bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of metastatic melanoma following immune checkpoint inhibitor treatment by tumor infiltrating lymphocyte of primary cutaneous site.
Authors: Hegde Upendra P. , Holmes Aaron N. , Stevenson Christina Elizabeth , Masternak Sophie , Bethany Cucka 
Published: May 2020

e22005 Background: TIL include antigen specific clonal T cells responding to tumor antigens (TA) in the tumor microenvironment. Biological relevance of TIL at the PCM following ICI treatment of MM is not clear. Since there is overlap of TA between primary and its metastasis, we hypothesized that TIL at PCM site may serve as a biomarker of response to ICI treatment of MM. Methods: We did a retrospective analysis of MM patients (pts.) receiving ICI treatment between 2012 and 2019 following an IRB approved protocol. Response and survival at 12, 24 and 36 months (mths) was correlated with PCM site TIL. Pts. who received at least one dose of ICI for MM were eligible and those with metastasis from unknown PCM, received anti-BRAF treatment or lacked information on TIL at PCM were excluded. Pts. were stratified as group (gr.) A, B and C representing brisk, non-brisk and absent TIL respectively. Responses defined by RECIST criteria (response, no response, stable disease) as well as overall survival calculated from time of initiation of ICI to death from any cause (OS) at 12, 24 and 36 mths was correlated to TIL at PCM. Results: 42 pts. received ICI for MM between 2012-2019 meeting the eligibility criteria. Median age is 68 years (yrs.) (63, 71 and 73 yr. respectively for group A, B and C), 27 male, 15 women. The median thickness of PCM was 3.5, 3.75 and 4.75 mm in group A, B and C respectively. 11 of 14, 9 of 16 and O of 12 pts. responded to ICI while 2, 5, 14 and 1,2, 0 patients showed no response and stable disease respectively. O.S. at 12, 24, and 36 mths. was 12/14, 11/16 and 1/12 pts.; 10/14, 7/16, 0/12 pts. and 8/14, 6/16 and 0/12 pts. respectively in three groups. Conclusions: Brisk and absent TIL correlated with favorable and unfavorable response to ICI treatment of MM while non-brisk TIL showed intermediate outcomes. Larger data set could help validate our findings.
The relationship between tumor-infiltrating lymphocytes, PD-L1 expression, and clinical outcomes of Asian melanoma patients treated with anti-PD-1 antibody.
Authors: Lee Soo Jung , Chae Yee Soo , Kim Jong Gwang , Kang Byung Woog , Baek Jin Ho , Choi Hyeokjin , Lee In Hee , Jeong Ji Yun 
Published: May 2020

e22010 Background: Clinical feature of Asian melanoma patients are distinct from those of Western patients. Acral and mucosal melanomas, which are common in Asian populations, predominantly occur in sun-protected areas. Immune-checkpoint inhibitors are standard treatment for inoperable melanoma, however, they are less effective against acral and mucosal melanomas. The aim of our study is to investigate the expression, clinical significance and association of programmed death-ligand 1 (PD-L1) with tumor-infiltrating lymphocytes (TIL) in Asian melanoma patient treated with anti-PD-1 therapy. Methods: Patients with unresectable stage III or metastatic stage IV melanoma who began anti-PD-1 antibody therapy between February 2016 and September 2018 were enrolled. Immunohistochemistry was used to evaluate PD-L1 expression and stromal CD8+ TIL, and PD-1+ TIL densities within the intratumoral regions and associated stromal regions. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes. Results: Of the 57 cases, the most common type was acral melanoma (n = 28, 49.1%) followed by mucosal melanoma (n = 19, 33.3%) and cutaneous (n = 10, 17.5%). The overall response was 8.8 % and disease control rate was 33.3%. The median progression-free survival (PFS) was 18.0 months (95% confidence interval, 12.57 to 23.43), and there was no difference in PFS according to subtypes. Overall, 29.8% (n = 17) showed PD-L1 expression in tumor cells and 26.3% in immune cells. PD-L1, CD8+TIL, LDH and BRAFV600 statues were not associated with response or survival. NLR (≥ 5) were independent poor prognostic factors by multivariate analysis. Conclusions: In our study, anti-PD-1 therapy showed less effective compared to western patients. High NLR (≥ 5) could predict response of anti-PD-1 therapy in patients with Asian melanoma. Considering the differences in genetic backgrounds and therapeutic efficacy of immunotherapy, specialized therapeutic strategies for Asian melanoma should be established.
Adjuvant systemic therapies for melanoma in Alberta: An early descriptive analysis of population characteristics and treatment outcomes.
Authors: Rigo Rodrigo , Koczka Kim , Batra Atul , Cheung Winson Y. , Monzon Jose Gerard , Cheng Tina 
Published: May 2020

e22013 Background: Adjuvant immunotherapies and adjuvant targeted therapy for melanoma became available in clinical practice in 2018 in Alberta, Canada. We describe the delivery of adjuvant systemic therapy, local-regional treatment, recurrence patterns, and treatment toxicity, in tertiary academic centers. Methods: We conducted a retrospective chart review of patients who received adjuvant systemic therapy for melanoma in Alberta. Adjuvant systemic treatment options included Nivolumab, Pembrolizumab, and Dabrafenib/Trametinib. Results: From September 2017 to January 2020, 71 patients were identified. Forty-one (61%) were male with a median age of 60 years (15-88). Seven (9.8%), 26 (36.6%), 27 (38%), 4 (5.6%), and 3 (4.2%) patients were stage IIIA, IIIB, IIIC, III-unspecified, and IV, respectively. BRAF mutations were detected in 31 (50.8%) patients. The median time from last surgical procedure to start of treatment was 10.8 weeks (4-28), with a median follow up time of 12 months. Sixty-one patients (85.9%) received Nivolumab, four (5.6%) patients received Pembrolizumab, and four (5.6%) Dabrafenib/Tremetinib. Twenty-eight (87.5%) of 32 patients with a positive sentinel lymph node biopsy did not complete elective regional lymph node dissection. Only two patients received adjuvant radiation. Local-regional surveillance with regular nodal ultrasound was not consistently performed. Seven (9.8%) patients had clinical or radiographic finding of enlarged regional lymph node while on treatment. At time of analysis, thirteen (18.3%) patients have completed adjuvant therapy, 18 (25.3%) discontinued therapy, and 39 (54.9%) patients were still on treatment. Eleven (15.4%) patients discontinued treatment due to toxicity, 8 (13.1%) from Nivolumab, 3 (75%) from Dabrafenib/Trametinib. Nine (12.6%) patients relapsed on treatment, of those, five (55.5%) had incidental findings on baseline imaging. Hypothyroidism affected 11 (15.4%) patients, hypophysitis and other immune-related side effects were described in 14 (19.7%) cases. Conclusions: Our cohort reflects excellent patient selection and delivery of adjuvant therapy consistent with clinical trial data. Surgical and radiation oncology care has adapted, and differs from trial procedure. Adjuvant immunotherapy was used in most patients. There appears to be a higher rate of discontinuation due to toxicity with Dabrafenib/Trametinib. Toxicity and recurrence findings are preliminary and will be updated.
Multiomics profiling of longitudinal melanoma specimens unravels molecular mechanisms of resistance to sequential targeted and cancer immunotherapies.
Authors: Lee Jinho , Labrie Marilyne , Yong Gen , Camp Todd , Ma Hongli , Grout Megan , Xu Wei , Beasley Georgia , Schuchter Lynn Mara , McGettigan Suzanne , O'Rourke Donald M. , Herlyn Meenhard , Corless Christopher L. , Mills Gordon B. , Zhang Gao 
Published: May 2020

e22015 Background: We evaluated spatially-resolved protein profiling of longitudinal tumor specimens derived from two patients with metastatic melanoma who progressed on sequential therapies including targeted therapy (TT) and immune checkpoint blockade (ICB) therapy targeting T cell-surface antigens (CTLA-4 and PD-1). The purpose of this study was to identify molecular determinants of resistance to sequential TT and ICB therapies. Methods: We performed multiplexed and multidimensional spatial protein profiling using NanoString’s GeoMx Digital Spatial Profiling (DSP) platform and single-cell level imaging analysis with Cyclic Immunofluorescence (CycIF) to simultaneously determine dynamic changes in tumor intrinsic signaling pathways and immune response in the tumor microenvironment (TME). Results: The first patient presented with a BRAFV600E-positive brain metastasis. This patient was sequentially treated with ipilimumab (Ipi), the combination of dabrafenib and trametinib, and pembrolizumab (Pembro) and progressed despite of high expression of CD56 NK cell after all treatments. In addition, CycIF analysis revealed drug resistance in a subpopulation of cells that had continued activation of mTOR (pS6) and EGFR pathways. The second patient presented with dermal metastases on the flank with NRASQ61K mutation. This patient was sequentially treated with Pembo, Talimogene Laherparepvec, the combination of Ipi plus nivolumab, and two different investigational agents combined with Pembro. This patient displayed stable disease (SD) on Pembro but eventually progressed on the subsequent therapies. DSP analysis demonstrated CD68/CD40 myeloid cell infiltrates as well as HLA-DR and CD44 in the TME after the last treatment. CycIF analysis revealed dynamic changes in tumoral characteristics including DNA damage and proliferation during treatment. Furthermore, the analysis suggested that there might be a resistant subpopulation in the last tumor biopsy, which is in line with progression of the disease. Conclusions: In this study, we conducted detailed analyses on serial specimens from two patients to precisely define the spatial distribution of immune responses and cancer signaling pathways. The findings propose that concurrent proteomics analysis and immune monitoring of longitudinal tumor biopsies can be informative in clinical evaluation in order to identify salvage therapies to overcome drug resistance.
Salvage chemotherapy in the treatment of metastatic melanoma after progression on immunotherapy.
Authors: Shah Payal , Boland Patrick , Pavlick Anna C. 
Published: May 2020

e22019 Background: Immune-checkpoint inhibitors (ICI) have dramatically altered the prognosis of metastatic melanoma (MM); however, fifty percent of patients will not respond to ICI. For these patients, the next choice of treatment includes targeted therapy or a clinical trial if eligible. If these treatment choices have already been utilized or are not available to the patient, there may be value in attempting a course of salvage chemotherapy (CTX). Limited clinical trial evidence has demonstrated unexpected efficacy of CTX after prior progression on ipilimumab, offering higher disease control rates than expected from what is seen in first-line chemotherapy. The phenomenon of a “priming” effect of ICI on CTX efficacy has been shown in patients of various solid tumors after progression on anti-PD1/PD-L1 therapy. The purpose of this retrospective analysis is to evaluate the efficacy of salvage CTX after prior ICI therapy for patients with MM. Patients with ocular melanoma were excluded, as this tumor subtype is known to have reduced response to immunotherapy. Methods: By retrospective analysis, patients were included under an IRB approved waiver of consent. We identified patients with MM treated with ICI therapy between Jan, 2011 and July, 2019 who were subsequently treated with salvage CTX as a result of progression of disease (POD). Salvage CTX included dacarbazine, carboplatin, temozolomide, paclitaxel, or a combination. We assessed response rate, duration of response, and time to progression (TTP) from the onset of salvage CTX. Results: A total of 22 patients who satisfied the above criteria were identified. The majority of this population had a course of single agent ICI as well as a course of combination ICI prior to salvage CTX (72.7%, n = 16/22). 13 (59.1%) patients had POD on salvage CTX with a median TTP of 10.9 weeks. 9 (40.9%) patients responded to salvage CTX. 3 (13.6%) patients achieved a complete response, 4 (18.2%) patients achieved a partial response and 2 (9.1%) patients achieved stable disease. Mean durability of response was 53.6 weeks, ranging from 7-194 weeks. Conclusions: ICI “priming” prior to salvage CTX efficacy may improve disease responsiveness to CTX. This sequence of therapy may offer patients another reasonable treatment option. Despite the small sample size of this study, a prospective clinical trial in MM exploring CTX following ICI progression should be considered.
Patterns of disease presentation, treatment choices and survival in real world for patients diagnosed with advanced melanoma: A prospective observational study by Spanish Melanoma Group (GEM-1801).
Authors: Marquez-Rodas Ivan , Berciano Guerrero Miguel Ángel , Muñoz-Couselo Eva , Manzano Mozo Jose Luis , CEREZUELA Fuentes Pablo , Crespo Guillermo , Puértolas Teresa , Berrocal Alfonso , Soria Ainara , Majem Margarita , Bellido Lorena , Espinosa Enrique , García Castaño Almudena , Gutierrez Sanz Lourdes , Medina Javier , Fernandez-Morales Luis Antonio , Aguado De La Rosa Carlos , López Castro Rafael , Ayala de Miguel Pablo , Martin-Algarra Salvador ,   Spanish Melanoma Group
Published: May 2020

e22022 Background: In the past decade, melanoma treatment has improved due to the advances in targeted therapy and immunotherapy. There are few data, however, about the treatment elections and the outcomes of the patients in the real world setting, specifically in a prospective manner. Methods: GEM1801 is a prospective cohort study that analyses the clinical and pathological disease presentation patterns, the different lines of treatment choices and the health outcomes derived from these treatments in 400 patients (pts) diagnosed with resected stage III (N = 47) and irresectable III/IV melanoma (N = 353). Here we focus on the pts diagnosed with advanced melanoma and the first line (1L) treatments. Results: Pts diagnosed after Jan 2018 were included from 35 hospitals in 15 different Spanish regions (recruitment Aug 2018 to Aug 2019). A survival cutoff was made by January 2020. 55.2% pts were male; median age was 65.1 (23.3- 95.2). 66% were cutaneous, 5.4% acral, 2.8% uveal, 17.3% non-disclosed and 4.2% were classified as “other” subtypes. According to AJCC 8th edition, 9.3% were unresectable IIIB/C/D and 90.7% IV (27.5% A, 16.6% B, 37.5% C and 18.4% D). ECOG was 0-1 in 85%; LDH levels were available in 282 pts (79.9%), being normal in 61.7%, > 1x to 2x ULN in 29.8% and > 2x ULN in 8.5%. BRAF was evaluated in 344 pts (97.5%), being 52.9% mutated. Median survival follow up was 9.7 months (0.2-24) with 73.9% patients alive at time of analysis (over 345 pts with data available). Median overall survival was not reached, with a median follow up of 9.7 months (0.2-24.0). 72.2% of pts were alive at the time of analysis. Table summarize the 1L options according to BRAF status in the 326 pts with data available (17 received no systemic treatment and in 10 was unknown). Conclusions: this study reflects real world data in a representative cohort of pts with melanoma in Spain. Survival results, pending on more follow up, could be considered consistent with the results of modern clinical trials. TT is the most frequent 1L choice for patients with BRAF+ melanoma (almost 2/3 of cases). In terms of IT, monotherapy based in anti PD-1 is the most frequent 1L choice, with a rank between 75-90% of cases. [Table: see text]
Real-world patterns of molecular testing in advanced melanoma (advMel): adherence to guidelines.
Authors: Olszanski Anthony J. , Farma Jeffrey M. 
Published: May 2020

e22031 Background: National guidelines (eg, NCCN and ESMO) recommend BRAF mutation testing to inform treatment (tx) decisions in high-risk stage III or IV cutaneous melanoma, but few studies have evaluated its implementation in a real-world setting. Here we report the testing patterns for BRAF and other mutations in advMel via an electronic health record (EHR)–derived database, to assess guideline adherence and implications for patient (pt) care. Methods: This retrospective observational study used Flatiron Health’s nationwide longitudinal database comprising de-identified EHR structured and unstructured data, curated via technology-enabled abstraction. Pts with stage III or IV cutaneous melanoma at initial diagnosis, or a locoregional or distant recurrence, with ≥ 2 clinic encounters starting January 1, 2011 were included in the advMel cohort. Data through October 2019 were analyzed. Results: A total of 9333 pts from 160 US cancer clinics were in the advMel cohort. Overall, 21% of pts had no evidence of BRAF testing. In the adjuvant setting, the percentage of pts with known BRAF status before initiation of systemic tx increased from 34% prior to the year 2018 to 56% post approval of adjuvant targeted tx in 2018. The rate of known BRAF status before initiation of first line (1L) metastatic tx declined from 80% in 2012 to 62% in 2018. Notably, within 30 days after tx initiation, BRAF status was reported in an additional 17% of pts in 1L metastatic setting. Next-generation sequencing (NGS) overtook polymerase chain reaction (PCR) as the most common assay (40% NGS vs 22% PCR in 2018, whilst 8% vs 53% in 2012). Of the 35-day (NGS) or 27-day (PCR) median turnaround time from sample collection to results, 21-25 days occurred from specimen collection to receipt in the lab. Despite this turnaround time, 35% of pts with known BRAF status before tx initiation had NGS testing. Of all pts tested for BRAF, 30% were also tested for NRAS and 32% for KIT. Among pts with a BRAF mutation, concomitant NRAS (1.1%) or KIT (0.6%) mutation was rare. Conclusions: Our real-world analysis shows that BRAF mutation status is known in ≈60% of pts with advMel before initiation of adjuvant or 1L metastatic tx. NGS and PCR are the most common testing platforms, with the use of NGS on the rise. Notably, a prolonged time was observed between collection and lab receipt of the specimen. These results indicate an opportunity for physicians to conduct earlier molecular testing at workup per the guidelines, and for improved logistical efficiency to facilitate timely receipt of genomic results to better inform individualized tx plans.
Bone metastasis as an independent prognostic factor for survival in patients with advanced melanoma treated with immune checkpoint blockade.
Authors: Teixeira Marcos Rezende , De Barros E Silva Milton Jos , Pandolfi Natasha Carvalho , Calsavara Vinicius Fernando , Oliveira Thiago Bueno , Tavares Monique Celeste , Rinck José Augusto , Garcia Daniel , Lima Joao Paulo SN , Duprat Joao 
Published: May 2020

e22045 Background: Immune checkpoint blockade (ICB) has changed the natural history advanced melanoma (AM) with response rates about 40% and overall survival in 5 years of more than 30%. Interestingly, the site of metastasis may have impact on immune response due to the quantity and quality of immune infiltrate as we have seen in patients (pts) with liver metastasis treated with ICB. We have hypothesized that bone metastasis(BM) represents an immune less responsive site of disease Methods: We conducted a retrospective observational analysis of patients with AM treated with ICB at A.C. Camargo Cancer Center (AC) in São Paulo, Brazil. We analyze the impact of BM on progression-free (PFS) and overall survival (OS) using Kaplan Meier method, log-rank test and time-dependent COX regression model. Results: We analyzed 170 pts with AM treated with anti-PD1 (79%) or anti-PD1 + anti-CTLA4 (21%) between September 2013 and December 2019. Fifty-five percent in first-line, 22.4% second-line and the remaining in third or more lines of therapy. Ninety- four were male (55.3%), median age of 60.5 years (24.8 to 88.3) and 61 (35.9%) pts had BRAF mutation. Among stage IV patients (94%), 52 (32.4%) were M1c, 36 (22.4%) M1d and 46 (27%) had elevated LDH. Forty-two (26%) pts had BM. The overall response rate was 30.9% for pts with BM compared to 57.7% for pts without BM (p:0.004). In a median follow-up of 23.6 months (95% CI: 18.0-29.1), the median PFS and OS for pts with and without BM were 3.8 x 18.8 months (p 0.005) and 19.4months x not achieved (p 0.001), respectively. The 24-month analysis shows an overall survival rate of 38% for patients with BM compared to 62% for the rest of the cohort population. In a multivariate analysis for overall survival, acral melanoma, elevated LDH, ECOG performance status of 1 or 2 and BM were independent adverse prognostic factors (bone metastasis - HR: 2.3; 95%CI: 1.18-4.1; p:0.013). Conclusions: In this analysis, the presence of bone disease seems to be a worse independent prognostic factor for survival. A hypothesis would be the unfavorable bone microenvironment for the action of the immunotherapy.
Effect of administration of systemic steroids on survival benefit associated with immunotherapy-induced skin toxicity.
Authors: Gulati Nicholas , Donnelly Douglas M. , Qian Yingzhi , Moran Una , Johannet Paul , Pavlick Anna C. , Zhong Judy , Osman Iman 
Published: May 2020

e22046 Background: Immune checkpoint inhibition (ICI) improves progression-free survival (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but treatment may cause serious immune-related adverse events (irAEs) that require the use of immunosuppressive steroids. Skin toxicity (ST), the most common side effect, has been reported to be associated with better response to ICI in some studies but not others. Herein, we tested the hypothesis that the portended survival benefit associated with ICI-related ST reaches a threshold in MM patients, dependent on the severity of the ST. Methods: We analyzed MM patients enrolled prospectively in a clinicopathological database with protocol-driven follow up and treated with ICI at NYULH. The patient and/or physician reported the ST, and an immunologist-dermatologist independently confirmed the event was ICI-related. Severe ST was defined as a skin event that required treatment with systemic steroids. Other site-specific toxicities were recorded using the CTCAE v5.0. We tested the associations between ST and PFS and OS, stratified by no, mild, and severe ST, adjusting for age, gender, number of metastatic sites, LDH, and ECOG score at treatment initiation. Results: The cohort included 256 MM patients (387 lines of ICI treatments). ST was the most common irAE (34%), and was significantly associated with development of endocrine toxicity (P = 0.007). Of the ST events (n = 130), 66% were mild and 34% were severe. Compared to none, mild ST was significantly associated with improved PFS (adjusted hazard ratio [aHR] = 0.58 [0.38, 0.89], P = 0.01), and a similar trend was observed with OS (aHR = 0.68 [0.45, 1.03], P = 0.06). However, the positive effect was reduced to insignificant (PFS P = 0.53; OS P = 0.25) in patients who developed severe ST irAEs that required systemic steroids. Conclusions: Our data demonstrate that ICI-induced ST is a complex phenomenon and might explain the discordance of reported data. While the worse outcome in patients with severe ST compared to mild may stem from steroidal immunosuppression, a threshold may also exist wherein severe ST itself might contribute to a relative reduction in ICI efficacy. More research is needed to elucidate the mechanisms that link ST and response to ICI in order to better characterize and treat skin irAEs without systemically suppressing anti-tumor immunity.