = 0.044). On analysis of melanoma subtypes, we identified non-acral cutaneous melanomas (CM, n = 94), acral melanomas (AM, n = 52), mucosal melanomas (n = 43), uveal melanomas (n = 16), and melanomas of unknown primary site (n = 20), with a disproportionate enrichment of AM (37.4%) and mucosal (29.3%) melanoma cases in the YUHS cohort and CM cases (68.6%) in the Stanford cohort. The IS varied across different melanoma subtypes, with the highest IS observed in CM (median, [IQR]; 34.0, [5.8–52.2]), and significantly lower scores in AM (22.3, [7.7–36.9]), mucosal (13.6, [0–31.4]), and uveal melanoma (5.5, [0–13.6]). Among CM patients, the inflamed phenotype was significantly associated with better post-immunotherapy PFS (HR = 0.476, 95% CI: 0.274 – 0.826, p = 0.007). In contrast, the inflamed phenotype did not correlate with survival in AM patients (p = 0.58), who exhibited universally poorer PFS compared to non-AM patients (HR = 2.124, 95% CI: 1.486 - 3.005). Conclusions: AI-powered immune phenotype assessment highlights a heterogeneity of immune phenotypes across specific melanoma subtypes, as well as differential association with outcomes after immune checkpoint inhibitor treatment. While CM patients were well-stratified by immune phenotype, the predictive value of immune phenotyping was less pronounced in acral melanomas, which demonstrated poorer outcomes following immunotherapy.
Identifying the high risk group in stage pT1bN0 cutaneous melanoma.
Authors: Teterycz Pawel , Sryukina Tatsiana , Kluz Agnieszka , Ziobro Anna , Skoczylas Jacek , Zdzienicki Marcin , Rutkowski Piotr 
Published: July 2024

9583 Background: In recent years, there has been a substantial improvement in prognosis for patients diagnosed with stage II or III melanoma due to the advent of adjuvant and neoadjuvant therapy. At the same time, significant percentage of melanoma deaths are caused by prevalent cases of thin melanoma. In this work, we aimed to identify the stage pT1bN0 melanoma subgroup with the worst prognosis. Methods: All cases of stage pT1b melanoma (with negative sentinel node biopsy) treated between 1998 and 2022 in high-throughput reference center were analyzed. Patients were followed for ten years or up to lost to follow-up or death. Patients alive at 10 year mark were censored. The patients were divided into groups with BOTH pT1b features (i.e., Breslow thickness > 0.8mm AND ulceration) vs those with just ONE of those features. Additionally, patients’ sex, the tumor’s pathological subtype, and mitotic index were analyzed. The Kaplan-Meier and the Cox proportional model were used in statistical analysis. Results: There were 665 cases identified. 63% of patients were female, median age was 49 (IQR: 38-60). 70% of patients were classified as pT1b due to Breslow thickness, 21% due to ulceration and 9% due to BOTH features. 48% of patients had superficially spreading melanoma, 3% - acral, 9% - nodular while other patients had other/unspecified subtype. The median mitotic index was 1/mm2, but this feature was missing in 46% of cases. Overall, 61 patients died during the follow-up. The 10-year overall survival (OS) rate for the whole group was 86% (95% CI: 83-90%). In a multivariable model, patients with BOTH IB features (HR 2.1, 95%CI:1.1-4.2), nodular or acral melanoma (HR 2.2, 95%CI:1.2-4.1) and males (HR 2.6, 95%CI:1.6-4.4) had worse prognosis; the mitotic index was not predictive for OS in this model. In patients with BOTH pT1b features the 10 year survival rate was 75% (95%CI: 62-89) and 87% (95%CI: 84-91%) in case of just one feature (log-rank p=0.008). Conclusions: There is a specific subgroup of patients diagnosed with stage IB who have a relatively bad prognosis. Focusing on perioperative treatment or on a more strict follow-up schedule in this group may prove beneficial.
Combined EORTC FDG-PET/CT and RECIST 1.1 response criteria and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.
Authors: De Barros E Silva Milton Jose , Tavares Monique Celeste , Lima Joao Paulo S. N. , Garcia Daniel , Rinck Jr Jose Augusto , Molina Andre , Lobo Matheus , Pinto Clovis Antonio Lopes , De Paula Rafaela Brito , van Akkooi Alexander Christopher Jonathan , Duprat Neto João Pedreira 
Published: July 2024

9590 Background: Accurate identification of pathological response to neoadjuvant therapy for clinical stage III melanoma before surgery may allow us to better tailor the treatment. RECIST 1.1 has shown poor concordance rates with pathological responses and EORTC FDG-PET/CT response criteria using SUV max is susceptible to internal and external variables leading to difficulty in determining accuracy appropriately. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1mg/kg(N3+I1) for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. RECIST 1.1 and EORTC PETCT criteria were used to classify patients in terms of response. The pathological results were correlated to the image findings. Results: Between Jan 2019 and Jan 2024, 37 patients with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), positive nodes on baseline exam:1=30 (81%), 2=4(11%), and 3 or more =3(8%). Stage AJCC 8th edition: IIIB=23 (62%), IIIC=12 (32%), IIID=2(6%). Among them, 34 had baseline and post-neoadjuvant therapy PET-CT. Twenty-one (62%) had major pathological response (MPR) and 13(38%) had non-MPR. Using objective response and non-objective criteria to capture MPR and non-MPR, respectively, we found the following results: RECIST 1.1 (sensitivity= 48%, specificity=100%, accuracy=68%), EORTC-PET (sensitivity=90%, specificity=69%, accuracy=82%). Combining RECIST 1.1 and EORTC-PET/CT analysis, we found that: double objective responders (CR/PR and CMR/PMR, n=10) had 100% specificity to MPR and double progressors (PD/PMD, n=9) had 95% specificity to non-MPR. The only patient classified as double progressor that did not have non-MPR presented an intense inflammatory response with fever, pain and erythema leading to an increase in the size and number of lymph-nodes. No viable cells were found in the pathological report. Conclusions: Using combined RECIST 1.1 and EORTC-PET/CT response criteria may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.