bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitors in cutaneous squamous cell carcinoma: A systematic review of clinical trials.
Authors: Anwar Muhammad Yasir , Aiman Wajeeha , Ali Muhammad Ashar , Dhanesar Gurneel , Zafar Maha , Omar Zainab , Afzal Fatima , Guron Gunwant K. , Shaaban Hamid Salim , Maroules Michael 
Published: June 2023

e21529 Background: Cutaneous squamous cell carcinoma (cSCC) with high-risk features is primarily treated with radiations or surgically. However, locally advanced (LA) or metastatic cSCC (mcSCC) may not be managed surgically and require systemic therapy. In this systematic review, we will assess the efficacy of immune checkpoint inhibitors (ICIs) in patients with resectable, LA, or mcSCC. Methods: A literature search was performed on PubMed, Embase, and clinicaltrials.gov with keywords, “cutaneous squamous cell carcinoma” and “immune checkpoint inhibitor” from the inception of data till 12/31/22. After screening of 883 articles, 8 clinical trials (N = 513) were included. Results: In 8 clinical trials (N = 513), 205 patients had LA cSCC, 99 patients had resectable cSCC, and 209 patients had mcSCC. 81 patients were newly diagnosed while 432 patients were relapsed/refractory (RR). Cemiplimab was used to treat 262 patients, pembrolizumab for 227 patients, and nivolumab for 24 patients. In 2 clinical trials (N = 142) on RR LA cSCC, complete response (CR), partial response (PR), overall response (OR), and progressive disease (PD) were 13-17%, 31-33%, 44-50%, and 12-17%, respectively, in patients treated with ICIs. In 3 clinical trials (N = 175) on RR mcSCC, CR, PR, OR, and PD were 7-18%, 25-41%, 36-64%, and 16-26%, respectively. In two clinical trials (N = 81) on ND cSCC patients, CR, PR, OR, and PD were 0-7%, 35-58%, 42-58%, and 32-20%, respectively. In 2 clinical trials (N = 99) on resectable cSCC, pathological CR, pathological major response, and PD were 51-75%, 13-20%, and 10%, respectively, in patients treated with ICIs. Table. Conclusions: ICIs including cemiplimab, pembrolizumab, and nivolumab were effective in the treatment of resectable, LA, and mcSCC. ICIs were effective in the treatment of both R/R and treatment naïve mcSCC. However, no results were available for randomized clinical trials and large-scale randomized studies are needed to confirm these results. [Table: see text]
Real-world efficacy and safety data of anti-PD-1 plus anti-CTLA-4 combination therapy in Chinese patients with advanced melanoma.
Authors: Wen Xizhi , Zhang Xiaoshi , Ding Ya , Li Dandan , Li Jingjing 
Published: June 2023

e21530 Background: Combination of anti-PD-1 plus anti-CTLA-4 has shown superior efficacy over monotherapy in advanced melanoma among Caucasian populations. However, it has not been evaluated in Chinese patients, and data on acral and mucosal melanoma are limited. We aimed to assess the efficacy and safety of anti-PD-1 antibody plus ipilimumab therapy in Chinese patients with advanced melanoma in clinical practice. Methods: Advanced melanoma patients treated with anti-PD-1 antibody combined with ipilimumab in Sun-Yat sen University Cancer Center from May 2015 to October 2022 were retrospectively assessed. Patient baseline characteristics, tumor responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity was assessed to estimate safety. Results: Altogether, 86 patients were included. The primary site was cutaneous, acral, mucosal, uveal and central nervous system (CNS) in 34, 21, 20, six and five patients, respectively. Among them, 21 patients were treatment-naive, 65 patients were previously treated, and 54 patients progressed of front-line ani-PD-1 therapy. 12 patients received ipilimumab 3mg/kg combined with low dose anti-PD-1 (Nivolumab 80mg or Pembrolizumab 1mg/kg) Q3w for four doses, and the other 74 patients received standard dose of anti-PD-1 plus ipilimumab 1mg/kg Q3w therapy. There were 25(29%) patients with liver metastasis and 26(30.2%) patients with CNS metastasis at baseline. The overall response rate (ORR) was 15.1% in the whole cohort, with complete response observed in six (6%) patients, partial response in 7 (8.1%), stable disease in 28 (32.6%). The response rate in the treatment-naive and prior systemic therapy group was 23.8% and 12.3%, respectively. For those treated with anti-PD-1 followed by the anti-PD-1+ ipilimumab as subsequent therapy after disease progression, the ORR was 11.1%. The response rate for cutaneous melanoma was 23.5%, and 37.5% in the naïve group. Response rates for acral, uveal, CNS and mucosal melanoma were 19.0%, 16.7%,0% and 0% respectively. The median progression-free survival (PFS) and overall survival (OS) in all patients was 4.5 (3.6-5.4) months and 22.0 (12.4-31.6) months, respectively. The 3-year OS were 100% in patients who achieved ORR. There were no significant differences in PFS or OS for patients with cutaneous or acral melanoma. mucosal primary tumor type, liver metastasis and elevated LDH were predictive of shorter PFS and OS. CNS metastasis, previous treatment, BRAF/NRAS mutation status and sex were not found to be related to survival. Adverse events occurred in 71% of patients and 13% were grade 3 or worse. Conclusions: The efficacy of anti-PD-1+ ipilimumab combination therapy in Chinese patients tended to be inferior compared to global studies but was well tolerated. OS were good in cases with CR or PR.
Neoadjuvant versus adjuvant therapy in patients with stage III or IV resectable melanoma: A systematic review and meta-analysis.
Authors: Madeira Thiago , Vilbert Maysa , Priantti Jonathan N , Moraes Francisco Cezar A , Koch Hein Erica C. , Ribeiro Mauricio Fernando , Cavalcante Ludimila , Lawson David H. 
Published: June 2023

e21542 Background: Neoadjuvant therapy (NAT) has emerged as a promising strategy to treat resectable melanoma patients by generating a robust immune response and longer immunologic memory. We performed a systematic review and meta-analysis evaluating the survival benefit of NAT compared to standard adjuvant therapy (AT) for melanoma patients. Methods: We searched for randomized clinical trials (RCT) comparing NAT versus AT in resectable stages IIIB/C or IV melanoma patients on PubMed, Scopus, and Cochrane Library databases. We assessed event-free survival (EFS), distant metastasis-free survival (DMFS), overall survival (OS), and safety. Studies included were limited to RCTs with an adjuvant control arm and reporting at least one of the outcomes of interest. Heterogeneity was examined with the I2 statistics, and the random effects model was fitted. Results: Four RCTs met inclusion criteria for a total of 504 patients. Most patients had stage IIIB/C (79.1%), and received NAT with immunotherapy (66%), target therapy (4.2%) and talimogene laherparepvec (TVEC) (29.8%). In the pooled analysis of 2-year follow-up: 71.3% of patients in the NAT arm and 53.2% in AT arm were event-free [Risk Ratio (RR): 0.57 95%Cl 0.39-0.83 p=0.003]. Albeit the difference in therapies, NAT decreased by 44% the risk of death compared to AT, with 89.4% and 81.2% of patients alive at two years, respectively (RR 0.56 95%Cl 0.36-0.87 p=0.01). DMFS was reported in three studies (n=191). Patients on NAT had numerically higher DMFS rate (44%) compared to AT (28.6%) (p=0.23). Two studies (n=170) have published 5-year follow-up results: OS rate has remained statistically significant, favoring NAT (RR 0.58 95%Cl 0.34-0.97 p=0.04). Significant differences were not observed in EFS (p=0.06) and DMFS (p=0.08). Adverse events were similar in both groups, and there were no treatment-related deaths. In these studies, there were no significant delays in surgery due to toxicity or unexpected perioperative complications. Combined immunotherapy caused the highest incidence of grade 3/4 toxicity (90%) among the therapies. Conclusions: This systematic review and meta-analysis indicate a significant survival benefit from NAT for stages IIIB/C and resectable stage IV melanoma. NAT induces better anti-tumor activity, leading to improved EFS and OS compared to AT, with similar safety profile. Phase 3 clinical trials with longer follow-up are warranted. [Table: see text]
Assessment of HER2 status in extramammary Paget disease and its implication for disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC) therapy.
Authors: Si Lu , Jia Jia , Mao Lili , Lin Jing , Yuan Pei , Li Wen Yu , Dai Jie , Li Zhong-Wu , Bai Xue , Li Caili , Guo Lei , Chen Yu , Ying Jianming , Guo Jun 
Published: June 2023

e21544 Background: Evaluation of HER2 status in extramammary Paget disease (EMPD) has been reported in a few studies with a small number of samples, and the HER2 overexpression rate ranges from 15% to 60%. The prognosis of advanced EMPD is poor and the treatment options is limited. Disitamab Vedotin (DV) is a novel humanized anti-HER2 antibody-drug conjugate (ADC), has been approved for metastatic urothelial carcinoma and gastric cancer in China. To determine the HER2 status and the efficacy of DV in advanced EMPD patients (pts) harboring HER2 expression, we conducted this multicenter retrospective study. Methods: Paraffin-embedded blocks, clinic-pathological data, and survival data of EMPD pts were retrospectively collected from 3 centers in China. HER2 IHC scoring and gene amplification evaluation were carried out according to the (ASCO/CAP) 2018 guidelines. The results of FISH and IHC were analyzed by two pathologists independently in a double-blinded manner. Data analysis was performed using SPSS v.26, Prism 8 and R version 3.6.5. Results: Finally, 129 cases with detailed data were enrolled between 2006 and 2022. Among them, HER2 IHC was performed in 102 cases, and FISH in 46 cases. HER2 expression was detected in 93.1% samples, with scores of 1+, 2+, and 3+ in 47.1% (48/102), 37.3% (38/102), and 8.7% (9/102) respectively. HER2 gene amplification was detected in eight cases (8/46, 17.4%), including all the cases with IHC 3+ (5/5, 100%), two with IHC 2+ (2/18, 11.1%), and one with IHC 1+ (1/22, 4.5%). For the subgroup of HER2 2+/3+, a higher frequency of lymph node metastasis (66.7% vs 33.3%, P = 0.034) and reduced survival time were detected than in HER2 1+/0. Two elderly male pts with advanced EMPD (one HER1+ /FISH-, one HER 2+/FISH-), who failed with chemo of paclitaxel, received 4 doses of DV infusion (2mg/kg every 2 weeks), and achieved partial responses both with tolerable toxicity. Conclusions: According to the study, the expression rate of HER-2 was very high in EMPD, indicating that it may be used as a routine treatment target. DV showed efficacy in these patients and need further validation.
Factors associated with overall survival in patients with melanoma leptomeningeal disease (M-LMD): A single institution retrospective review.
Authors: Nyman Karl , Kundalia Ronak , Ospina Oscar , Wallace Gerald Carter , Pina Yolanda , Smalley Inna , Forsyth Peter A. J. 
Published: June 2023

e21548 Background: Leptomeningeal disease (LMD) is characterized by tumor metastasis to the membranes and cerebrospinal fluid (CSF) surrounding the brain and spinal cord. This devastating complication confers a poor overall survival (OS) measured in weeks for untreated patients. Melanoma has one of the highest rates of dissemination to the leptomeninges. The advances in targeted and immune therapies have revolutionized OS for patients with melanoma systemic metastases and there is a growing number of individual case reports showing clinical responses to these agents in patients with melanoma-LMD (M-LMD) . However, few studies have examined the association between these and other therapies with the OS of a large cohort of melanoma-LMD (M-LMD) patients. Methods: M-LMD patients treated at Moffitt Cancer Center between 2011 and 2020 were retrospectively identified. M-LMD diagnosis was confirmed radiographically via magnetic resonance imaging (MRI) and/or positive CSF cytology indicating the presence of malignant cells. Demographic data and pre/post LMD diagnosis treatment data were collected and analyzed using the Kaplan-Meier method to determine factors that improve OS. Results: 86 M-LMD patients were identified. 50 were male and 36 were female, but patient gender did not have an impact on OS. 53 patients were diagnosed via MRI only and 33 patients had positive CSF cytology confirming M-LMD diagnosis. 34 patients did not receive any treatment post-LMD diagnosis and had a median OS of 3.72 weeks, while 52 patients receiving treatment (i.e. systemic, intrathecal [IT], and/or whole brain radiation therapy [WBRT]) had a median OS of 10.80 weeks (p < 0.0001). More specifically, 30 patients receiving targeted BRAF/MEKi treatment had an 18.8 week median OS compared to 6.68 weeks for the 56 patients who did not receive such treatments (p = 0.0015). Furthermore, 44 patients received immune therapy and had a median OS of 12.00 weeks compared to 5.88 weeks for those who did not (p = 0.002). The 16 Patients that received IT chemotherapy had a prolonged median OS when compared to the 70 patients who did not (9.72 weeks vs 4.72 weeks, p = 0.009). Furthermore, WBRT also improved median OS in the 22 patients that received the therapy (15.72 weeks vs 7.88 weeks, p = 0.0007). The 36 patients that received BRAF/MEKi treatment prior to their LMD diagnosis had a slightly shorter OS (7.00 weeks) compared to the 46 patients that did not receive such treatment beforehand (10.80 weeks, p = 0.005). Conclusions: The current data supports the use of systemic, IT, and radiation therapies to prolong OS for M-LMD patients; however, the OS for these patients remains grim despite advances in such therapies. Further research is necessary to understand the pathophysiology of LMD, and new clinical trials are urgently needed to identify novel therapies that improve M-LMD prognosis.
Long-term efficacy of BRAFi/MEKi rechallenge in metastatic melanoma: Report of 9 years of clinical practice.
Authors: Czarnecka Anna Malgorzata , Cybulska-Stopa Bozena , Plachta Iga , Rogala Pawel , Galus Łukasz , Piejko Karolina , Dziura Robert , Bal Wieslaw , Kubiatowski Tomasz , Teterycz Pawel , Wisniewska Magdalena , Zietek Marcin , Brandys Piotr , Kempa-Kamińska Natasza , Borkowska Aneta , Suwiński Rafał , Kamińska-Winciorek Grażyna , Mackiewicz Jacek , Rutkowski Piotr 
Published: June 2023

e21550 Background: First line BRAFi/MEKi therapy in metastatic melanoma eventually result in drug resistance and disease progression. Because drug resistance develops at least partially by epigenetic mechanisms, it may potentially be reversed after BRAFi/MEKi discontinuation. Therefore we aim to explore the clinical efficacy of BRAFi/MEKi rechallenge in 3 line treatment. Moreover the reports on the efficacy of BRAFi/MEKi after immunotherapy were contradictory, so we enrolled patients treated sequentially to explore this clinical scenario. Methods: In country-wide multicenter retrospective analysis 86 patients with metastatic BRAF-mutated melanoma were enrolled since 1/Jan/2014. Patients were treated with 1st line BRAFi/MEKi, 2nd line immunotherapy (anti-PD-1 or anti-CTLA-4) and were rechallenged with BRAFi/MEKi. Survival analyses were performed using the Kaplan-Meier method, log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2022. Results: Median age at BRAFi/MEKi rechallenge was 50 (range: 20-81 y/o). Median overall survival (OS) from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 34 and 9 months, respectively; whereas median progression-free survival (PFS) was 10.5 and 4.4 months respectively. At the time of analysis 88% progressed on third line therapy and 78% patients died. Six-month, one-year, and two-year OS rates were: 99%, 93% and 70% on first line treatment; and 65%, 40% and 2% on BRAFi/MEKi rechallenge. Objective response rate and disease control rate on first line BRAFi/MEKi and rechallenge were 57% and 28%; and 91% and 64%, respectively. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. The most common treatment sequence was dabrafenib/trametinib – immunotherapy – encorafenib/binimetinib. Conclusions: Rechallenge with BRAFi/MEKi after second line immunotherapy results in a clinically significant benefit in majority of eligible patients. Third line treatment should be considered for fit patients. [Table: see text]
Long-term outcomes of PD-1 blockade in metastatic or unresectable cutaneous squamous cell cancer.
Authors: Ali Shawn Ahmed , McGillivray Erin Elizabeth , Savage David James , Bollin Kathryn Blount , Swanson Mark , Kokot Niels , Hu Jenny , Ito Fumito , In Gino Kim 
Published: June 2023

e21551 Background: Cutaneous squamous cell carcinoma (CSCC) is the 2nd most common malignancy in the US. Approximately 10% of patients will experience either recurrent or metastatic disease, leading to worsened morbidity and mortality. In 2019, anti-PD1 therapy was FDA approved for metastatic or unresectable CSCC, and has been established as the standard frontline systemic therapy for this disease. Here we present our long-term, follow-up data investigating the efficacy, safety, and durability of PD-1 therapy for CSCC. Methods: This is a retrospective cohort study of metastatic or unresectable CSCC patients treated with PD-1 therapy at the University of Southern California Norris Comprehensive Cancer Center and the Scripps MD Anderson Cancer Center between June 2016 and January 2023. Patient demographics, tumor characteristics, and treatment related variables were collected. Objective response (ORR) was collected per RECIST criteria. Kaplan-Meier curves were used to estimate progression free survival (PFS) and overall survival (OS). For patients receiving salvage therapy post-PD1, progression free survival 2 (PFS2) and objective response rate 2 (ORR2) were also calculated. Toxicities were graded per CTCAE v5.0. Results: A total of 39 patients diagnosed with CSCC received at least one cycle of PD-1 therapy; among these 8 were excluded from efficacy analysis. Patients were on average 68 years old (range 22-97), predominantly male (69.2%) and Caucasian (74.4%). The most common primary tumor location was head/neck (64.1%), followed by extremity (15.4%). The mean tumor diameter was 6.0 cm (4.5-7.5, 95% CI). The majority of tumors were either moderately (33.3%) or poorly (28.2%) differentiated. The most common sites of metastatic disease included lymph node (41.0%), skin/soft tissue (33.3%) and bone (25.6%). Patients received on average 7 cycles of PD-1 therapy (range 1-26) and were followed for median 13.8 months. ORR for all patients was 39.0%, including CR and PR in 7 (22.6%) and 4 (13.0%) patients, respectively; 10 patients (32.2%) achieved stable disease (SD), while 7 patients (22.6%) had progression of disease (PD). Median PFS was 6.8 months, while OS was 26.7 months. Among 10 patients receiving salvage therapy after PD-1, 6 (60.0%) received a platinum-containing regimen. Median PFS2 was 4.4 months, while ORR2 was 10.0% with 1 PR, 4 SD, and 5 with PD. PD-1 therapy was well tolerated with 13 patients (33.3%) experiencing Grade 1-2 toxicity and 2 patients (5.2%) experiencing Grade 3-4. Conclusions: In this study of long-term outcomes of CSCC patients treated with PD-1 blockade, we found that initial responses to PD-1 therapy were durable, although PFS2 was less durable for patients who required salvage therapy and ORR2 was low. Novel treatment options are needed for patients with advanced CSCC who do not achieve durable responses to PD-1 based therapy.
Real-world experience of tebentafusp for uveal melanoma via an Australian access program.
Authors: Inderjeeth Andrisha Jade , Hurwitz Josh , Joshua Anthony M. , Kee Damien 
Published: June 2023

e21554 Background: Uveal melanoma (UM) is a rare melanoma subset, with distinct biology, genetics, and limited active therapies. Tebentafusp (tebe) has demonstrated a survival advantage however low response rates and a toxicity profile making real-world administration challenging. Methods: Data was retrospectively collected for patients (pt) enrolled into a tebentafusp access program at two tertiary Australian centres. Data fields included: baseline patient, disease and prior treatment characteristics; and tebe administration, response, toxicity and survival outcomes. Results: From May 2021 to February 2023, 19 pt received tebe for UM: 7 males, average age 61 years (range 39-86). All pt presented with local disease at diagnosis, with time to metastases greater than 12 months (mo) in 15/19. Prior to tebe, all patients had hepatic and 6/19 extra-hepatic metastases (6 bone, 4 lymph node, 2 peritoneal, 2 dermal and/or subcutaneous). Baseline PET scan demonstrated FDG-avid disease in 13/14. Primary disease treatment included enucleation (7/19) and radiotherapy 13/19). For advanced disease, prior systemic therapies included: none (12/19); anti-PD1 (3) or anti-CTLA4 (2) as monotherapy; or in combination (5); and anti-PD1 with anti-LAG3 (2). Prior to tebe baseline LDH was elevated in 10/19 (53%) and average neutrophil to lymphocyte ratio was 9.22 (range 0.9-49.5). The median time receiving tebe was 5.5 mo (range < 1-18). The median progression free survival (PFS) was < 3mo. 5 pt remain on tebe with 2 pt treated with tebe beyond 12 and 18mo duration. Best response obtained by PET or cross-sectional imaging was: a partial response in 4/19, stable/mixed in 4/19, progressive disease in 8/19, and unknown/not evaluable in 3/19. The majority of patients ceased tebe due to disease progression (10), change of therapy (4) or death (2). Only one patient ceased due to toxicity. At last review 14/19 (74%) patients were still alive and 4/19 had received one or more lines of systemic therapy after tebe including immunotherapy (1), targeted therapy (1) and/or clinical trials (4). Common adverse events included: rash (63%), hypotension (47%), pruritis (42%) and pyrexia (32%). Supportive measures were required (e.g. hydration, antihistamines, topical steroids) for 13 patients. Cytokine release syndrome (CRS) was reported in 63% (12/19) with only 3 demonstrating grade 2 severity. CRS management included oral (1) or intravenous steroids (2) and zero patients required additional immunosuppression. The median number of cycles administered as an inpatient was 3 (range 2-10). Conclusions: Within experienced tertiary centres tebe could be safely administered outside of a clinical trial setting. Median time on treatment greatly exceeds progression free survival, likely due to unique response characteristics and limited access to subsequent therapy. Identifying features that enrich for clinical benefit remain necessary for optimising tebe use.