bluuebunny/crossref_metadata_2025 huggingface dataset:
RB1 mutation had influenced on bone metastases in advanced treatment-naïve lung cancer.
Authors: Zhou Chengzhi , Xu Ying , Lin Xinqing , Wang Fei , Deng Huojin , Xie Xiaohong , Liu Ming , Xie Zhanhong , Zhang Jiexia , Ouyang Ming , Li Shiyue , Chen Rongchang , Qin Yinyin , Chen Rongrong , Xia Xuefeng
Published: May 2020

e21668

Background: RB1 is one of the most vital cancer suppressor genes in various cancer types. RB1 mutation always occurs in treatment-naïve small cell lung cancer (SCLC) patients or in resistance to EGFR TKI therapy of non-small cell lung cancer (NSCLC) patients. However, we observed a group of clinical NSCLC patients, and found that RB1 mutations also occurred in treatment-naïve patients. Methods: RB1 is one of the most vital cancer suppressor genes in various cancer types. RB1 mutation always occurs in treatment-naïve small cell lung cancer (SCLC) patients or in resistance to EGFR TKI therapy of non-small cell lung cancer (NSCLC) patients. However, we observed a group of clinical NSCLC patients, and found that RB1 mutations also occurred in treatment-naïve patients. Results: Nonsense and frame-shift mutations were the major pathogenic mutations found in RB1 gene, which predicted RB1 protein-deficient in these mutational patients. Furthermore, we found these RB1 mutation patients had TP53 mutations at the same time. Patients with RB1 mutation had a higher smoking prevalence than patients who had wildtype RB1 genes (P < 0.0001). Gene testing showed RB1 mutations patients also developed EGFR driver mutations, while the mutation frequency was significantly lower than RB1 wildtype patients ( P = 0.0368). Eight RB1 mutated patients diagnosed with actionable EGFR mutations, including exon 19 del, L858R, L861Q, G719S and S768I, while no patients diagnosed with EGFR exon 20 insertion. 10 (62.5%, 10/16) patients in RB1 mutated group, and 25(32.1%, 25/78) patients with RB1 wildtype had bone metastases. The proportion of bone metastases in patients with RB1 mutation was significantly increased than others ( P = 0.0216). Conclusions: This study demonstrates that the function of tumor suppressor gene RB1 in advanced stage of NSCLC. From the results, we considered RB1 mutation had influence on bone metastases. Although loss-of-function mutations in tumor suppressor gene (TSG) RB1 always had no targets therapeutic drugs, it also suggested that some other clinically treatment can be performed as soon as possible.
The prognostic value of neutrophil-to-lymphocyte ratio in patients with epidermal growth factor receptor mutated advanced non-small cell lung cancer (NSCLC).
Authors: Yun Nicole , Rouhani Sherin Juliet , Gilmore Brendan , Ritz Ethan M. , Bestvina Christine M. , Tarhoni Imad , Batus Marta , Borgia Jeffrey Allen , Bonomi Philip D. , Fidler Mary J.
Published: May 2020

e21675

Background: An elevated neutrophil-to-lymphocyte ratio (NLR) indicates a poor prognosis across multiple cancers, including non-small cell lung cancer (NSCLC). Our study aims to validate these findings in EGFR-mutated NSCLC patients receiving tyrosine kinase inhibitor (TKI) therapy, and to evaluate other factors that may impact NLR. Methods: We retrospectively analyzed 95 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and The University of Chicago Medical Center from August 2011 to August 2018. The prognostic value of NLR was assessed at the start of therapy, and after 6 and 12 weeks of treatment. The median progression free survival (mPFS) and median overall survival (mOS) were calculated by the Kaplan-Meier method and compared with the log rank test. Spearman rank correlation was used to correlate number of disease sites with NLR at diagnosis. T test analysis compared mean NLR between patients with high grade (≥ 3) toxicity versus low or no (grades 0-2) toxicity. The relationship between NLR and body mass index (BMI) changes were analyzed using Pearson correlation. Results: At therapy start, patients with NLR < 5 (n = 57) had a mPFS of 15.3 months and a mOS of 56.7 months, while those with NLR ≥ 5 (n = 35) had a mPFS of 13.8 months ( p= 0.024) and mOS of 40.0 months ( p= 0.0056). After 6 weeks of treatment, patients with NLR < 5 (n = 69) had a mPFS of 14.6 months and mOS of 56.2 months, while those with NLR ≥ 5 (n = 23) had a mPFS of 10.0 months ( p= 0.052) and a mOS of 37.74 months ( p= 0.049). After 12 weeks of treatment, patients with NLR < 5 (n = 66) had a mPFS of 14.2 months and mOS of 54.8 months, while those with NLR ≥ 5 (n = 17) had a mPFS of 3.0 months ( p= 0.0016) and a mOS of 22.4 months ( p= 0.0012). Patients who had a decrease in NLR did not have significantly better mPFS or mOS compared to patients whose NLR increased at either 6 or 12 weeks. Baseline number of disease sites and BMI did not correlate with NLR at diagnosis. Changes in BMI did not correlate with a change in NLR at 6 weeks or at 12 weeks. There was no significant difference in NLR between patients with high grade (≥ 3) versus no or low grade (0-2) drug toxicities. Conclusions: NLR can be used as a prognostic factor to predict which EGFR mutated NSCLC patients on TKI therapy may have worse PFS or OS outcomes. Closer monitoring and potential therapeutic escalation may be beneficial in patients with elevated NLR ≥ 5. Further work studying NLR in patients being treated with a larger osimertinib cohort is ongoing.
A phase I study of ADXS-503 alone and in combination with pembrolizumab in subjects with metastatic squamous or non-squamous non-small cell lung cancer (NSCLC).
Authors: Ramalingam Suresh S. , Stinchcombe Tom , Gerstner Gregory James , Haigentz Missak , Vangala Surya , Parsi Megan , Heyburn John W. , Kabala Victor , Prasad Tuhina , Gutierrez Andres A. , Goldman Jonathan Wade ,   ADXS-503 Author's Group
Published: May 2020

e21682

Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programed death receptor-1 (PD-1)- blocking antibody with proven efficacy in NSCLC. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: This is a phase I study of A503 ± Pembro in patients (pts) with metastatic squamous or non-squamous NSCLC. Dose escalation with A503 alone has been tested at two dose levels (i.e., 1 and 5 x108 CFU) in Part A in pts refractory or intolerant to prior systemic therapy. In dose escalation Part B, A503 is being evaluated at the same dose levels (DLs) in combination with Pembro in pts with disease progression on Pembro. Part C will be a dose expansion cohort with A503 + Pembro as first-line treatment in the metastatic setting. A503 ± Pembro (200 mg) will be infused intravenously every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data. Results: Nine patients have been treated: 7 with A503-alone in Part A and two pts with A503+ Pembro in Part B-DL1. No pts in Part A experienced dose-limiting toxicities at the 2 DLs tested. Two Grade 3 adverse events occurred in one pt related to the infusion: hypertension and flu-like syndrome. A transient and manageable SAE (Grade 2 acute kidney injury) was possibly related to A503 alone at 5 x108 CFU. A503+ Pembro have been well tolerated in 2 pts in Part B-DL1. Four pts achieved a best overall response of stable disease, three in Part A and one in Part B. A503 alone induced immune responses in pts so far evaluated in Part A. Conclusions: ADXS-503 alone has demonstrated a manageable safety profile and immune responses in Part A. The 1x108 CFU was identified as the recommended phase II dose. Dose escalation with A503+ Pembro is ongoing and dose expansion in first line treatment is due to start shortly. Clinical trial information: NCT03847519.
Efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients with different metastatic sites: A systematic review and meta-analysis.
Authors: Yang Kaili , Zhao Lin , Li Jiarui , Bai Chunmei
Published: May 2020

e21684

Background: Previous studies have demonstrated that bone, brain and liver metastases are poor prognosis factors of immune checkpoint inhibitors (ICIs) therapy in patients with non-small-cell lung cancer (NSCLC). This study aims to compare the efficacy of ICIs with conventional therapy in NSCLC patients with bone, brain or liver metastases. Methods: MEDLINE, Embase and CENTRAL were searched for prospective studies comparing ICIs with conventional therapy in NSCLC patients with bone, brain or liver metastases. Quality assessment was performed using the Newcastle-Ottawa Scale. The pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) among included studies was analyzed using the random-effects model. Results: From 1,195 relevant articles, eight studies with high methodological quality consisting of 988 patients were included in the analysis. ICIs significantly improved OS for patients with brain metastases (HR = 0.57; 95%CI: 0.37-0.86; P = 0.007). Among patients with liver metastases, OS (HR = 0.72; 95%CI: 0.57-0.91; P = 0.006) and PFS (HR = 0.72; 95%CI: 0.49-0.87; P = 0.004) improvement was observed in the ICI treatment arm. No available study with bone metastases information was identified. Subgroup analysis revealed that PD-1 inhibitors could benefit patients on OS and PFS regardless of metastatic sites. Sensitivity analysis indicated good stability of this analysis. No obvious heterogeneity or publication bias was detected. Conclusions: ICIs could significantly improve OS in patients with brain metastases and both OS and PFS in patients with liver metastases. Although brain and liver metastases are generally regarded as poor prognostic factors for immunotherapy, this study still indicates ICIs are effective therapeutic options for NSCLC patients with these metastatic sites.
Dynamic changes in circulating PD-1+CD8+ T lymphocytes for predicting treatment response to PD-1 blockade in patients with non-small cell lung cancer.
Authors: Kim Chang Gon , Hong Min Hee , Kim Kyung Hwan , Pyo Kyoung-Ho , Xin Chun-Feng , Cho Byoung Chul , Shin Eui-Cheol , Kim Hye Ryun
Published: May 2020

e21690

Background: The predictive value of dynamic changes in the expression of programmed cell death-1 (PD-1) among circulating CD8+ T lymphocytes for treatment response to PD-1 inhibitors has not been explored in non-small-cell lung cancer (NSCLC). This study aimed to investigate whether dynamic changes in PD-1+CD8+ T lymphocytes have predictive value with respect to durable clinical benefit (DCB) and survival after PD-1 blockade. Methods: Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled between March 2016 and August 2018 (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8+ T lymphocytes was conducted using multi-color flow cytometry. Predictive values of dynamic changes in circulating PD-1+CD8+ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with PD-1 inhibitor (NCT03486119). Results: Circulating PD-1+CD8+ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1+ cells among CD8+ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in analysis of tumor antigen NY-ESO-1-specific CD8+ T lymphocytes and in the validation cohort. Conclusions: Dynamic changes in circulating PD-1+CD8+ T lymphocytes predict clinical and survival benefit from PD-1 blockade treatment in NSCLC. Thus, tracking these changes may be useful for identifying NSCLC patients who will optimally benefit from the treatment.
Detection of ALK and ROS1 fusion transcripts in FFPE samples of non-small cell lung cancer patients using a novel RT-PCR based assay and targeted RNA sequencing.
Authors: Denis Marc G. , Vallee Audrey , Sagan Christine , Herbreteau Guillaume , Theoleyre Sandrine , Rajamani Jaya , Lee Michael , Ordinario Ellen
Published: May 2020

e21695

Background: Detection of genomic rearrangements like ALK and ROS1 fusions are mandatory in non-small cell lung cancer (NSCLC) as those alterations can be targeted by an increasing number of drugs. Fluorescence in-situ hybridization (FISH) has been so far the gold standard but multiplexed technologies would allow analysis of many potential targets simultaneously. We have evaluated a novel RT-PCR based assay and a targeted RNA sequencing solution for the detection of ALK and ROS1 rearrangement in NSCLC patients. Methods: 41 patients with late stage NSCLC were included in the study. ALK and ROS1 status were screened on FFPE tissue sections using immunohistochemistry and confirmed with FISH. Total nucleic acids were extracted from tissue sections using the Maxwell RSC RNA FFPE kit (Promega). Detection of rearrangements was performed by RT-PCR using the prototype ALK/RET/ROS1 Fusion Panel assay (Roche), which detects 7 ALK fusion variants, 13 ROS1 variants and 6 RET variants. For RNA sequencing, the libraries were prepared with the QIAseq Targeted RNAscan Lung Cancer Panel (Qiagen). Sequencing was performed on a MiSeq instrument (Illumina). Results: We tested 16 ALK FISH+ tumors, 4 ROS1 FISH+ tumors, and 21 samples that were either IHC- or IHC+/FISH-. The RT-PCR assay detected 15 of the 16 ALK FISH+ tumors, and 3 of the 4 ROS1 FISH+ tumors. In the 21 IHC- or IHC+/FISH- samples, 1 additional ROS1 fusion and 1 RET fusion were detected. The remaining 19 assays samples were negative. 2 fusions were missed by RT-PCR because the assay design does not cover these rearrangements (KLC1-ALK and CTNND1-ROS1). With targeted RNA sequencing, we were able to detect 14 of the 16 ALK FISH+ tumors and all 4 of the ROS1 FISH+ tumors. We also identified 1 additional ROS1 fusion and 1 RET fusion in the 21 IHC- or IHC+/FISH- samples. 17 patients were negative and 2 tests were not contributive. Overall, using FISH as a reference, the sensitivity of both assays was 90% (18/20). Conclusions: Using limited amount of biological material, both RT-PCR and targeted RNA sequencing were able in one assay to detect the overwhelming majority of ALK and ROS1 fusions identified with FISH. These approaches also allowed us to detect gene rearrangements that were missed by the initial IHC/FISH screening. The RT-PCR assay requires less RNA (as little as 3 ng) and has a much faster turn-around time. The RNA sequencing approach allowed us to identify the fusion partners, but it requires much more RNA and is rather difficult to implement in routine practice.
Using real world data to examine outcomes in immunotherapy-treated patients with metastatic non-small cell lung cancer.
Authors: Luciano Sierra , Haudenschild Christian , Kuranz Seth
Published: May 2020

e21715

Background: Important questions have been raised about whether real world data (RWD) can be relied upon to support clinical and regulatory decision-making. The aims of this study were to assess overall survival (OS), time-to-treatment (TTT), follow-up time, and treatment pathways in metastatic non-small cell lung cancer (mNSCLC) patients treated with programmed cell death protein 1 inhibitors (PD-1i). Methods: Two mNSCLC cohorts were identified in a US based EMR network. To explore treatment pathways, patients had to have an advanced (stage 3/4) diagnosis of NSCLC confirmed by a tumor registry record. A line of treatment (LOT) was defined as a PD-1i or chemotherapy taken within 30 days. OS, time to treatment, and follow-up time were also calculated. In another cohort patients had to have at least one PD-1i (pembrolizumab, nivolumab, durvalumab, or atezolizmab) and an oncology treatment within 3 months of an advanced stage diagnosis. OS was calculated using Kaplan-Meier analysis and stratified by time after nivolumab approval, quarter of PD-1i initiation, and line of therapy of first PD-1i. Patient characteristics were defined by ICD, CPT, LOINC, and RxNorm terminology. Results: Median overall survival was found to be 213 days (IQR 109, 425.25). In the treatment pathways analysis, 58.3% of patients started on a non-PD-1i chemotherapy as an initial line of treatment for mNSCLC. PD-1i was the most common second line treatment and 41.4% of patients who started on a non-PD-1i therapy switched to a PD-1i as their second line therapy. Median time from advanced diagnosis to PD-1i inhibitor initiation (9.6 months (IQR 3.45, 21.45)) and median structured follow-up times from advanced diagnosis (21.87 months (IQR 11.94, 38.97)) and from inhibitor initiation (8.71 months (3.06, 17.26)) were comparable to results found in other RWD. Conclusions: Overall survival, time to treatment, and other outcomes were consistent with comparable RWD sources, (Stewart M, 2019; Sean K 2018) regardless of treatment timeframe. We demonstrated that our real world evidence based approach provides a robust method for analyzing clinical outcomes, supporting the validity of real world data to complement clinical trials and inform clinical decisions.
Real-world outcomes of pembrolizumab plus carboplatin plus paclitaxel or nab-paclitaxel in non-small cell lung cancer (NSCLC).
Authors: Tabah Ashley , Huggar David , Kish Jonathan , Bapat Bela , Liassou Djibril , Gajra Ajeet , Miller Talia , Copher Ronda , Patel Manali I.
Published: May 2020

e21717

Background: Pem+carbo+pac or nab-pac are approved first-line (1L) treatments for metastatic squamous NSCLC since 10/30/2018. Difference in real-world outcomes of these triplet combinations are unknown. Methods: Providers from community oncology practices in the USA reviewed the charts of consecutive NSCLC patients initiating 1L treatment with either pem+carbo+pac (“pac”) or pem+carbor+nab-pac (“nab-pac”) from 06/01/18-12/31/18; data were collected 11/22/2019-12/23/2019. Patient characteristics, treatment patterns, grade 3/4 toxicities, disease response, date of progression/death were retrospectively abstracted into an electronic case report form (eCRF). Univariate statistics were used to compare demographics, clinical characteristics and treatment patterns between cohorts. Overall survival (OS) from 1L was calculated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare the risk of death between the two cohorts adjusted for multiple variables. Results: eCRFs were completed for 254 patients: nab-pac = 115, pac = 139. Median follow-up was 13.1 mos in both cohorts. No differences in demographics/clinical characteristics were noted (table). Median duration of therapy was 3.9 mos (nab-pac) and 3.8 mos (pac) (p = 0.58). Objective response rate: nab-pac = 69.6%, pac = 69.8% (p = 0.96). Receipt of maintenance therapy: nab-pac = 44.4%, pac = 48.9% (p = 0.47) . Median time to progression was 6.4 mos for nab-pac (n = 32) and 3.5 mos for pac (n = 29) (p = 0.10). 13.9% of nab-pac and 7.9% of pac patients had grade 3/4 toxicities (p = 0.16). At data cut-off, 18 nab-pac (15.7%) and 30 pac (21.6%) patients were deceased. Median OS from initiation of 1L was not reached. 12-month OS: nab-pac = 87.8% (95% CI: 81.8-93.8), pac = 79.3% (95% CI: 72.5-86.2). Adjusting for sex, age, race, PD-1 expression level, charlson comorbidity index (CCI) and ECOG-PS patients treated with nab-pac had a 40% reduction in mortality risk (HR = 0.55, 95% CI: 0.30-1.01, p = 0.05). Conclusions: No significant differences in demographics and clinical characteristics between patients treated with nab-pac or pac were observed. Median duration of treatment was equivalent with a marginally longer 12-month survival rate, and a lower adjusted mortality risk, among patients treated with nab-pac. [Table: see text]
Prognostic role of filgrastim and derived neutrophil-to-lymphocyte ratio (dNLR) in the effectiveness of PD1/PDL1 inhibitors in previously treated non-small cell lung cancer.
Authors: Marin Pozo Juan Francisco , Muñoz Cid Carmen Lucia , Merino Almazán Macarena , Claramunt García Raquel , Marin Caba Elvira , Pérez Cano Encarnación , Ortega Granados Ana Laura
Published: May 2020

e21729

Background: A neutrophil/lymphocyte ratio (NLR)> 5 or its derivative (dNLR)> 3 have been proposed as a prognostic factor for non-effectiveness of nivolumab in non-small-cell lung cancer (NSCLC). Filgrastim (GSGF) increases the absolute counts of neutrophils in patients (pts) with neutropenia. The aim of this study is to determine whether the use of GSGF, during the first line therapy of nSCLC, influences the effectiveness of the anti-PD1/PDL1 inhibitors (aPD1-i) used in subsequent line. Methods: We designed a single center, observational and retrospective study. We included NSCLC pts treated with Nivolumab (NIV), Pembrolizumab (PEM) or Atezolizumab (ATE) between January-16 and November-19 after primary platinum-based chemotherapy at one hospital from south Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Results were assessed using Kaplan-Meier method for GSGF-use stratified by NLR, dNLR, or aPD1-i. Results: 79 pts were enrolled (91% men), mean age was 66.7 years, 78.8% of pts had ECOG = 0-1. NIV was used at 55.7%, ATE 25.3% and PEM 19.0% of pts. 50.6 % of tumors were squamous histology. GSGF was used at 19 pts (24.1%). The mean WBC at the start of therapy with aPD1-I was 9300 cell/µL (sd=3900), range 3600-25800 cell/µL. NLR was less than 5 in 46 pts (58.2%) and dNLR was less than 3 in 51 pts (64.6%). The mean time from the start of line previously to start the treatment with aPD1-i was 9.7 months (sd=8.6). The median for treatment duration was 4.1 months [IC 95%; 2.3-5.8].OS was 7.3 months [IC 95%:3.4-11.3] and PFS was 4.4 months [IC95%:2.3-6.5]. We found statistically significant difference in OS between patients with dNLR <3, median 13.9 months [IC95%; 5.4-22.4] vs patients with dNLR> 3, median 3.6 months [IC95%; 2.4-4.7], p=0.037. The median OS was higher in pts GSGF-treated (6.1 months) vs pts no GSGF-treated (3.3 months), p=0.347, no reaching statistical significance. No difference was found in OS by NLR. The analysis for OS by GSGF use stratified by dNLR is shown in the table. Conclusions: The effectiveness of aPD1-i in nSCLC patients previously treated and with dNLR>3, a priori poor prognosis, is greater in the group of patients treated with GSGF, reaching OS like pts with dNLR <3. [Table: see text]
Cause of mortality in patients with lung cancer and brain metastasis.
Authors: Thawani Rajat , Fakhoury Kareem , Becker Kevin Douglas
Published: May 2020

e21743

Background: Lung cancer is the most common cause of cancer-related mortality and most deaths are associated with metastatic disease, with brain being a common site. Historically, whole brain radiation therapy was the treatment of choice and resulted in median survivals in the range of 6 months. There is no consensus in management of patients who have brain metastasis with systemic disease.We aim to evaluate patients with brain metastasis from lung cancer for cause of death, to investigate whether patients died from central nervous system (CNS) progression or systemic disease or other/undetermined causes. Our hypothesis is that most deaths in contemporary patients with brain metastasis in lung cancer are due to systemic disease, and less commonly due to CNS progression. Methods: In this retrospective observational study, we did a chart review of all adult patients with non-small cell lung cancer and brain metastasis or leptomeningeal disease, who received treatment at Maimonides Cancer Center between 2010 and 2017. Patients with unavailable or incomplete medical records were excluded. Baseline characteristics, pathological factors of the tumor and cause of death was collected from the chart. The cause of death was categorized into systemic and brain causes, and difference in characteristics of patients and tumor were studied. Results: A total of 132 patients were included and their charts were reviewed. Out of 132, 96 could have a clear cause of death categorized into systemic or brain causes, the rest were either mixed or uncategorized. We found that 33% patients died of brain metastasis, and related causes, whereas 67% died of systemic disease progression. There were no different in the two groups in terms of gender, smoking status, histology, size of lung lesion, or number and size of brain lesion. The patients who died of brain metastasis had a significantly higher age, and worse Eastern Cooperative Oncology Group status. Interestingly, the patients who died of systemic causes more commonly had adrenal metastasis (12 vs 0) which was statistically significant, and liver (14 vs 3) metastasis which was not statistically significant. Conclusions: Two-thirds of patients with brain metastases died of systemic disease rather than CNS progression. This may reflect improvements in systemic and local therapies to forestall cancer progression in the CNS. This finding suggests that delaying systemic therapy for CNS treatment may negatively impact overall cancer control. More research needs to be done to answer this question with certainty, including prospective clinical trials.
Comparison of baseline patient characteristics in immunotherapy versus targeted therapy trials for advanced melanoma.
Authors: Handa Shivani , Petrone Giulia , Rutledge John R , Friedlander Philip Adam
Published: May 2020

e22012

Background: Immune checkpoint inhibitors (ICI) or BRAF/MEK targeted therapy are both FDA approved first line options for BRAF mutant advanced melanoma. However, the optimal sequencing of these approaches and the profile of patients who benefit the most from one treatment over the other is suboptimally defined. Methods: We compared the baseline characteristics of the participants enrolled in the immunotherapy (IT) and targeted therapy (TT) trials quoted in the NCCN guidelines as the guidelines are used by many oncologists who do not subspecialize in melanoma to formulate treatment plans. Data was gathered about age, sex, race, ECOG score, LDH levels, stage, BRAF mutation status, PD-L1 expression and prior lines of therapy. Results: Median age range was younger in the TT population (48-57 y) as compared to the IT population (56-65 y); > 50% were males. 54-82% patients in the IT trials had an ECOG score of 0. Relatively more patients (pts) with ECOG score of 1 were included in Dabrafenib/ Trametinib and Vemurafenib/Cobimetinib trials (62-65%). Most pts had stage IV M1c disease. LDH levels were similar in IT and TT trials. V600E mutation was uniformly more common in the TT trials as expected. PD-L1 expression varied widely; from 23% to 81% patients with a high PD-L1 expression. Trials evaluating pembrolizumab included patients (7-26%) who were previously treated with BRAF/MEK inhibitor, however TT trials did not include as many pts exposed to ICI. Conclusions: Age range and sex ratio of the pts included in the trials were representative of the epidemiology of melanoma, but race was underreported. TT studies trended towards a younger median age range than patients treated in the IT studies. However optimal biomarkers for initial treatment choice cannot be determined by the patient demographics and characteristics presented in the studies discussed in the NCCN guidelines. Studies randomizing treatment sequence and identification of biomarkers prognostic of patient specific treatment efficacy are needed. Comparison of the IT and TT studies support the choice of either approach as initial treatment in pts with BRAF mutant melanoma lacking contraindications.
Skin cancer and deep learning for dermoscopic images classification: A pilot study.
Authors: Belaala Abir , Bourezane Yazid , Terrissa Labib Sadek , Al Masry Zeina , Zerhouni Noureddine
Published: May 2020

e22018

Background: The prevalence of skin cancer is increasing worldwide. According to World Health Organization (WHO),there is one in every three cancers diagnosed in US is a skin cancer. Traditional ways for skin cancer diagnosis have shown many limitations: inadequate accuracy, consume much time, and effort. In order to assist dermatologists for earlier and accurate diagnosis, we propose to develop a computer aided diagnosis systems for automatic classification of skin lesions. Deep learning architectures are used in this area based on a new convolutional neural network that can classify skin lesions with improved accuracy. Methods: A public dataset of skin lesions HAM10000 ("Human Against Machine with 10000 training images") is used for training and testing. For the validation of our work, a private dataset is collected from a dermatology office in Besançon (France). This dataset contains 45 different dermatoscopic images of skin lesions (Basal cell carcinoma, squamous cell carcinoma and Actinic keratosis) with their histology results. In this research, a three-phase approach was proposed and implemented: Phase one is preprocessing the data; by amputate missing values using the mean filling method. The dermoscopy images in the dataset were downscaled to 224X224 pixels. Then, data augmentation was applied to solve the imbalanced data problem. Finally, the ten-fold cross-validation method was applied to compare the performance of three CNN architectures used in literature: DenseNet 201, ResNet 152, and VGGNet with our proposed architecture. Results: Results obtained with our model show the highest classification accuracy 0.95, a sensitivity of 0, 96, a specificity of 0.94, and outperforms other algorithms in classifying these skin lesions. Conclusions: Our research improves the performance of computer aided diagnosis systems for skin lesions by giving an accurate classification. The use of this system helps dermatologists to make accurate classification with lower time, cost, and effort. Our future work will focus on generalizing the domain by developing a model that can classify various lesions using various types of data (dermoscopic images, histological images, clinical data, sensors data...etc) using the advanced techniques in literature of transfer learning and adaptors models.
Second primary melanoma in advanced melanoma patients treated with anti-PD-1 monoclonal antibodies.
Authors: Funck-Brentano Elisa , Charvet Estelle , Chaplain Louise , Gantzer Amelie , Kassem Oula , Longvert Christine , Blom Astrid , Dupin Nicolas , Aractingi Sélim , Hamon Maxime , Zimmermann Ute , Emile Jean-François , Sohier Pierre , Kramkimel Nora , Saiag Philippe
Published: May 2020

e22025

Background: Development of a second primary melanoma (SCPM) has not been reported in melanoma patients treated with anti-PD-1 monoclonal antibodies (mAb), in contrast with those reported in BRAF-inhibitor-treated patients. Our aim was to report arising SCPM in patients with advanced melanoma treated with anti-PD-1 therapy. Methods: Retrospective study, conducted in 2 referral centres, including advanced melanoma patients who developed a SCPM after anti-PD-1 mAb initiation, between September 2010 and May 2019. BRAF or NRAS mutational status was assessed by targeted NGS panels, real-time PCR, and immunohistochemistry. Results: Among a total of 509 patients treated with anti-PD-1 mAb, 4 had a SCPM (incidence: 0.8%; 95%CI: 0.02-1.57%). All patients were treated with nivolumab, in first (N = 3) or second line after progression with BRAF + MEK inhibitors (N = 1). No immune-related adverse event greater than grade 2 according to Common Terminology Criteria for Adverse Events version 5.0. was observed in these 4 cases; a vitiligo-like depigmentation (grade 1) was observed in two patients. The median time from the first nivolumab infusion to the SCPM diagnosis was 17.5 months (range: 5-21). All patients developed the SCPM after achieving a complete response. Nivolumab administration had been discontinued (4 months prior) in one patient. Histology revealed 4 superficial spreading melanomas (SSM): one invasive (without BRAFV600 mutation) and 3 intraepidermal melanomas (2 with a BRAFV600E mutation and one with a NRASQ61H mutation). 3 patients had risk factors for developing multiple melanomas: a dysplastic nevus syndrome, a high number of nevi (≥100 nevi), and a family history of melanoma in first-degree relatives and constitutional heterozygous mutation of exon 2 of the CDKN2A gene. Occurrence of SPCM did not alter advanced melanoma treatment. With a median follow-up of 29 months [range: 18-41] from the first anti-PD-1 mAb infusion, all patients had prolonged CR, and treatment was discontinued in all patients, without relapse after a median 11.5 months [0-18] off therapy. The median duration of nivolumab treatment was 15.5 months [10-24]. Conclusions: Although anti-PD-1 mAb could theoretically decrease the risk of developing another melanoma in metastatic melanoma patients, we found 4 such cases, highlighting the importance of regular clinical screenings for new primary melanoma in patients with metastatic melanoma even when responsive to anti-PD-1 therapy. Immune checkpoint inhibitors do not totally prevent the risk of occurrence a SCPM.
A process mining approach to real-world advanced melanoma treatments.
Authors: Gerard Camille Lea , Tavazzi Erica , Gatta Roberto , Delyon Julie , Cuendet Michel A , Michielin Olivier
Published: May 2020

e22040

Background: Process Mining (PM) is an emerging discipline with promising potential in oncology, which offers a time-oriented perspective on the clinical events that define the patient’s (pts) path of care, from diagnosis to follow-up. PM enables us to 1) build unsupervised models that automatically discover frequent patterns and detect unexpected behaviors, and 2) show the pts flow through predefined models, allowing quantitative assessments of conformance/divergence between reality and expected behaviors or medical guidelines. Methods: We explored the potential of PM to analyze treatments in a real-world melanoma cohort of 212 advanced melanoma pts treated with tyrosine kinase inhibitors (TKI), chemotherapy, or immunotherapy (IO) since 2010. 44% of pts are BRAF mutated, 24% NRAS mutated, and 16% WT. Using PM, we characterize the sequences of treatment according to type of drugs, order and timing of consecutive lines. We use kernel density estimations, Fisher or Wilcoxon tests to assess differences between groups. As main endpoint we assess the overall survival (OS) with respect to specific patterns of care followed by the pts using Kaplan-Meier analysis with log-rank test. Results: This approach provides important self-consistency checks for data and reveals the most frequent treatment sequences, and the associated outcome. The 324 administered treatments, characterized in terms of type and occurrence, are: TKI (23%), antiCTLA4 + antiPD1 (22%), antiPD1 (21%), and antiCTLA4 (20%). The overall 3-year OS is 56.9% (95% CI: 49.2 – 65.8). We identified 50 distinct patterns, which can be further aggregated into relevant cohorts to provide real-world answers to medical questions. Among others, we probed the influence of treatment order: IO single (any BRAF status), IO → TKI, TKI → IO (see table). Preliminary results suggest that pts treated with TKI → IO had shorter OS despite balance prognostic factors to IO → TKI group. IO → TKI provides short-term benefits with 1.5-year OS similar to IO alone, but degraded 3-year OS. Conclusions: The PM approach enables fast and efficient visual inspection of the data, emphasizing treatment sequences over time and allowing stratification at different levels. More population attributes and outcomes will be included to further characterize treatment sequences and provide real-world insights into future personalized care options. [Table: see text]
Circulating tumor DNA (ctDNA) in patients (pts) with metastatic uveal melanoma (UM) treated with protein kinase C inhibitor (PKCi).
Authors: Park John J. , Diefenbach Russell J. , Byrne Natalie , Kefford Richard , Long Georgina V. , Scolyer Richard A. , Gray Elin , Carlino Matteo S. , Rizos Helen
Published: May 2020

e22054

Background: UM is the most common primary intraocular malignancy. About 50% of pts with UM will develop metastatic disease and currently there is no effective treatment in metastatic UM. Nearly 95% of UM harbour mutually exclusive activating mutations in GNAQ, GNA11, CYSTLR2 and PLCb4. We sought to evaluate ctDNA in metastatic UM pts receiving experimental early phase clinical trial of LXS196, a PKCi, using digital droplet PCR (ddPCR) and targeted ion torrent next generation sequencing (NGS). Methods: 17 pts with metastatic UM were identified from a single institution. Pt characteristics including mutation status, disease volume using sum of product of disease (SPOD), best response and clinical benefit defined as partial response (PR) or stable disease (SD) > 6 months were assessed. Plasma samples at baseline and early on treatment (EOT) (14 – 30 days on treatment) were analysed for ctDNA using mutation specific ddPCR. A custom made NGS panel covering 95% of UM mutations was used on plasma ctDNA samples at baseline and on treatment. The allele frequency (AF) of activating mutations identified using ion torrent NGS analysis were then validated using ddPCR. Results: Using ddPCR, 16/17 pts had a +ve ctDNA at baseline with baseline ctDNA copies correlating with LDH (n = 17, p = < 0.001, Spearman’s rank r = 0.8015) and SPOD (n = 17, p = 0.005, r = 0.6642). 16/17 pts had paired samples at baseline and EOT and only 4/16 pts were undetectable at EOT. These 4 pts were GNA11 Q209L positive, had below median SPOD (median 5986, range 200 – 16782), and low numbers of liver metastases (median 9, range 1 – 49). Of these 4 pts, one had PR and three had SD (two with SD > 6 months) as best response. A further 8 pts had +ve ctDNA at baseline and showed a reduction in EOT (reduction range 46 – 99%). Of these 8 pts, one had PR, four had SD (two with SD > 6 months) and three had progressive disease (PD) as best response. The remaining 4 pts showed increasing ctDNA from baseline to EOT and all had SD/PD. Using ROC analysis, EOT ctDNA predicted clinical benefit to PKCi (AUC 0.84, [95% confidence interval, 0.65-1.0, p = 0.026]). AF of ion torrent NGS correlated significantly with ddPCR AF (n = 30, p = < 0.001, r = 0.968). Ion torrent NGS was able to detect additional mutations implicated in UM prognosis including SF3B1 mutations in 4 pts. Conclusions: Baseline ctDNA correlates with baseline LDH level and disease volume. EOT ctDNA predicted clinical benefit to PKCi. The ctDNA AF derived from ddPCR and NGS was comparable and targeted ion torrent NGS was useful in detecting driver as well as additional mutations in UM.
Open label, phase II study of axitinib, a selective inhibitor of vascular endothelial growth factor receptors, in patients with stage III malignant melanoma.
Authors: Zhuang Eric , Jakowatz James G. , Yamamoto Maki , Fruehauf John P.
Published: May 2020

e22062

Background: This open-label, phase II study investigated the clinical activity and safety profile of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) in patients with stage III melanoma. Methods: Eligible patients had histology proven stage III melanoma, at least 1 target lesion as defined by RECIST, and no prior systemic therapy. Primary end point was objective response rate (ORR) according to RECIST v1.1; response was also considered if there was a ≥ 25% reduction in the involved nodal basin specific uptake value (SUV) on PET/CT. Secondary endpoints included duration of response (DOR), progression free survival (PFS), and overall survival (OS). Axitinib 5mg was given orally twice each day; treatment continued until tumor progression, unmanageable toxicity, or if the patient withdrew consent. After two months of therapy, patients then underwent definitive surgical resection of their involved nodal basins; one month after surgery patients would restart axitinib. In the 1st stage, 18 patients were to be enrolled; if there was ≥ 1 response, then the study would proceed to the 2nd stage with enrollment of additional 14 patients. At the end of the study, if there were at least 4 confirmed responses, then axitinib would be recommended for further studies in this patient population. Results: Fifteen patients were screened, and eleven patients were initiated on protocol therapy. Median age was 63 years (range 37-88). Three patients (27%) had BRAF mutations. Objective response rate was 45.5% [95% confidence interval (CI), 16.7-76.6], comprised of one complete and four partial responses, with two patients ongoing. Median duration of response was 8 months (95% CI, 3.5-13.3). Stable disease was observed in one patient, with an overall disease control rate of 54.5% (95% CI, 23.3-83.2]. Median progression free survival was 4 months [95% CI, 2.8-8.5]. Median overall survival was 59 months [95% CI, 29.6-67.5]. The most frequently reported ( > 15%) nonhematologic, treatment-related adverse effects were hypertension, fatigue, and diarrhea. Conclusions: Axitinib showed single-agent activity among patients with stage III melanoma and had favorable effect as a neoadjuvant therapy. Axitinib was well tolerated and safety profiles were consistent with previous reports from previous studies in patients with melanoma. Axitinib alone or combined with other therapies merits further research. Clinical trial information: NCT01321437.
Effectiveness of PD1-inhibitors in advanced Merkel cell carcinoma: Real life data in a Swedish cohort.
Authors: Bjorn-Andtback Hannah , Masucci Giuseppe V. , Villabona Lisa Elena Esther
Published: May 2020

e22063

Background: Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer that affects the elderly. Most cases are associated with the Merkel cell polyomavirus. It has previously been shown in clinical trials that MCC respond to immunotherapy with PD1 and PDL1-inhibition. PD1-inhibitiors have been used to treat MCC at Karolinska University Hospital in Sweden since 2016. The aim of this study is to describe the PD1-MCC-cohort at Karolinska. Methods: Patients with inoperable MCC that were treated with PD1-inhibitor at the oncology dept between August 2016 and February 2020 at Karolinska were included in the study, and response data was assessed retrospectively. Response was assessed clinically and through CT-scans. Results: Among 12 treated pts, median age was 75 yrs, 8 male and 4 female, 10 were treatment naive, 2 with prior chemotherapy. 10 pts received pembrolizumab and 2 pts nivolumab. No pts discontinued treatment due to side-effects. Comorbidities seen in the cohort were amongst others Atrial fibrillation (4 pts), Systemic Lupus Erythematosus (1), Hypertension (6), COPD (1), Aortic stenosis (2) and congestive heart failure (1). Follow-up time was median 10 months (range 2-43). First evaluation varied between 2-4 months with the majority at ~3 months. At first evaluation ORR was 75% and PFS and OS was 75% and 100% respectively. At 10 months, PFS and OS rates were 58% and 67% respectively. At study end mean PFS was 15,4 months and mean OS 17,8 months. 6 pts (50%) were still in response. Conclusions: PD1-inhibitors in clinical use in this cohort induced rapid and durable tumor responses in patients with advanced MCC, and the treatment was well tolerated. Our conclusion is that a PD1-inhibitor is a feasible and effective treatment for advanced Merkel Cell Carcinoma in the clinical setting.
Cutaneous melanoma mutation pathways and driver mutations as racially biased.
Authors: Sanchez Margaret I , Grichnik James Michael
Published: May 2020

e22066

Background: Cutaneous melanoma (CM) demonstrates differences in its clinical prevalence in different racial groups. CM generally exhibits a high tumor mutational burden (TMB) and mutually exclusive driving mutations in NRAS, BRAF or KIT. TMB may be driven by different pathways including ultraviolet radiation (UVR), oxidation and deamination. UVR is the most common mutational signature found in CMs, but deamination and oxidation are also present. Methods: We analyzed 321 CMs exome data from The Cancer Genome Atlas network. BRAF, NRAS, KIT and those without (WT) were used to divide the melanomas. Germline SNPs with racial information (Caucasian, African and Asian) that were enriched in melanomas with a particular driving mutation were identified. Results: We compared the 3 racial groups across the 4 driving mutation types, Asian SNPs were significantly higher in KIT, African in WT and Caucasian in BRAF and NRAS. The melanomas were also evaluated by the type of substitution mutations including CC > TT for UV, G > T for oxidative damage and (G/A)C (G) > (G/A)T(G) for deamination. UV and deamination appeared inversely proportional, while oxidative damage appeared to be independent. UV signal was more prominent in BRAF and NRAS groups. KIT had a greater percentage of deamination while WT revealed more oxidative damage. We further compared UV and non-UV (CC > TT absence) KIT subgroups for racial differences. Asian SNPs were greatly increased in non-UV subgroup whereas Caucasian SNPs were in UV subgroup. Further, the non-UV KIT subgroup was divided into deamination and oxidative damage subgroups to compare racial differences. Deamination was significantly increased in Asians whereas oxidative damage was higher in Caucasians. In the case of the WT group, African SNPs were significantly higher in the non UV subgroup and were primarily correlated with oxidative damage. Conclusions: This study suggests that racial genetic background may predispose the distinctive mutational and genetic environments of melanoma development.
Efficacy and safety of IO103 a novel anti PD-L1 vaccine in basal cell carcinoma.
Authors: Jørgensen Nicolai Grønne , Kaae Jeanette , Grauslund Jacob Handlos , Met Özcan , Svane Inge Marie , Ehrnrooth Eva , Andersen Mads Hald , Zachariae Claus , Skov Lone
Published: May 2020

e22070

Background: Basal cell carcinoma (BCC) is the most frequent malignancy. Case reports have described effect of immune checkpoint blocking antibodies (ICB) against PD-1 in BCC (Cannon et al. 2018, Chang et al. 2017, Ikeda et al. 2016, Winkler et al. 2017). Autoimmune side effects of ICB are well known and limits a wider use in BCC. IO103 is a peptide vaccine against major programmed death (PD) ligand 1 (PD-L1). In a first-in-man study of IO103 in patients with multiple myeloma (NCT03042793) regression of co-existing BCC was observed in two patients which prompted the current study. Methods: A single arm phase IIa study of subcutaneous IO103 (q2w six times followed optionally by q4w an additional 3 times) with the adjuvant Montanide for patients with BCC (NCT03714529). Eligible patients had at least one biopsy verified BCC suitable for sequential biopsies, and no severe autoimmune comorbidity. The primary endpoints were categorical clinical responses of target tumors, percent change in largest diameter of target tumor and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor, if more than one tumor the remaining were designated non-target tumors. Only target tumors were sequentially biopsied during vaccinations. Results: Ten patients were included at the department of Dermatology, Herlev and Gentofte Hospital, Denmark between November 19th, 2018 and October 21st, 2019. Based on target lesion assessment, one patient achieved partial response. Two additional patients achieved CR in non-target lesions, including one lesion that had recurred after previous surgery. Categorical clinical responses are given in table. Adverse events were max CTCAE Grade 2 and related events were only CTCAE Grade 1 reversible reactions. Vaccine induced immune responses against PD-L1 were detected in blood samples from eight of ten patients and vaccine specific skin-infiltrating lymphocytes from five of eight tested patients. Conclusions: In this exploratory study, one target tumor achieved partial response. Nonetheless, the two clearances and one partial response of non-target tumors suggest that IO103 may be effective against BCCs. The vaccine was well tolerated. Understanding the underlying molecular mechanisms would be needed to select patients for further studies with IO103. Clinical trial information: NCT03714529. [Table: see text]