bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired EGFR-resistant mutations in non–small cell lung cancer (NSCLC).
Authors: Raez Luis E. , Baca Yasmine , Nieva Jorge J. , Mamdani Hirva , Lopes Gilberto , Borghaei Hossein , Socinski Mark A. , Nabhan Chadi , Wozniak Antoinette J. , Vanderwalde Ari M. , Uribe Carlos Carracedo , Khan Hina , Liu Stephen V. , Nagasaka Misako 
Published: June 2022

9113 Background: EGFR mutations are present in more than 10% of patients (pts) with NSCLC in the US. While EGFR with tyrosine kinase inhibitors (TKIs) are effective, acquired resistance is expected. Known mechanisms include acquired EGFR mutations (e.g. 718V, c797x, 724s, 721s or T790M); copy number amplifications in MET, ERBB2, and PIK3CA; gene fusion events; and histological transformation. We herein present the prevalence of resistance mutations in the largest reported cohort of EGFR mutant NSCLC. Methods: Non-small cell lung cancer (NSCLC) tumor samples were submitted to Caris Life Sciences (Phoenix, AZ) for NextGen Sequencing (NextSeq, 592 Genes) and whole exome sequencing (NovaSeq, WES). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff >1). TMB was measured by totaling somatic mutations (TMB-high cut-off > 10 mutations per MB), genomic loss of heterozygosity (gLOH) was determined by WES. Patient treatment information was obtained from insurance claims data. Results: A total of 27,848 NSCLC tumors were evaluated and 3,223 (12%) had a EGFR sensitizing mutations. We found 60 tumors with common missense resistance mutations: 790 (n = 30, 0.9%), 797 (n = 38, 1.2 %), 718 (n = 11, 0.3%), 724 (n = 7, 0.2%) and 721 (n = 4, 0.1). Table 1 describes the frequencies, PD-L1 expression and the most common co-mutations. TMB-H (> = 10) was found in 12.5% of the tumors and dMMR/MSI-H in 1.8%. The most prevalent co-alterations were TP53 54%), gLOH (28%), CTNNB1 (19%), NFKB1A (13%), APC (10%), PIK3CA (11%), SMAD4 (9%) and other 15 co-mutations in less than 7% were seen. In the 30 T790M mutants, in addition to TP53 mutations, other prevalent co-mutations were PIK3CA (14%) and CTNNB1 (17%). In 797-mutant tumors, in addition to T790M, the most prevalent co-mutations were TP53 (53%), CTNNB1 (22%), APC (16%) and PIK3CA (11%). L718 mutations co-occurred with either L858R (8/11), exon 19 (3/11) or T790M mutations (3/11). G724 mutations were found in 7 patients (0.02%) and G721 mutations in 4 patients (0.01%). Conclusions: Acquired resistance in EGFR mutant NSCLC is very heterogeneous and their frequency is still low most likely due to lack of enough sequencing of EGFR resistant tumors. While T790M and C797S mutations are well described, this report also notes a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the NGS evaluation of patients with resistant EGFR mutant lung cancers. [Table: see text]
Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067.
Authors: Hodi F. Stephen , Chiarion -Sileni Vanna , Lewis Karl D. , Grob Jean-Jacques , Rutkowski Piotr , Lao Christopher D. , Cowey Charles Lance , Schadendorf Dirk , Wagstaff John , Dummer Reinhard , Queirolo Paola , Smylie Michael , Butler Marcus O. , Hill Andrew Graham , Marquez-Rodas Ivan , Haanen John B. A. G. , Durani Piyush , Wang Peter , Wolchok Jedd D. , Larkin James 
Published: June 2022

9522 Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI); median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9–NR), 24.7 mo (16.0–38.7), and 8.0 mo (6.5–8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up; updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI; 3 NIVO; 2 IPI), none were treatment-related; 4 were due to melanoma progression; 1 was due to an unknown cause; and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses. Clinical trial information: NCT04540705. [Table: see text]
Autoantibodies as potential biomarkers of immune-related adverse events in patients with advanced cutaneous melanoma treated with immune checkpoint inhibitors.
Authors: Gandhi Aesha , Taylor John , Morici Michael , Reid Anna , Meniawy Tarek , Khattak Muhammad Adnan , Gray Elin , Millward Michael , Zaenker Pauline 
Published: June 2022

9536 Background: The majority of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAE). It is currently not possible to predict the development of irAEs using biomarkers. Here we evaluated the IgG autoantibodies (AAbs) profile in pre-treatment sera of cutaneous metastatic melanoma patients treated with ICIs to identify AAbs that are associated with irAEs. Methods: Clinical data of patients with metastatic melanoma treated with pembrolizumab or nivolumab monotherapy (n = 48) or combination ipilimumab and nivolumab (n = 37) was retrospectively evaluated. irAEs were graded using CTCAE v5.0. Sera from the 85 patients were evaluated for IgG AAbs using the HuProt™ microarray v4.0 covering 23,059 proteins ( > 81% of the human proteome). AAb profiles were compared between groups (any irAEs vs no irAEs), using the no irAEs group as control group. Results were inputted into the Advaita Bio’s iPathwayGuide software to find significantly differentially expressed AAbs using p < 0.05 and Log2FC > 0.6, and identify relevant biological pathways. Results: Out of 85 patients, 60 experienced any grade irAEs, 29 of 48 (60.4%) in the PD-1 group and 31 of 37 (83.8%) in the combination group. We found 758 proteins were differentially elevated, 102 in the in the PD-1 group and 666 in the combination treatment group. A comparison of these groups identified 10 AAbs that were elevated in patients experiencing irAEs independent of ICI regimen. These targeted proteins are highly expressed in tissues that are commonly affected by irAEs. Previous studies have shown their links to autoimmune and inflammatory conditions such as dermatitis and thyroiditis. Pathway analysis shows the RIG like receptor signalling pathway, which has been associated with autoinflammatory conditions, was significantly affected in the PD-1 group (p = 0.011), but not in the combination group (p = 0.442). Other pathways involved included the NOD-like receptor, purine and D-amino acid metabolism which play a role in innate immune system and assembly of inflammasomes and maturation, pro-inflammatory cytokines and mediators that contribute to inflammatory response. Conclusions: Further analyses are being conducted to identify the correlation of irAE type and severity to specific autoantibodies which will be presented. Prospective studies are required for validation of these AAbs specificities. This approach could be used to identify patients at high risk of irAEs, for treatment monitoring to maintain an effective stimulation of the patient’s anti-cancer immune response, to determine if treatment cessation is required and prevent hospitalisation or lengthy immunosuppression to treat irAEs.
Prognostic significance of the CP-GEP assay combining clinicopathologic factors and gene expression profiling in patients (pts) with AJCC v8 stage I/II cutaneous melanoma (CM).
Authors: Amaral Teresa Maria Santos , Sinnberg Tobias , Chatziioannou Eftychia , Niessner Heike , Leiter Ulrike M. , Keim Ulrike , Forschner Andrea , Dwarkasing Jvalini , Meerstein-Kessel Lisette , Rademaker Thomas , Wever Renske , Eggermont Alexander M. , Flatz Lukas , Forchhammer Stephan 
Published: June 2022

9564 Background: AJCC v8 includes Breslow thickness and ulceration to subdivide stage I and II CM pts into risk groups. In light of the results from adjuvant therapy in stage II CM, it has been discussed that pts’ follow-up and eventually treatment should consider additional markers, namely CP-GEP, to further refine the risk classification provided by the AJCC v8. The aim of this single center study was to clinically validate a prognostic CP-GEP-based risk score for stage I/II CMs combining Breslow, age and the expression of 8 genes SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA. Methods: All obtainable formalin-fixed paraffin-embedded primaries of stage I/II CMs with negative sentinel lymph node (SLN) from the Central Malignant Melanoma Registry of Germany diagnosed between 2000-2017 and archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. Quantitative reverse transcription polymerase chain reaction of the 8 genes was performed and combined with age and tumor thickness to define CP-GEP low- vs. high-score groups. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier curves. CP-GEP score performance was tested using multivariate Cox regression adjusted for tumor thickness, ulceration and age. Results: We included 543 pts with Stage IA (n=78); IB (n=223); IIA (n= 123); IIB (n=73); IIC (n=46). 43% were females, median Breslow was 1.7mm and 25% of tumors had ulceration. The median follow-up was 78 months (IQR 47-116). 311 (57%) patients had a high-risk CP-GEP score. The 5-y RFS rate was 71% and 92% (HR 4.2; p<0.001), the 5-y DMFS rate was 86% and 96% (HR 4.35; p<0.001) and the 5-y OS was 85% and 95% (HR 3.2; p=0.001), respectively for high and low-risk CP-GEP score. In multivariate Cox regression analysis for RFS including Breslow thickness, ulceration and age, contribution of CP-GEP score remained independently significant (HR 2.75; p=0.0008) compared to age (HR 1.03; p<0.0007), Breslow (HR 1.21; p<0.0001) and ulceration (HR 1.37; p=0.1694). Conclusions: CP-GEP risk score is a non-invasive and independent prognostic model for risk of relapse in stage I/II melanoma validated in this study. It identifies SLN negative pts at high risk of relapse and should be considered for complementing AJCC classification and for inclusion in future clinical trials.[Table: see text]
The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases: A multicenter cohort study.
Authors: Olofsson Bagge Roger , Holmberg Carl Jacob , Hieken Tina J. , Zager Jonathan S. , Long Georgina V. , Van Akkooi Alexander Christopher Jonathan , Karakousis Giorgos C , Pallan Lalit , Vetto John T. , Gyorki David E. , Ascierto Paolo Antonio , Dummer Reinhard , Hui Jane Yuet Ching , Schachter Jacob , Helgadottir Hildur , Kroon Hidde , Rothermel Luke Daniel , Carlino Matteo S. , Broman Kristy Kummerow , Ny Lars ,   The ITforIT Research Collaboration
Published: June 2022

9569 Background: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The aim of this study was to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international high‐volume melanoma centers. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c and N3c) and without distant disease (M0). Patients were treated with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). We assessed response rates, progression-free survival (PFS), melanoma-specific survival (MSS) and overall survival (OS). Results: A total of 287 patients from 21 institutions in 8 countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. Monotherapy with a PD-1 or CTLA-4 inhibitor was given in 233 (81%) and 23 (8%) patients respectively, while 31 (11%) received both in combination. Overall response rate was 56%, complete response (CR) rate 36% and progressive disease (PD) rate 32%. Median PFS was 10 months (95% CI 7.4-12.6 months) with a 1-, 2- and 5-year PFS rate of 48%, 33% and 18% respectively. Median MSS was not reached, and the 1-, 2- and 5-year MSS rates were 95%, 83% and 71% respectively. Conclusions: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the optimal role for systemic immunotherapy in the context of multimodality therapy including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
Use of Merlin Assay to identify patients with a low-risk for SN metastasis in a prospective multicenter Dutch study of a primary melanoma gene-signature (CP-GEP model) to predict sentinel node status during COVID-19.
Authors: Stassen Robert , Mulder Evalyn , Veringa Antoine , Mooyaart Antien , Dwarkasing Jvalini , Tempel Dennie , van der Hage Jos A. , Lendfers Sandra , Aarts Maureen J.B. , Verhoef Cornelis , Francken Anne Brecht , Grunhagen Dirk J. 
Published: June 2022

9571 Background: Approximately 70%-85% of patients who undergo sentinel lymph node biopsy (SLNb) show no nodal metastasis in the sentinel node (SN). The clinicopathological and gene expression profile (CP-GEP) model ( Merlin Assay) was developed and validated to identify patients that may forgo the SLNb surgery due to their low risk for for nodal metastasis This study was initiated during the first wave of Covid-19 pandemic to allow for surgical triage on SLNb and evaluate the implementation of the Merlin assay in clinical practice. Methods: This study was conducted in four designated melanoma centers in the Netherlands. Patients (age > 18y) with newly diagnosed melanoma of the skin, eligible to undergo SLNb were screened for study inclusion. Main exclusion criteria was prior history of primary melanoma ( > T1b) in the past 5 years. After enrollment, tissue sections of the primary melanoma were centrally reviewed at the Erasmus MC Cancer Institute to determine Breslow thickness at primary diagnosis. FFPE tumor tissue was dispatched for molecular analysis of eight target genes known to play a role in cancer development. In combination with age, Breslow thickness, and GEP outcome, risk of having nodal metastasis was calculated. Results were binary presented as 'CP-GEP low risk' and 'CP-GEP high risk'. SLNb status was used as gold standard for comparison. Results: A total of 177 patients were analyzed using the CP-GEP model. Median age was 64 years (IQR 52-73) Median Breslow thickness was 1.4mm (IQR 1.0-2.4). Of all patients 28.2% was diagnosed with T1, 40.7% with T2 and 20.9% with T3 melanoma. Corresponding positivity rate was 7%, 14% and 29% respectively. A total of 24 out of 177 patients had a positive SLNb. Median turn-around time from inclusion to CP-GEP result was 15 days. Overall 37.1.% of patients had a CP-GEP low risk profile. The CP-GEP model had a NPV of 94.6%. Conclusions: This is the first prospective multicenter implementation study for the Merlin assay. Results are in line with previous validation studies. The CP-GEP model could accurately identify patients at low risk for SN metastasis. Implementation in clinical practice is feasible based on current turn-around time. In the future, using the Merlin assay to deselect patients for SLNB may allow for a reduction of surgery in patients with melanoma.
A single-center experience of 98 patients (pts) with regionally metastatic Merkel cell carcinoma (MCC) of known (MCCKP) and unknown (MCCUP) primary at presentation.
Authors: Cope Brandon , Witt Russell G. , Chiang Yi-Ju , Seervai Riyad Navroz , Fisher Sarah B. , Lucci Anthony , Wargo Jennifer Ann , Lee Jeffrey Edwin , Farooqi Ahsan Saleem , Bishop Andrew , Gershenwald Jeffrey E. , Goepfert Ryan , Wong Michael K.K. , Guadagnolo Beverly Ashleigh , Ross Merrick I. , Aung Phyu P , Mitra Deverati , Keung Emily Zhi-Yun 
Published: June 2022

9576 Background: MCC is a rare skin cancer historically associated with poor survival rates and which is increasing in incidence. A small number of retrospective series suggest that MCCUP may be associated with better prognosis than MCCKP while others report worse outcomes. Recent advances in immunotherapy have changed the multimodal treatment landscape and outcomes of advanced MCC pts. We describe our experience with the management and outcomes of pts presenting with regional MCC metastasis of known and unknown primary origin. Methods: A retrospective review of pts with clinical regional disease at MCC diagnosis treated at our institution from 3/2003-3/2021 was performed. Clinicopathologic variables and outcomes were assessed. Overall survival (OS), recurrence-free survival (RFS) and progression-free survival (PFS) were estimated by the Kaplan Meier method. Results: Of 98 pts with regional disease on exam at presentation, 56 (57%) had MCCUP and 42 (43%) had MCCKP. Median follow-up from diagnosis to last follow-up or death was 33 months. Pts were generally older (MCCUP vs MCCKP: 68.7 vs 73.1 years), male (MCCUP vs MCCKP: 82% vs 74%) and Caucasian (MCCUP vs MCCKP: 84% vs 83%). Over half the pts had a history of another malignancy (MCCUP vs MCCKP: 52% vs 60%) with 9% and 14% being immunocompromised at diagnosis, respectively. After completion of staging workup, MCCUP pts had earlier stage disease at presentation compared with MCCKP pts (stage IIIA: 80% vs 55%, IIIB: 5% vs 31%, IV: 15% vs 14%, respectively). The cervical nodal basin was most commonly involved in MCCUP pts while regional disease was more varied in MCCKP pts (MCCUP vs MCCKP: cervical 54% vs 28%, axillary 15% vs 33%, inguinal 33% vs 3%, inguinal and pelvic 0% vs 11%, in transit 0% vs 14%). Formal lymphadenectomy (LND) was performed in 27 (48%) and 18 (43%) of MCCUP and MCCKP pts, respectively. Of these pts, 33% and 50% received neoadjuvant systemic therapy, most commonly immunotherapy; 70% and 55% received adjuvant radiotherapy. MCCUP pts had better outcomes compared to MCCKP pts (Table), with longer RFS in pts who underwent LND (not reached [NR] vs 13.1 months) as well as longer PFS in pts who did not undergo LND (17 vs 9 months) with longer OS in both subgroups (LND: NR vs 102.7 months; no LND: 74.4 vs 48.7 months). Conclusions: MCCUP patients with regional disease on exam at presentation have improved survival compared to MCCKP. Current stage III survival estimates may underestimate survival in patients with resectable disease. [Table: see text]
Successful management of Australian patients with extensive skin field cancerization (ESFC) with widefield volumetric arc radiation therapy (VMAT): Report with 12-month follow-up.
Authors: Curran Walter J , Potter Andrew , Baker Christopher , Shumack Stephen , Sinclair Robert , Christie David , Wong Bradley , Foley Peter , Spelman Lynda , O'Brien Peter 
Published: June 2022

9582 Background: Non-melanomatous skin cancer (NMSC) diagnoses are associated with a high risk of developing new skin cancers in adjacent areas. Patients with extensive skin field cancerization (ESFC) have large areas (generally ≥50cm2) of compromised skin characterized by pre-cancerous actinic keratoses often requiring repeated interventions. Lesion-directed therapies have excellent cure rates, but therapies targeting a wider region have limited durability, including topical agents such as 5-flurouracil. The development of volumetric modulated arc radiation therapy (VMAT) to precisely target large, curved skin surfaces has generated interest in its application to ESFC. This is a report on the efficacy, safety, and cosmetic outcomes of VMAT in the management of patients with ESFC at facilities across five Australian states. Methods: Sixty-three ESFC zones on 60 patients were prescribed widefield VMAT and prospectively enrolled in the National (Australian) Dermatology Radiation Oncology Registry (NDROR). Over 80% of patients had received up to 4 prior non-radiotherapy interventions. Fields included lower and upper limb, face, scalp, or trunk regions. Total widefield VMAT RT doses ranged from 45-50 Gy delivered in 25-30 daily fractions across 5-7 weeks. 3-, 6-, and 12-month follow-up assessments rated the percentage of disease clearance, cosmesis using the Lovett’s scale, and toxicity based on CTCAE. Results: At 12-month follow-up, 97% of treated zones had achieved and maintained clinical success, defined as > 90% field clearance. Five percent of patients exhibited recurrence of original disease, whereas 10% of patients developed a new actinic keratosis or NMSC. Cosmesis was rated as excellent or good in 98% of patients. Most patients exhibited grade 1-2 radiation-induced dermatitis during therapy, which resolved by 3-month follow-up. Grade 3 dermatitis at end of treatment was exhibited in 7% of the patients, which also resolved. Eight percent of patients discontinued treatment due to acute toxicities. The most common persistent toxicity at 12-month follow-up was localized grade 1 xerosis (dryness) at 43% and/or alopecia at 33%. Conclusions: Widefield VMAT achieved very promising clinical success in patients with ESFC for whom other therapies had failed. VMAT yielded favorable cosmetic outcomes, and treatment-related toxicity was manageable and transient in most patients. While additional follow up is necessary, these results demonstrate that widefield VMAT may be an excellent option for some patients with increasingly unmanageable presentations of ESFC.