bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of LNS8801 alone and in combination with pembrolizumab in patients with metastatic uveal melanoma.
Authors: Shoushtari Alexander Noor , Chaney Marya F. , Cohen Justine Vanessa , Garyantes Tina , Lin Jessica Jiyeong , Ishizuka Jeffrey Joseph , Mita Alain C. , Mita Monica M. , Muller Carolyn , Natale Christopher , Orloff Marlana M. , Papadopoulos Kyriakos P. , Patel Sapna Pradyuman , Rodon Ahnert Jordi 
Published: June 2023

9543 Background: LNS8801 is an oral, selective, small molecule agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 treatment results in increased melanocytic differentiation, reduced c-Myc protein levels in cancer cells, inhibition of proliferation, suppression of invasion, and enhancement of immune recognition. In preclinical models, LNS8801 has demonstrated increased activity in combination with immune checkpoint inhibitors (ICIs). In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with advanced solid tumors (NCT04130516). Methods: Patients with measurable metastatic uveal melanoma (mUM) received LNS8801 (125 mg, QD, PO) alone or with pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective was safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics, objective response rate (ORR) and disease control rate (DCR, CR+PR+SD) per RECIST v1.1. Presence of a consensus, fully-functional, germline GPER coding sequence was assessed via Sanger sequencing on DNA extracted from blood as a potential predictive biomarker. Results: As of 1/25/23, 15 patients with mUM were treated with LNS8801 alone (n = 8) or a combination of LNS8801 and pembrolizumab (n = 7). Patients were previously treated with a median of 2 prior lines of systemic therapy. 4 of 8 monotherapy patients had AEs potentially related to study drug (all grade 1), with no AEs occurring in more than one patient. 6 of 7 combination patients had AEs potentially related to study drugs (grades 1-2), with fatigue occurring in more than one patient. Of the 14 patients evaluable for efficacy (7 mono, 7 combo), 7 had disease control (4 mono, 3 combo) resulting in a disease control rate of 50%. 1 patient treated with combination achieved a confirmed partial response. Consensus germline GPER was present in 2 of 12 sequenced patients (1 mono, 1 combo), and both of these patients have ongoing disease control lasting longer than 24 weeks. Conclusions: LNS8801 alone and in combination with pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients with mUM. The hypofunctional germline GPER variant appears over-represented in this cohort compared to the normal population, suggesting a potential significant role for GPER in the development of mUM. These data support further development of LNS8801 alone and in combination with pembrolizumab as a therapeutic approach to treat mUM patients, especially for patients with consensus germline GPER. Clinical trial information: NCT04130516 .
Real-world comparison between 6 weeks versus 3 weeks adjuvant pembrolizumab in high-risk stage IIB-IIID cutaneous malignant melanoma: Experience from an academic cancer center.
Authors: Shah Manan , Shafi Saba , Kendra Kari Lynn , Verschraegen Claire F. , Wu Richard Cheng Han 
Published: June 2023

9545 Background: The KEYNOTE-555 trial demonstrated similar efficacy and safety profile of 6-week (q6w) pembrolizumab (400 mg/m2) vs 3-week (q3w) in unresectable and metastatic melanoma leading to FDA’s approval of this dosing schedule for adults in 2020. Limited real-world data is available on the use of 3 weeks vs 6 weeks pembrolizumab in the adjuvant setting in cutaneous melanomas. Q6w is hypothesized to cause more adverse effects due to higher drug concentration. Methods: We conducted a retrospective study of surgically resected Stage IIB-IIID cutaneous melanomas receiving adjuvant pembrolizumab from 2019-2022 at The James Comprehensive Cancer Center with a follow-up of ~1 year. Fifty patients [n=35 (q6w) and n=15 (q3w)] were included. The primary objectives were to compare disease free survival (DFS) and safety profile based on the NCI-CTCAE (v 5.0) criteria. Kaplan-Meier curves were generated for DFS comparisons between the two groups. Fisher’s exact test was used to compare the safety profile between the two groups. Accuracy of the sample size for final analysis was planned based on log rank test. With 15 patients (q3w) and 35 patients (q6w), our study had 80% power to detect differences in clinical outcomes. A p-value of less < 0.05 was considered statistically significant. The secondary objective was to compare overall survival (OS) which will be reported later with a longer follow-up. Results: The mean age in the q6w and q3w groups was 59 years and 69 years, respectively. The median follow up was ~ 9 months with males predominating in both groups (54% and 18%). In the q6w group, 68% had ECOG status 0 (vs.30% in q3w) and most of our patients (32%) were stage IIIB (vs. 6% in q3w) and 28% were stage IIIC (vs 12% in q3wk). BRAF mutation was present in 32% in q6w vs. 2% in q3w. Toxicity profile was noted to be similar in both groups with no significant statistical difference ( p-value=0.4), though there were more Grade-3 immune-related toxicities in 7 patients in the q6w group (vs 3 in q3wk). The most common grade 3 toxicity noted was colitis (n=4, q6w; n=1, q3w). Notably, no significant difference was noted in the DFS between the two groups ( p-value=0.6). At the time of analysis, 3/15 (20%) patients in q3w and 7/35 (20%) in the q6w group had disease progression with the most common site being the regional lymph-nodes. At the time of the last follow up, 96% of the patients were alive with only 2 deaths occurring due to non-cancer related causes. Conclusions: We demonstrate comparable efficacy of q6w and q3w adjuvant pembrolizumab for advanced stage melanoma, with a trend towards increased immune-mediated colitis events in q6w. [Table: see text]
Neoadjuvant T-VEC + nivolumab combination therapy for resectable early metastatic (stage IIIB/C/D-IV M1a) melanoma with injectable disease: NIVEC trial.
Authors: Zijlker Lisanne P. , van Houdt Winan J. , Stahlie Emma H.A. , Franke Viola , Rohaan Maartje W. , Delatzakis Antonios , Zuur Charlotte , Klop Willem M.C. , van de Wiel Bart A. , Kuijpers Anke , de Boer Elianne , van Thienen Johannes V. , Haanen John B. A. G. , Van Akkooi Alexander Christopher Jonathan 
Published: June 2023

9546 Background: Neoadjuvant systemic treatment with checkpoint inhibitors (ICI) has shown high response rates in patients with resectable metastasized melanoma. In patients with unresectable stage IIIB-IVA melanoma, intralesional treatment with talimogene laherparepvec (T-VEC) has also shown high and durable response rates. In this trial we investigated the safety and efficacy of neoadjuvant treatment with a combination of nivolumab and T-VEC in regionally metastasized melanoma. Methods: In this single arm phase II open-label trial (NCT04330430), 24 patients with resectable stage IIIB-IVA melanoma were included. Inclusion criteria were a RECIST 1.1 measurable lesion of ≥10mm and no prior systemic therapy. Treatment consisted of four doses of intralesional T-VEC (dose in ml according to the size of the lesions) and three doses of nivolumab 240 mg flat dose every two weeks, followed by surgery. The primary endpoint was pathological response rate according to the International Neoadjuvant Melanoma Consortium (INMC) criteria, secondary endpoints were delay or failure to perform surgery, event free survival (EFS) from time of randomization and safety. Results: Baseline characteristics are presented in the table. The overall pathological response rate was 74%, with a major pathological response (MPR = pathologic complete response (pCR) + near-pCR (max 10% viable tumor cells) in 15 patients (65%), a partial response in two patients (9%), a non-response in 4 patients (17%) and progression of disease (PD) in two patients (9%). In one patient the response was not evaluable because surgery was delayed due to a vena cava thrombosis. The two patients with PD had evidence of distant metastasis on preoperative imaging and therefore did not proceed to surgery as planned. Grade 2 treatment related adverse events (trAE) occurred in 7 patients (29%) and grade 3 in 2 (8%). There were no grade 4-5 trAEs. The 1-year EFS was 75% (95%CI 0.55-1). Conclusions: Neoadjuvant combination therapy of nivolumab and T-VEC for patients with regionally metastasized melanoma (satellite/in-transit +/- lymph node metastases) has an acceptable toxicity profile and has shown a significant major pathological response rate of 65%. Clinical trial information: NCT04330430 . [Table: see text]
Retreatment and rechallenge with BRAF/MEK inhibitors in patients with metastatic melanoma: Results from the observational study GEM1801.
Authors: Ayala de Miguel Pablo , Berciano-Guerrero Miguel-Angel , Muñoz-Couselo Eva , Manzano Jose Luis , CEREZUELA Fuentes Pablo , SORIA RIVAS AINARA , García Castaño Almudena , Crespo Guillermo , Puértolas Teresa , Aguado De La Rosa Carlos , Gutiérrez Sanz Lourdes , López Castro Rafael , Espinosa Enrique , Lecumberri Maria Jose , Majem Margarita , Medina Martinez Javier , Bellido Lorena , Fernandez Luis Antonio , Martin-Algarra Salvador , Marquez-Rodas Ivan 
Published: June 2023

9547 Background: Most patients with BRAF-mutant melanoma eventually develop resistance to therapy with BRAF/MEK inhibitors and immune-checkpoint blockade. Alternative treatment strategies are required in these patients since further therapy options lack survival benefit. Small series have shown promising activity from re-exposure to BRAF/MEK inhibitors after a treatment free interval of targeted therapy (TT), probably due to regression of resistant tumors and proliferation of clones that maintain sensitivity to BRAF/MEKi. However, prospective evidence for this approach is limited. Here we report the results of 30 patients who received a second course of TT at relapse after adjuvant therapy (retreatment) or after first progression on TT in the advanced setting (rechallenge). Methods: GEM1801 is a prospective observational study from the Spanish Melanoma Group (GEM) including 893 patients with melanoma treated in 37 centers. This is a descriptive analysis of basal characteristics, response rates (RR), progression free survival (PFS) and overall survival (OS) from 30 patients that received retreatment or rechallenge with BRAF/MEKi in GEM1801 study. Results: 4 patients received retreatment and 26 rechallenge. For retreatment, BRAF/MEKi median free interval from end of adjuvant TT to subsequent retreatment was 17.8 months (range: 12.4 - 57.7). RR with retreatment were 25%, with a median PFS and OS of 5.7 and 8.5 months. For rechallenge, RR was 38.5% and median PFS and OS 11.1 and 22.2 months respectively. Patients who were selected for rechallenge had higher complete response (CR) rates to first TT (26.9% vs 20.3%; p= 0.026). Patients who experimented deeper responses with 1st TT in the metastatic setting showed a correlation to longer PFS to 2nd TT with 12-m PFS rates of 66.7% versus 35.7% (HR 9.09 [95%CI: 1.42-58]; p= 0.02). OS showed a not statistically significant improvement in patients who reported CR to first TD (24-m OS rate of 75% versus 40.7% respectively). BRAF/MEKi free interval since first progression and retreatment or rechallenge was not associated with prognosis. Prognostic factors as LDH and number of metastatic sites did not correlate with the efficacy of retreatment. Conclusions: Retreatment or rechallenge with BRAF/MEKi in the metastatic setting achieved encouraging efficacy and may be a valid therapeutic strategy in a selected group of patients. Response to first treatment, retreatment and rechallenge with BRAF/MEKi. Clinical trial information: NCT03605771 . [Table: see text]
A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.
Authors: Shaheen Montaser F. , Segar Jennifer Margaret , Chmielowski Bartosz , Drabick Joseph J. , McKean Meredith , Reeves James A. , Karapetis Christos Stelios , Orloff Marlana M. , Tolcher Anthony W. , Beck J. Thaddeus Thaddeus , Gastman Brian , De Asit , Paudyal Ben , Winkler Robert E , Li Mingyu , Ahmad Mohammad , Yang Dajun , Zhai Yifan 
Published: June 2023

9559 Background: Alrizomadlin is a novel, orally active small-molecule MDM2 inhibitor that activates p53-mediated apoptosis in tumor cells, also functions as a host immunomodulator, and may restore antitumor activity in patients with cancer that has progressed on PD-1/PD-L1 inhibitors. Alrizomadlin is currently being investigated for treatment of patients with unresectable or metastatic cutaneous melanoma that progressed on prior immunotherapy. Methods: This multicenter clinical trial was conducted in the United States and Australia in patients with unresectable or metastatic cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy. Eligible patients had an ECOG performance status of 0-2. Alrizomadlin 150 mg was administered orally every other day for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg intravenously for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 12, 2022, preliminary and interim results are reported for 31 patients with cutaneous melanoma, of whom 21 were male and 10 female, with a median (range) age of 65 (27-84) years. Treatment-related adverse events (TRAE) of any grade ( > 10%) for either alrizomadlin or pembrolizumab were reported in 30/31 (96.8%) patients. These AEs included nausea (71%), vomiting (38.7%), fatigue (35.5%), thrombocytopenia (32.3%), diarrhea (25.8%), neutropenia (19.4%), decreased appetite (16.1%), and decreased leukocyte count (12.9%). A total of 4/31 (12.9%) patients reported treatment-related serious AEs, including anemia, thrombocytopenia, deep vein thrombosis, joint effusion, pulmonary embolism, and vomiting. In 26 efficacy-evaluable patients, the confirmed overall response rate (ORR; partial response [PR] + complete response [CR]) was 23.1%, including 2 patients reporting CRs and 4 reporting PRs based on RECIST v.1.1. The initial analysis indicated that the ORR observed in patients whose disease had failed IO treatment was primarily due to alrizomadlin combined with pembrolizumab, not the delayed effect of prior immunotherapy. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates clinical efficacy in these patients with highly refractory unresectable or metastatic cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy. Internal study identifier: APG-115-US002. Clinical trial information: NCT03611868 .
Correlation of DNA methylation signatures with response to immune checkpoint inhibitors in metastatic melanoma.
Authors: Ressler Julia Maria , Tomasich Erwin , Hatziioannou Teresa , Ringl Helmut , Heller Gerwin , Silmbrod Rita , Zila Nina , Tschandl Philipp , Hoeller Christoph , Berghoff Anna Sophie , Preusser Matthias 
Published: June 2023

9561 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma with objective response rates of 40-58%. However, reliable biomarkers to predict treatment response are lacking. Tumor tissue methylation profiles were recently proposed to have predictive value in various solid organ tumor entities. Methods: Patients with metastatic melanoma, American Joint Committee on Cancer (AJCC; 8th Edition) stage IV, receiving first-line ICI-based therapy, were retrospectively identified and formalin-fixed paraffin-embedded tumor tissue samples (FFPE) prior to ICI therapy were retrieved. We analyzed DNA methylation profiles of > 850.000 CpG sites in tumor specimens by Infinium MethylationEPIC microarrays. DNA methylation profiles were then correlated with radiological response (iRECIST). Results: 71 patients with metastatic melanoma (44 (62.0%) male, 27 (38.0%) female) were investigated; median progression free survival (PFS) was 8.5 months (range: 0 – 104.1 months) and median overall survival (OS) was 30.6 months (range: 0 – 104.1 months), respectively. 29 (40.8%) patients achieved an objective response to ICIs. Microarray analyses revealed a methylation signature including mainly hypomethylation, corresponding to the response to ICIs. Based on the 500 mostly differentially methylated genes, a total of 3 clusters were identified with the majority of responders being in cluster 2 (12/12) and 3 (12/22). The predictive performance of the methylation signature was high with 80% sensitivity, 81% specificity, and an AUC of 0.853. Conclusions: Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICIs in patients with metastatic melanoma.
Exploring the clinical significance of specific immune-related adverse events (irAE) in patients with melanoma undergoing immune checkpoint inhibitor (ICI) therapy.
Authors: Asher Nethanel , Bar-Hai Neta , Ben-betzalel Guy , Stoff Ronen , Grynberg Shirly , Schachter Jacob , Shapira-Frommer Ronnie 
Published: June 2023

9566 Background: Several studies have demonstrated that patients who experience irAE as a result of ICI treatment, exhibit significantly improved outcomes compared to patients without toxicity. However, data regarding the impact of specific irAE is currently lacking. Methods: This is a real world single-site cohort of advanced melanoma patients who were treated with ICI as first line between 2014 and 2020. This study explores the effects of specific irAE on treatment efficacy. Results: Three hundred and ninety-five (395) patients were treated with either monotherapy anti PD-1 (65.4%), combination ICI (24.3%), or anti CTLA-4 (10.3%). Median age was 68 years (12-99y), and 57% were male. The median follow up was 24.5m. Any-grade irAEs were seen in 72% (n = 299), and 26% experienced high-grade irAE (n = 104). The most frequent irAE were dermatologic (n = 110, 27.8%), vitiligo (n = 48, 12.1%), rheumatologic (n = 68, 17.2%), gastro-intestinal (n = 66, 16.7%), and endocrine (n = 61, 15.4%). The development of irAE was associated with a significantly longer median PFS (19.3m vs 4.5m; HR 0.46, p < 0.001) and median OS (55m vs 16.9m; HR 0.44, p < 0.001). Specific irAE that were significantly associated with survival benefic were rheumatologic (HR 0.34 for PFS, p < 0.001; HR 0.38 for OS, p < 0.001), dermatologic (HR 0.58 for PFS, p < 0.001; HR 0.54 for OS, p = 0.001), vitiligo (HR 0.30 for PFS, p < 0.001; HR 0.29 for OS, p < 0.001) and endocrine (HR 0.6 for PFS, p = 0.01; HR 0.52 for OS, p < 0.001). After adjustment for ECOG performance status, LDH level, type of ICI protocol and M-substage - the rheumatologic, dermatologic and vitiligo irAE remained significant on multivariate analysis for both PFS and OS. Conclusions: The development of rheumatologic, vitiligo and other dermatologic irAE during ICI treatment, is correlated with a noteworthy survival advantage. These irAE may reflect a hyper-activated immune response and thus can serve as meaningful clinical biomarkers.
NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma.
Authors: Ascierto Paolo Antonio , Bossi Paolo , Mandalà Mario , Queirolo Paola , Spagnolo Francesco , Bassetto Franco , Rampinelli Vittorio , Giovacchini Francesco , Pennacchioli Elisabetta , Caraco Corrado , Parrinello Gianpiero , Mallardo Domenico , Giannarelli Diana , Trojaniello Claudia , Massi Daniela , Chiarion-Sileni Vanna 
Published: June 2023

9576 Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( < 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .