bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I clinical trial to assess the safety, pharmacokinetics, and antitumor activity of glumetinib (SCC244) in patients with advanced non-small cell lung cancers (NSCLCs).
Authors: Chen Hua-Jun , Yang Jin-Ji , Yang Xuening , Zhou Qing , Sun Minghui , Li Yue , Xiang Ziyong , Wu Yilong
Published: May 2020

e21702

Background: Aberrant activation of the MET pathway is associated poor prognosis and poor response to standard therapies in cancer patients. Glumetinib (SCC224) is an oral potent and highly selective MET inhibitor. This is an open label, dose-escalation, phase I clinical study to determine the safety, pharmacokinetics and anti-tumor activity in patients with advanced NSCLC regardless of MET status. Methods: Patients with advanced NSCLC failed standard treatments received glumetinib orally according to one of four dose escalation regimens on a 28-day cycle: 100 mg, 200 mg, 300mg and 400 mg once daily, in a Pharmacologically Guided Dose Escalation (PGDE) design (a variation of the standard 3+3 design). The primary endpoints are the incidence of dose limit toxicity (DLT), maximally tolerated dose (MTD), biologically effective dose (BED). The secondary endpoints are treatment-emergent adverse events (TEAE), safety and tolerability, anti-tumor efficacy, pharmacokinetics, and its metabolites. Results: As of Feb 7, 2020, a total of eighteen eligible (18) patients were enrolled into this study: 3 at 100 mg, 3 at 200 mg, 6 at 300 mg and 6 at 400 mg. Only one patient among 6 evaluable patients at 400mg cohort reported one DLT of grade 3 vomiting. Treatment-related adverse events mostly were grade 1 or 2 nausea, vomiting, elevated alkaline phosphatase, elevated conjugated bilirubin, edema, headache, asthenia and decreased appetite. Non-DLT treatment related G3/4 adverse events were peripheral edema (n = 1, 5.5%), hypothyroidism (n = 1, 5.5%). Absorption was rapid after dosing and the median time to reach maximum plasma drug concentration ( Tmax) was 2.0‐6.0 hours. The mean value of half-life(t1/2) in each dose group ranged from 20.43h to 35.36 h. In response to glumetinib, one patient with MET overexpression at 200mg dose level had a best of response of partial response and completed 44 weeks glumetinib treatment, 4 patients (3 with MET amplification) had a best of response of stable disease. Conclusions: Glumetinib was well tolerated at doses up to 400 mg once daily and demonstrated clinical activity in advanced NSCLC with MET alterations. Glumetinib is used in ongoing clinical trials to further explore safety and efficacy in NSCLC. Clinical trial information: NCT03466268.
A phase I study to evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of TQ-B3101.
Authors: Fang Yong , Pan Hongming , Lu Shun , Hu Hong , Lu Qin
Published: May 2020

e21705

Background: TQ-B3101 is a novel compound, which deacetylated metabolite targets to receptor tyrosine kinases including ALK, ROS1 and MET. Preclinical studies showed TQ-B3101 had a better Inhibition activity and duration compared with equimolar crizotinib. Methods: Patients (pts) with advanced solid tumor failed to standard therapy were enrolled into dose escalation and expansion cohorts. TQ-B3101 was orally administered at doses of 100~300mg QD or 200~350mg BID in a 28-day cycle, then received the same dose until disease progression or intolerable toxicity. Dose escalation was based on dose-limiting toxicities (DLTs) in the first cycle and used “3+3” design to get the maximal tolerated dose (MTD) or recommended phase II dose (RP2D). Other objectives included safety and pharmacokinetics (PK) for all pts, and objective response rate (ORR) for ALK+, ROS1+ and MET amplification pts. Results: As of 20 Dec 2019, 30 pts (median age 51.3, males: 16, females: 14, ALK+: 19, ROS1+: 6, MET amplification: 2, lung cancer: 27, asymptomatic brain metastasis: 8, ECOG PS 1: 30) were enrolled into 7 dose escalation cohorts and 2 dose expansion cohorts (350mg BID/ 300mg BID). One DLT (grade 3 ALT increased) occurred at 350 mg BID. The MTD has not been reached. The most common grade 3 adverse events were neutrophils count decreased (20%), ALT increased (6.67%), leucocyte counts decreased (3.33%) and QT internal prolongation (3.33%). Grade 3 adverse events rate were 40% in 350mg BID cohort and 16.67% in 300mg BID cohort. PK analyses indicated TQ-B3101 metabolized into its deacetylated product rapidly, and exposure (Cmax and AUC) of which generally increased in a dose-proportional manner. Tumor response was evaluated in 24 pts with ALK+/ROS1+/MET amplification. ORR were 62.5% (15/24) in all cohorts, and 87.5% (7/8) in 350mg BID cohort. In 8 pts with brain metastases at baseline, ORR was 62.5% (5/8) . In 22 pts without brain metastases at baseline, the incidence of brain metastasis was 4.55% (1/22). 1 patient with MET amplification is evaluable and the tumor response is PR. Conclusions: TQ-B3101 was well tolerated and showed preliminary antitumor activity in ALK+, ROS1+ and MET amplification pts. Recommended phase II dose (RP2D) might be 300mg BID according longtime safety data. Further anti-tumor research in pts with ROS1+ is under going as multicenter clinical study in China. (NCT03972189). Clinical trial information: NCT03019276.
Molecular profiling of lung adenocarcinoma using pleural effusion specimens.
Authors: Zhang Wei , Zhang Bei , Zhou Yifan , Zhao Xiaochen , Bai Yuezong
Published: May 2020

e21709

Background: Molecular profiling of lung adenocarcinoma is essential for therapeutic decision-making and prognosis predicting. Pleural effusion may provide an opportunity for molecular profiling and thereby possibly provide information enabling targeted therapy. In this study, we performed next generation sequencing (NGS) in pleural effusion samples in order to study molecular profiling of lung adenocarcinoma using pleural effusion specimens. Methods: 45 Chinese lung adenocarcinoma patients with pleural effusion specimens were included. The pleural effusion samples were centrifugated, then cell pellets were collected and prepared into cell blocks. Genetic mutations were assessed using a validated targeted next generation sequencing assay. Immunohistochemistry (IHC) of PD-L1 was performed with 22C3 kit. Results: In 45 pleural effusion samples collected, 43 (95.5%) patients had at least one mutation classed as pathogenic or likely pathogenic. There were 245 somatic mutation and 160 germline mutations were detected, with an average of 8.0 mutations per patient. Of the 45 specimens with somatic mutations, seventeen (37.8%) of harbored EGFR mutations. The most frequent mutations were the deletion mutation in exon19 (15/17, 40.9%), the point mutation (L858R) in exon 21 (13/17, 76.5%), and resistance mutation (T790M) in exon 20(4/17,23.5%). Aside from the EGFR mutation, 1 case exhibited KRAS mutation (G12C), 1 case harbored ERBB2 mutation(Y772_A775dup),1 case harbored TP53 mutation, and 2 cases exhibited fusion (EML4-ALK, KIF5B-RET). 2 cases exhibited CD274 copy number gain, 2 cases exhibited CDK4 copy number gains, and one case carried CDK6 copy number gain, one case carried CKD6 copy number loss. The top frequent germline mutation genes were APC (5/45), ALK (4/45), ARID1A (4/45) and BARD1 (4/45). Regarding biomarkers for immunotherapy, three sample showed TMB-H (6.7%), and one sample showed MSI-H (2.2%). Of 29 samples underwent PDL1 IHC test, 21 samples (72.4%) show positive PDL1 expression, in concordance with previous reported rates. Conclusions: These results suggest that pleural effusions are important specimens for oncogene mutation analysis and enable targeted therapy for patients with lung adenocarcinoma.
Evaluation of the fully automated Idylla EGFR Mutation Assay in Chinese patients with lung adenocarcinoma.
Authors: Qiu Tian , Junling Li , Zheng Bo , Ying Jianming
Published: May 2020

e21716

Background: Epidermal growth factor receptor ( EGFR) mutation testing is nowadays an essential part of lung adenocarcinoma diagnosis. Its rapid detection is of utmost significance in order to ensure that patients receive timely and appropriate treatment. However, the current techniques for EGFR examination in China, ARMS-PCR and NGS, often take 3~7 days to deliver the final results. In contrast, the fully automated Idylla EGFR assay could detect 51 EGFR mutations directly from formalin-fixed, paraffin-embedded (FFPE) samples within 2.5 hours with < 2 minutes of hands-on time. The test has proven both accurate and robust among Caucasian lung adenocarcinoma patients but has never been clinically validated in Chinese patients. Methods: FFPE samples were retrospectively collected from 94 lung adenocarcinoma patients followed by EGFR testing using the Idylla system. Seventy-eight samples were also previously assessed with ARMS-PCR, 9 with NGS and 7 with both. In case of discordance, repeat testing was performed on the same tissue block with a third method. The sensitivity and specificity of the Idylla EGFR assay were evaluated against ARMS-PCR or NGS. Mutations beyond the scope of detection by the Idylla EGFR assay were not included in the analyses. Results: Of the 94 tumors enrolled, 77 were stage I-II. The Idylla system was consistent with ARMS-PCR or NGS for the EGFR mutational profiles of 92 tumors: 80 positive and 12 negative. Among the 2 cases of discrepancy, one was wild-type using Idylla but were found to harbor G719X/S768I using ARMS-PCR (and confirmed by NGS), while the other one carried L858R according to Idylla, as confirmed by ARMS-PCR, but was discovered to have an additional mutation L861Q using NGS. The Idylla EGFR test had a sensitivity of 97.6%, a specificity of 100% and an overall concordance of 97.9%. Conclusions: The Idylla system provides a rapid, accurate and user-friendly solution to EGFR characterization, especially in time-sensitive scenarios where special expertise and staff training could be a challenge.
Immune checkpoint inhibitors’ (ICI) efficacy according to PD-L1 expression for advanced or metastatic NSCLC: Systematic review and meta-analysis.
Authors: Maciel Glauber , Carlos Paula , Murad Junior Munir , Araújo Vânia Eloísa , Guerra Augusto , Acúrcio Francisco Assis
Published: May 2020

e21723

Background: Blocking PD-1 pathway has become a milestone in treating many tumors, including non-small cell lung cancer (NSCLC) for first and second line therapies. Although their benefits for some patients, these drugs are not full available in developing countries due to high treatment cost. In this study, we assessed the efficacy of five PD-1 or PD-L1 blockers (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab), associated or not to chemotherapy, according to PD-L1 expression. Methods: We performed a systematic review and meta-analysis of randomized clinical trials in the databases MEDLINE/Pubmed, EMBASE, COCHRANE Library and LILACS up to November 2018. We selected trials comparing ICI alone, or associated with ICI or chemotherapy, versus chemotherapy or placebo. Primary outcome was overall survival (OS) and secondary outcome was progression free survival (PFS). Risk of bias of included trials was assessed by Cochrane’s recommended tool and data meta-analysis was performed by Review Manager V5.3 software. Results: We assessed OS and PFS of 12 trials in our meta-analysis. The methodological quality was considered moderate according to Cochrane’s tool. The pooled hazard ratio were 0.70 (95% CI 0.63, 0.78; p < 0.01; I² = 58%) for OS and 0.75 (95% CI 0.64, 0.89; p < 0.01; I² = 88%) for PFS. Subgroup analysis for PD-L1 < 1%, ≥ 1% and ≥ 50% showed OS of 0.78 (95% CI 0.64, 0.95; p = 0.09; I² = 46%), 0.69 (95% CI 0.59, 0.81; p < 0.01; I² = 79%) and 0.57 (95% CI 0.48, 0.68; p = 0.10; I² = 40%), respectively. Data for PFS were 0.85 (95% CI 0.71, 1.03; p = 0.21; I² = 31%), 0.77 (95% CI 0.64, 0.92; p < 0.01; I² = 83%) and 0.53 (95% CI 0.46, 0.62; p = 0.14; I² = 36%), respectively. Conclusions: Our data suggest a dose-response relationship between PD-L1 level and survival outcomes. It was not possible to conduct our meta-analysis by median OS and median PFS difference once these data were not available for every trial we selected. Considering the high price of immune therapy and budget limitations in developing countries’ health system, our findings could optimize health technology assessment agencies recommendations for treating NSCLC with high expression of PD-L1.
Activin as a biomarker for platinum resistance in non-small cell lung cancer.
Authors: Lim Jennifer Wen Ying , Murphy Alexander David , O'Toole Sandra , Nagrial Adnan , Karikios Deme John , Daneshvar Dariush , Murphy Angela , McCloy Rachael , Watkins Neil , Chin Venessa T.
Published: May 2020

e21737

Background: Lung cancer is the leading cause of cancer death in Australia with 13,000 new cases per year. Although targeted therapy and immunotherapy have drastically changed the treatment landscape, the majority of patients will receive platinum-based chemotherapy for which the response rate is approximately 30% (Reck et al, 2016). An immunohistochemistry-based, predictive biomarker would be beneficial for patients and help avoid toxicity for patients unlikely to respond. Marini et al (2018) identified 3 biomarkers associated with in-vitro platinum resistance – activin A, growth differentiation factor-11 and transforming growth factor-b – which were investigated in a real-world retrospective cohort to determine their relation to objective radiological response and overall survival. Methods: We identified 101 patients with advanced non-small cell lung cancer who received platinum chemotherapy at 2 cancer centres between 2014-2015. Archival formalin-fixed paraffin embedded tissue samples were stained with activin A. Slides were manually scored by 2 independent clinicians using the multiplicative quickscore method (Detre et al, 1995). Kaplan Meier analysis for overall survival, a Cox-proportional hazards model for confounding variables and a chi-square analysis was performed to analyse the relationship between high immunohistochemistry scores (greater or less than 6) and radiological response. Results: We performed statistical analysis around the median cytoplasmic score (6). The overall median survival was 15.3 months. No significant difference in survival was detected between the two populations (p value = 0.97). The immunohistochemistry score was also not associated with rates of partial response (p value = 0.98) or progressive disease (p value 0.22). Conclusions: Despite an association with lower progression-free survival in a retrospective cohort in a previous study, high expression of activin does not appear to be a useful biomarker for platinum response in the setting of non-small cell lung cancer. Further research into associated antibodies including GDF-11 and TGF-b is in progress.
Molecular features for selecting Asian metastatic melanoma patients who benefit from check-point inhibitors.
Authors: Byeon Seonggyu , Kim Hyera , Yeo Ja Hyun , Kim Jinchul , Kwon Minsuk , Lee Jiyun , Kim Seung Tae , Lee Jeeyun
Published: May 2020

e22011

Background: There was few data for molecular characteristics of Asian metastatic melanoma patients with distinct clinical features as compared to West patients with metastatic melanoma. We conducted the molecular profiling for Asian metastatic melanoma patients with check-point inhibitors (CPIs) to find novel biomarkers to CPIs. Methods: 164 Asian patients with metastatic melanoma who received CPIs were simultaneously tested by the next generation sequencing (NGS) in tumor samples. We collected all NGS data and clinic-pathologic factors and also analyzed biomarkers for tumor response to CPIs. Results: The most common subtype was acral melanoma (39.6%) followed by cutaneous melanoma (32.3%), mucosal melanoma (26.2%) and others (1.8%). 163 pts are evaluable for efficacy; we observed 40 complete response (24.4 %), 34 confirmed partial responses (20.7%), 41 stable disease (25.0%) and 48 disease progression (29.3%). The overall confirmed response rate from the dose escalation is 45.1%. There was no significant difference of tumor response among subtypes of melanoma (p = 0.295). NRAS and TP53 mutation and NF2 deletion were significantly related to patients without the response to CPIs (p < 0.05). Meanwhile, MYC and RPS6KB1 amplification were found with those with the response (p < 0.05). The median progression free survival (PFS) to ICIS was 5.9 months (95% CI 3.8 - 8.05 months). Univariate analysis showed that TP53 and BRAF mutation, NF2 deletion, and BIRC2 amplification were poor prognostic values for PFS (p < 0.05). Conclusions: This study reported molecular characteristics of 164 Asian patients with metastatic melanoma. The specific molecular alterations influenced on the tumor response and PFS to CPIs in those.
Metastatic melanoma of the heart: A systematic review.
Authors: Balinski Alexander M. , Kerndt Connor C. , Parry Nathan P. , Rehman Rafey A. , Yeow Raymond Y. , Hayek Salim S.
Published: May 2020

e22017

Background: Melanomas are highly aggressive tumors that can metastasize to a wide array of organs, including the heart. Cardiac metastasis is rare and most often diagnosed post-mortem. Here, we perform a systematic review evaluating patient demographics, characteristics, management, and outcomes of cardiac melanoma metastases. Methods: A comprehensive literature review was performed in Cochrane Library, PubMed, and EmBase databases. Study quality was determined based on study design and clinical endpoints using the Oxford Center for Evidence Based Medicine (OCEBM) Levels of Evidence categorization. Demographic data, patient symptomatology, imaging findings, management strategies, and patient outcomes were collected and analyzed. Results: Thirty studies, all case reports or case series, met inclusion criteria. In total, 33 patients with cardiac metastasis from melanoma were identified and histologically confirmed. All 30 studies included in this review received an evidence level of 4 based on OCEBM Levels of Evidence categorization. The most common presenting symptom at the time of diagnosis of cardiac metastasis was shortness of breath (36.4%) and the most common physical exam finding was tachycardia (24.2%). The most common site of cardiac metastasis was the left ventricle (41.9%), followed by the right atrium (35.5%). Notable echocardiogram findings included right ventricular inflow obstruction (27.6%) and valvular dysfunction (24.1%). Valvular dysfunction, classified as prolapse, regurgitation, or stenosis, always involved the tricuspid valve. Treatment strategies typically involved surgical intervention (66.7%), chemotherapy (39.4%), or chemotherapy with surgical intervention (15.2%). Of the 22 cases that reported outcomes, the majority (59.1%) were disease-free without evidence of recurrence. Two patients (9.1%) experienced recurrence within one year of treatment and eight patients (36.4%) expired within 12 months. Conclusions: When symptomatic, cardiac melanoma metastases typically present with shortness of breath and tachycardia, with a predilection for the left ventricle and right atrium. Surgical intervention is currently the mainstay of treatment for successful cardiac melanoma metastasis management. [Table: see text]
Observational cross-sectional study evaluating the sociodemographic and clinical characteristics of patients with metastatic melanoma harboring a BRAF V600 mutation, treated with cobimetinib and vemurafenib based on routine clinical practice.
Authors: Álamo de la Gala Maria Carmen , Ochenduszko Sebastian , Crespo Guillermo , Corral Monica , Oramas Rodriguez Juana Maria , Sancho Maria Pilar , Medina Javier , Garicano Goldaraz Fernando , López Leiva Pedro , Campos Balea Begona , Rodriguez Analia Adela , Muñoz-Couselo Eva
Published: May 2020

e22028

Background: The drug combination of BRAF inhibitors with MEK inhibitors delays the onset of resistance and enhances apoptosis. Objectives: The main objective was to evaluate the percentage of long responders to the combination therapy. Methods: Participants were patients with advanced melanoma harboring a BRAF V600 mutation, who received Cobimetinib + Vemurafenib as first line, and who started treatment at least 12 months before inclusion. Patients were classified as long responders (patients who have reached at least 12 months of objective response -complete response CR/ partial response PR- to the treatment) or non-responders. Sociodemographic, anthropometric, clinical characteristics, baseline tumor characteristics and treatment dose modification were compared between long responders and non-responders. HADS scale, WPAI-GH and SMAQ questionnaires were used to evaluate the anxiety and depression, productivity and treatment compliance respectively, in patients under active treatment at the moment of the study visit. Results: 41 patients were evaluated. Mean (±SD) age was 57.8 (14.0) years. 56.1% were male. Almost one third of the population (29,3%) was classified as long responder. There were no statistically significant differences in the baseline tumor characteristics, demographic data nor in the clinical characteristics neither in treatment dose modification. CR was the best response achieved by 29.3% of patients, 46.3% achieved PR and 12.2% SD (stable disease). Mean of time to response was 6.9 months for CR patient, and 3.3 and 2.2 months for PR and SD patients respectively. Mean of duration of response was 9.4 months for CR patients, and 10.1 and 9.5 months for PR and SD patients respectively. 42.5% of Adverse Events (AEs) were related with the combination treatment. In the 68.5% of AEs the severity was mild, and in 19.4% moderate. In most cases no action was taken (74.9%) and the outcome was recovered (83.4%). Conclusions: Vemurafenib and Cobimetinib have an important impact in long term survival, leading to a steady complete response in one third of the patients.
Real-world clinical outcomes in avelumab-treated patients (pts) in the United States (U.S.) from SPEAR-Merkel –Study informing treatment Pathway dEcisions in Merkel cell cARcinoma (MCC).
Authors: Cowey Charles Lance , Liu Frank Xiaoqing , Kim Ruth , Boyd Marley , Fulcher Nicole , Krulewicz Stan , Kasturi Vijay , Bhanegaonkar Abhijeet
Published: May 2020

e22029

Background: MCC is a rare, aggressive disease associated with poor prognosis. Avelumab, a fully human anti–PD-L1 monoclonal antibody, was the first immune checkpoint inhibitor approved by the FDA for the treatment of metastatic MCC (mMCC). In the JAVELIN Merkel 200 trial (Clinical trial information: NCT02155647), avelumab resulted in durable responses and a high objective response rate (ORR) in pts with mMCC. This retrospective descriptive study assessed real-world clinical outcomes in avelumab-treated pts with locally advanced MCC (laMCC) and mMCC in a US community oncology setting. Methods: This study included data on avelumab-treated laMCC and mMCC pts from 1/1/17 to 3/31/19 within The US Oncology Network. Study data were captured through 9/30/19 using structured fields and chart review of iKnowMed electronic healthcare records. Real-world ORR was assessed. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 33 pts initiated treatment with avelumab (laMCC n = 11; mMCC n = 22) and were followed up for a median of 10.9 months (range, 0.5-27.2 months). Median age was 77 years (range, 44-90+ years), 78.8% of pts were male, and the majority (84.8%) of pts were treated in the first-line setting. During treatment, 27.2% of pts had emergency department visits and 39.4% were hospitalized; 1% and 23.1%, respectively, were treatment related. Clinical outcomes are reported in the table. Conclusions: This is the first study to examine pts with laMCC treated with avelumab in a real-world setting. Although the sample population is small, results suggest the clinical benefits in the real world in pts with mMCC treated with avelumab are consistent with benefits reported in the JAVELIN Merkel 200 trial. Clinical trial information: NCT02155647 . [Table: see text]
Association of K1505Ac IHC signal loss and response to immunotherapy in patients with metastatic cutaneous melanoma.
Authors: Altman Daniel S. , Vershvovsky Maria , Jiang Wei , Yang Haifeng , Jagannathan Geetha , Redfield Rachel , Mastrangelo Michael J. , Sato Takami , Orloff Marlana M. , Wilson Melissa
Published: May 2020

e22049

Background: Immune checkpoint inhibitors (ICI) have become a mainstay of treatment for patients with metastatic cutaneous melanoma. Currently, there are no reliable biomarkers to predict which patients will benefit from ICI therapy. K1505Ac immunohistochemistry (IHC) signal loss is equivalent to loss of functional PBRM1 protein, which has previously been shown to predict response to ICI therapy in metastatic renal cell carcinoma. We hypothesized that loss of K1505Ac IHC expression in patients’ tumors may predict benefit to ICI therapy. Methods: An exploratory study was conducted in patients with metastatic cutaneous melanoma (n = 25) who were treated with ICI therapy at Thomas Jefferson University. Retrospective chart review was performed to determine best clinical response using RECIST 1.1 criteria. Tumor samples from these patients were tested for loss of K1505Ac IHC signals to determine the correlation to best clinical response to ICI therapy. The pathologist was blinded to clinical responses during IHC analysis. Results: The chart below demonstrates the percentage of patients with K1505Ac IHC signal loss ≥ 40% and their correlating best clinical response to ICI therapy. Four of five patients (80%) with complete or partial response displayed K1505Ac IHC signal loss ≥ 40%. Fifteen of twenty patients (75%) with stable disease or progression of disease displayed K1505Ac IHC signal loss < 40%. Conclusions: Loss of K1505Ac IHC signal was associated with better clinical response to ICI therapy for patients with metastatic cutaneous melanoma. These findings suggest that K1505Ac IHC signal loss may serve as a biomarker to help determine which patients will benefit from ICI therapy. A larger cohort of patients is currently under investigation to better evaluate this association. [Table: see text]
A randomized phase II study of adjuvant sunitinib or valproic acid in high-risk patients with uveal melanoma.
Authors: Sato Takami , Orloff Marlana M. , Valsecchi Matias Emanuel , Shimada Ayako , Chervoneva Inna , Sharpe-Mills Erin , Klose Haley , Norcini Jessica , Belinsky Jill , Sato Shingo , Hulse Liam , Shields Carol L , Shields Jerry A , Mastrangelo Michael J.
Published: May 2020

e22059

Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite successful treatment of primary tumors, up to 50% of patients later die of distant metastases. Currently, no effective adjuvant treatment is available. Presence of both monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 in the primary uveal melanoma characterizes a group of patients with high metastatic death rates with reported 2-year survival rates ranging from 50% to 78%. This study aims to decrease or delay the death from metastatic uveal melanoma. Methods: Uveal melanoma patients with high risk for systemic metastasis defined as any of the following were eligible: A) M3 + 8q amp; B) Class 2. Patients must show no evidence of systemic metastasis and they need to be enrolled within 6 months of initial treatment of primary uveal melanoma. Patients were randomized to receive either sunitinib 25 mg daily or valproic acid (VPA) 750 mg daily as adjuvant treatment for 6 consecutive months. Improvement of 2-year overall survival (OS) rate from historical reference (70%) to 85% was the primary endpoint. The secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. The study was not powered to compare the efficacy between each arm. Results: A total of 90 patients were enrolled in this study. Two patients were excluded from the study including one in the sunitinib arm (did not start treatment after randomization) and one in the VPA arm (refused to stop VPA at 6 months). Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). The rest of patients completed the 6-month course of study treatments and all patients were followed at least for 2 years. With a median follow-up of 40.2 months, the 2-year OS rates of the sunitinib and VPA group were 95.6% (90% CI 86.5-98.6) and 90.7% (90% CI 80.1 - 95.8), respectively. The 18-month RFS rates of the sunitinib and VPA group were 75.6% (90% CI 63.1 - 84.3) and 62.8% (90% CI 49.4 - 73.5), respectively. Conclusions: Although the study is still ongoing, adjuvant sunitinib and VPA were considered to be safe and tolerable treatments for high-risk uveal melanoma. Sunitinib showed a tendency for a better outcome, thus a Cohort 2 was created to investigate the safety and potential improvement of 18-month RFS rate with 12 months of treatment with sunitinib. Clinical trial information: NCT02068586.
Performance of a prognostic 31-gene expression profile test in patients with node-negative cutaneous melanoma.
Authors: Gerami Pedram , Covington Kyle R. , Zolochevska Olga , Quick Ann P. , Cook Robert W. , Wayne Jeffrey D.
Published: May 2020

e22071

Background: The National Comprehensive Cancer Network guidelines recommend considering sentinel lymph node biopsy (SLNB) for cutaneous melanoma (CM) patients with a 5-10% risk of SLN positivity and offering it to those with > 10% risk. However, SLNB limitations include identification of only 1/3 of patients who end up with distant metastasis and a regional metastasis false negative rate ranging from 5-21% indicating a need to detect the risk of metastasis in patients with a negative SLNB. The 31 gene expression profile (31GEP) test uses the molecular biology of the primary tumor to predict 5-year recurrence-free (RFS), distant metastasis-free (DMFS), melanoma-specific (MSS), and overall survival (OS). Therefore, the objective of this study is to determine whether the 31GEP can stratify risk for patients with SLN-negative results to help guide CM management. Methods: 607 primary CM tumors were collected from patients with SLN-negative status who were enrolled in multi-center IRB-approved studies. Tumors were staged according to the AJCC 8th edition and analyzed by 31GEP testing to differentiate low-risk (Class 1A), intermediate-risk (Class 1B/2A), and high-risk (Class 2B) tumor biology. Clinical data were recorded and Kaplan-Meier (KM) and Cox regression analyses were performed to assess the relationship between 31GEP class and patient outcomes including RFS, DMFS, MSS, and OS. Results: KM analysis for 5yr RFS, DMFS, MSS, and OS stratified by 31GEP class are listed in Table. Multivariate Cox regression analysis demonstrated that the 31GEP Class 2B status was an independent predictor of RFS, DMFS, MSS, and OS with hazard ratios of 4.4 (95% CI, 2.7-7.2; p < 0.001), 4.4 (95% CI, 2.3-8.5; p < 0.001), 15.6 (95% CI, 3.4-71.2; p < 0.001), and 5.4 (95% CI, 2.6-10.9; p < 0.001), respectively. Conclusions: The results indicate that the 31GEP can stratify risk for a subset of patients with SLNB-negative results with the highest 5-year survival rates being associated with a Class 1A result. Moreover, GEP Class 2B is a significant independent predictor of metastatic risk in patients who are node negative. [Table: see text]
CDC20 is a novel potential therapeutic target in NF1-mutant melanoma.
Authors: Donnelly Douglas M. , Giles Keith M. , Vega-Saenz de Miera Eleazar , Betensky Rebecca , Winskill Carolyn , Yeh Yu hsin , Osman Iman , Jour George
Published: May 2020

e22075

Background: NF1-mutant melanoma (NF1-MT) is a distinct molecular subtype with worse overall prognosis than NF1-wild melanoma (NF1-WT). Despite its prevalence in 20% of patients and associated clinical disadvantage, there is no specific targeted therapy available to treat NF1-MT as its biological impact remains understudied. We tested the hypothesis that NF1-MT possess distinct genomic and transcriptomic characteristics from NF1-WT, which can potentially inform therapeutic innovation. Methods: Tumor DNA from metastatic melanoma (MM) patients treated with checkpoint inhibition at NYU was genotyped using exome sequencing. Microenvironment-related transcripts (n = 770) were then compared in NF1-MT versus NF1-WT using unsupervised clustering, differential gene expression, and gene set enrichment analyses. Verification of genomic and transcriptional findings was performed using qPCR and immunohistochemistry (IHC). TCGA melanoma (SKCM) data were analyzed as an independent cohort. Results: Pathogenic NF1 mutations were detected in 31/121 (27%) cases and were significantly associated with higher tumor mutational burden (P = 0.02). NF1-MT showed recurrent homozygous deletion in the membrane regulatory gene SYT1 and amplifications in oncogenes including CCND1 and MDM2, verified by qPCR. NF1-MT showed upregulation of proliferation with significantly increased expression of Ki-67 and cell division cycle protein 20 CDC20 (P = 0.03) validated by IHC (P = 0.03). Cell cycle was the top enriched pathway in NF1-MT (P = 0.003, FDR = 0.04). Analysis of TCGA melanoma data (n = 440) corroborated upregulation of MKI67 and CDC20 in NF1-MT melanoma (P = 0.01, P = 0.03). Conclusions: NF1-MT is associated with a hyper-proliferative tumor phenotype that cannot be only attributed to MAP kinase activation. Our data suggest that NF1-MT may be vulnerable to pharmacological inhibitors of cell cycle progression and proliferation, such as those targeting CDC20 or CDK4/6.
Molecular profiling and clinical characteristic of malignant melanoma in younger patients.
Authors: Chantharasamee Jomjit , Wong Karlton , Chmielowski Bartosz
Published: May 2020

e22087

Background: Combination of clinical and molecular data has not yet been well established in adolescent and younger adult patients with melanoma Methods: We performed a retrospective analysis of the molecular profiles and clinical outcome of patients diagnosed at the age younger than 40 treated at UCLA during 2010 to 2019. Patient’s molecular profile, characteristics, and treatment outcome were described using descriptive statistic. Kaplan-Meier curve was used for disease-free survival (DFS) and overall survival (OS). Results: 150 patients with a median age of 29 year (12-39) were analyzed. 101 (67.3%) patients had cutaneous melanoma, 49 (32.7%) had localized uveal melanoma. Of those 101, 23.8% had pre-existing benign or congenital nevus. 70/101 (69.3%) was stage I-II, 26/101 (25.7%) stage III and 5/101 (4.9%) stage IV. Of those 37 patients with molecularly characterized tissue, 23 (62%) had BRAF mutation including 17 V600E, 4 V600 unknown codon, 2 G469A, 2 NRAS and 1 NF-1 mutation. 11/37 were BRAF negative. 79.6% of patients who were not tested were stage I. For patients with stage III, 16/26 (61%) received adjuvant immunotherapy, none of adjuvant targeted therapy. At 35.1 months follow-up time, 27/96 (28%) localized cutaneous melanoma experienced relapse. 1-year DFS was 73% in adjuvant vs. 90% in no adjuvant immunotherapy group. Among 49 uveal melanoma patients, the median age was 27 years old. 23/49 (49%) had a T1 tumor, 18/49 (36.7%) T2, 6/49(12.2%) T3, 1/49(2%) T4. At 45 months follow-up time, three (6.1%) patients developed metastasis. 5-year DFS and OS was 90% and 100%, respectively. 45 patients had tissue for gene expression profiling and/or FISH testing. 15/45 (33%) had class IA, 13/45 (28%) had class IB, and 8/45 (17.7%) had class 2. 24 samples were analyzed by FISH: 14 with disomy 3, 5 with complex disomy 3 with gain of chromosome 6 or 8, and 5 with monosomy 3. Conclusions: Similarly to general population, most of younger patients with melanoma are diagnosed with stage I disease. Among patients with stage III melanoma treated with adjuvant immunotherapy 1-year DFS was comparable to the general population. Patients with stage III who did not receive adjuvant therapy had an excellent DFS which confirms that the decision on selecting patients for treatment was appropriate. The prognosis of younger patients with uveal melanoma was much better than predicted by molecular testing, and much better than expected regardless of gene expression profile or cytogenetic testing.
Rate of complete and durable responses of intralesional therapy with talimogene laherparepvec for stage IIIB-IVM1a melanoma and association with tumor load.
Authors: Stahlie Emma H.A. , Franke Viola , Zuur Charlotte L. , Klop Willem M.C. , Van Der Hiel Bernies , Van De Wiel Bart A. , Wouters Michel W.J.M. , Schrage Yvonne , van Houdt Winan J. , Van Akkooi Alexander Christopher Jonathan
Published: May 2020

e22089

Background: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus, which is used as an oncolytic immunotherapy in stage IIIB-IVM1a melanoma patients. It is known to be an effective therapy for injectable cutaneous, subcutaneous and nodal melanoma lesions, as approved by the European Medicines Agency (EMA). Combination therapy is not yet approved by EMA pending the results of the phase 3 Masterkey-265 trial. The objective of the current study was to identify prognostic factors for achieving a complete response (CR) that can be used to select patients for treatment with T-VEC monotherapy. Methods: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2019-05 with a follow-up time > 6 months, were included. Data was collected on baseline characteristics, responses and adverse events (AEs). Durable response rate (DRR) was defined as the percent of patients with a CR or partial response (PR) maintained continuously > 6 months. Univariable analyses were conducted and a prediction model was developed to identify prognostic factors associated with complete response. Results: For this study, a total of 71 patients were included with a median follow-up of 16.1 months. The median age was 70 years (range: 35-90). As best response, 47 patients (66%) had a CR and 10 patients (14%) had a PR, resulting in an overall response rate of 80%. Twenty-one patients (30%) stopped treatment because of progressive disease and sixteen patients (23%) developed a recurrence during follow-up after achieving a PR or CR. Median duration of CR was 11 months. The durable response rate was 42%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, previous treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving a CR and for progression-free survival. Achieving a CR was associated with a reduced risk of death. The prediction model includes tumor size, type of metastases (only cutaneous vs. subcutaneous (+/- cutaneous) vs. nodal (+/- cutaneous/subcutaneous)) and number of lesions as predictors. Conclusions: This study shows that intralesional T-VEC monotherapy for stage IIIB-IVM1a melanoma is able to achieve high complete and durable response rates. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting T-VEC should perhaps be used earlier in the course of the disease.
Unknown primary tumor high-risk melanoma as a unique patient population with distinct prognosis in the adjuvant setting: An ECOG-ACRIN E1609 study analysis.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Hodi F. Stephen , Cohen Gary Irvin , Rao Uma , Sondak Vernon K. , Kirkwood John M.
Published: May 2020

e22090

Background: E1609 enrolled 1670 adult patients (pts) with resected AJCC7 stages IIIB, IIIC, M1a, M1b melanoma and compared adjuvant ipilimumab at 3 or 10 mg/kg (ipi3 and ipi10) to high dose interferon-alfa (HDI). With over 5 years of follow up, the risk of relapse and death by primary tumor status and by stage group is expected to inform the design of future adjuvant trials and ultimately, clinical practice. Methods: Unknown primary melanoma status was defined as initial presentation with cutaneous, nodal or lung metastasis that was completely resected without a history of known primary melanoma. We evaluated the pt distribution by the initial site of metastasis. Further, we evaluated the risk of relapse and death by primary tumor status and by stage group. Five-year relapse-free survival (RFS) and overall survival (OS) rates and 95% CIs were estimated by Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Two-sided p-values were derived. Results: Unknown primary melanoma represented 12.8% of the total study population including 11.7% on the ipi arms and 14.7% on HDI. Site of metastasis at initial presentation among unknown primary cases included cutaneous and nodal (97%) and lung (3%). Among the overall study population, M1a stage group included the highest proportion of pts with unknown primary (42.2%). Stratifying by stage, RFS (p = 0.001) and OS (p = 0.009) were significantly better for pts with unknown primary compared to known primary. Including only ipi3 and ipi10 pts, RFS (p = 0.005) and OS (p = 0.023) were consistently significantly better in favor of unknown primary. Five-year RFS and OS rates by primary tumor status and stage group among pts treated with ipi (ipi3 and ipi10) are summarized in Table. Conclusions: Unknown primary status represents a unique population among high-risk melanoma pts treated with ipi with improved RFS and OS outcomes that support their separate assessment in future immunotherapy adjuvant trials. In-depth analyses of the tumor biology and host immunology are ongoing. Outcome analyses by the overall study stage groups and the HDI arm will be reported at the meeting. Clinical trial information: NCT01274338. [Table: see text]
Influence of chronic neuropathic pain on VEGFA in tumors of mice with genetically determined inhibition of tumor growth.
Authors: Frantsiyants Elena M. , Kaplieva Irina V. , Surikova Ekaterina I. , Neskubina Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Cheryarina Natalia D. , Nemashkalova Ludmila A. , Lesovaya Natalia S. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V. , Khokhlova Olga V. , Przhedetskaya Viktoria Yu. , Zakharova Natalia A. , Kit Oleg I. , Ushakova Natalya D.
Published: May 2020

e22103

Background: Chronic neuropathic pain (CNP) demonstrates the ability to stimulate tumor growth and neoangiogenesis. Our purpose was to study VEGFA levels in the growth of B16/F10 melanoma with CNP in mice with genetically determined inhibition of tumor growth. Methods: Females of С57ВL/6 mice (normal genome (uPA+), n = 26) and C57BL/6-Plautm1.1BugThisPlauGFDhu/GFDhu mice (urokinase gene knockout (uPA–), n = 16) received subcutaneous transplantation of B16/F10 melanoma 2 weeks after bilateral sciatic nerve ligation (CNP model). After 3 weeks of carcinogenesis in CNP, tumor volumes were measured and levels of VEGFA were studied in tumors by ELISA. Results: Tumor volumes in (uPA+) females with CNP in week 3 of carcinogenesis were similar to that in (uPA+) females without CNP and were on average 2.6 cm3 (2.5 and 2.8 cm3 respectively). Tumor volumes in (uPA–) females were 0.04 cm3, i.e. 70 times lower (p < 0.001) than in (uPA+) females without CNP. Tumor volumes in (uPA–) females with CNP were 144 times higher (p < 0.001) than in (uPA–) females without CNP and were 5.76 cm3. VEGFA levels in tumors of (uPA+) females with CNP were 11.1 times higher (p < 0.001) than in (uPA+) females without CNP. VEGFA in tumors of (uPA–) females with CNP was 5.2 times higher (p < 0.001) than in (uPA–) females without CNP. Conclusions: The CNP state showed higher VEGFA concentrations in tumor tissues of female mice with normal genome and uPA-deficient females (with genetically determined inhibition of tumor growth) which may cause a larger tumor volume in (uPA–) female mice.
Tanning bed exposure in association with multiple primary melanoma.
Authors: Karapetyan Lilit , Yang Xi , Wang Hong , Karunamurthy Arivarasan , Sander Cindy , Moyer Ashley , Wilson Melissa , Kirkwood John M.
Published: May 2020

e22107

Background: Patients with primary cutaneous melanoma are at increased risk of subsequent new primary melanoma. Indoor tanning is a risk factor for melanoma. The primary objective of this study was to determine the association between indoor tanning and multiple primary melanoma (MPM). The secondary objective was to compare clinical and pathological characteristics of primary and secondary malignant melanoma. Methods: This retrospective case-control study of MPM and gender-matched controls with single primary melanoma retrieved at 2:1 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank from January 1996 through October 2019. Logistic regression models were used to examine the association between MPM and risk factors. Results: In total, 330 patients (39.1% men; median [SD] age, 51 [15] years) were enrolled, including 110 with single and 220 with MPM. Median time between diagnosis of first and second primary melanoma was 13 months. 22.7% of patients with MPM had 3 or more primary melanomas. Compared with patients who had a single primary melanoma, patients with multiple melanomas were younger at diagnosis of first melanoma (median age 46 vs 52, p = 0.006), more likely to be discovered at Stage 0 and 1 (68% vs 49%, p < 0.0001), and to have had indoor tanning exposure (34% vs 10%, p < 0.0001), family history of melanoma (18% vs 8%, p = 0.0045), atypical moles (37% vs 13%, p < 0.0001), dysplastic nevi (21% vs 5%, p < 0.0001), and Breslow thickness of less than 1 mm (61% vs 33%, p < 0.0001). Compared with the patient’s first melanoma, subsequent melanomas were more likely to be thinner (0.6mm vs 1.2mm, p = 0.0007) or in situ (24% vs 13%, p = 0.0004). The estimated probability of locus that was the same for first and second primary melanomas was 34% with (95% CI 25%, 44%). The most common location for second primary melanoma was upper extremity (34%). In univariate analysis, lifetime tanning bed exposure of > 10 sessions was associated with an increased risk of second primary melanoma OR 4.60 [95% CI, 2.52-8.42, p < 0.0001]. In multivariate analysis after adjusting for age, family history of melanoma, presence of atypical and dysplastic nevi, recreational sun exposure, indoor tanning remained significantly associated with MPM (OR 4.32 [95% CI, 1.54-12.15, p = 0.0026]). Conclusions: Indoor tanning for > 10 sessions is associated with increased risk of second primary melanoma. Subsequent melanomas are more likely to be thin or in situ, and to occur in different anatomic locations.