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Rationale: Lung cancer is the leader in high mortality rates among other malignancies. This is largely due to the asymptomatic course of the disease and, as a consequence, to its late diagnosis. To optimize the oncology service of the Novosibirsk region in terms of diagnosis, treatment, follow-up and management of this patient category, it seems prudent to study the epidemiological characteristics of non-small cell lung cancer (NSCLC) with consideration of its histologic types. Aim: To perform the survival analysis in patients with squamous cell lung cancer (SCLC) and adenocarcinoma of the lung (ACL) depending on their age, sex and disease stage. Materials and methods: We analyzed medical files of patients diagnosed with SCLC (n = 3007) and ACL (n = 3049) who were treated in the Novosibirsk Regional Oncologic Dispensary from 2015 to 2019. The study included 4758 men and 1298 women (mean age, 68 years; men 66.8 years, women 69.1 years). Results: The majority (96%) of the NSCLC patients were above 50 years of age. The 5-year survival rate of the patients with SCLC and ACL was below 20%. Median survival of the SCLC patients was 443 days (interquartile range [IQR] 138; 1241), of those with ACL, 552 (IQR 107; 1511) days. At the diagnosis of NSCLC, 67% of the patients had stage III/IV of the disease. Maximal survival (10 to 15 years) was found in the NSCLC patients aged 61 years who had been diagnosed at stage III of the disease. Testing of the hypothesis on the impact of histological type of NSCLC on survival at a particular disease stage (Wilcoxon-Gehan test for unpaired samples) showed an association between the survival and histological type only for stage IV (p = 0.000001); median survival in ACL IV was 80 days and in SCLC IV, 104 days. Men comprised 87% of the SCLC group and 73% of the ACL one. In SCLC, there was no gender difference in the median survival rates (log rank test, p = 0.48). The median survival of the female patients with ACL was longer than that of the male ones (329 vs 169 days, log rank test, p = 0.000001). The major proportion of the SCLC and ACL patients was in the age range of 61 to 75 years (59% and 50%, respectively). The least favorable outcomes were seen in the patients below 50 years of age, and the most favorable, in those above 75 years. In SCLC, the median survival was 156 days in the patients below 50 years of age, 238.5 days in those aged from 51 to 60 years, 300 days in the age of 61 to 75 years, and 487 days in the patients above 75 years of age (chi-square test 98.77097; df = 3; p = 0.000001). In ACL, the respective values were 143, 201, 210.5, and 230 days (chi-square test 23.93492; df = 3; p = 0.00003). Conclusion: The analysis of survival of the patients with SCLC and ACL in the Novosibirsk region has shown that the disease stage and age significantly impact the median survival. These are the characteristic features of the general morbidity and mortality from NSCLC.

Dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) are known to be crucial for the antitumor response and are still included in various treatment regimens in cancer immunotherapy research. In the present study, a cell-based protocol was evaluated, involving the use of original DNA constructs encoding the wide range of TAA epitopes expressed on different epithelial cancers. The constructs were transfected into in vitro-generated DCs of patients with various types of cancer, including breast, colorectal and non-small cell lung cancer. The direct cytotoxicity assay of effector cells, activated with the transfected DCs, revealed a significant increase in cytotoxicity against autologous tumor cells. The use of DNA constructs encoding a large number of TAAs for insertion into DCs in vitro, aiming to activate a T-cell response may prove to be a reliable and unified approach for immunotherapy and for the prevention of relapse in patients with epithelial cancers.

In the context of the slowdown in the recovery of the American economy in 2022 big US businesses faced a number of problems: ongoing difficulties with production in China, rising inflation and the conflict in Ukraine. Nevertheless, the rise in raw material prices that followed in connection with these events compensated for losses to a number of American corporations as a result of which they came out with record profits in the second quarter of 2022. Nevertheless, one of the negative consequences of this was the tendency to monopolization, in the field of housing construction, threatening problems for the US market economy.

Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC.Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/mA total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia.Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days.gov Identifier. NCT03098030.

Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months. Results: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59–2.79]; P =0.53). Conclusions: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02663908.

EGFR tyrosine-kinase inhibitors (TKIs) are used as targeted therapeutics for the treatment of advanced non-small cell lung cancer (NSCLC) with EGFR-activating mutations. EGFR C797S is common causes of acquired resistance to third-generation TKIs. There is wide-spread opinion that resistance-conferring mutation present even in a small proportion of cancer cells before the start of therapy could potentially predict poor response to a targeted drug. In our study, we tested whether C797S can be found in previously untreated NSCLCs. We analyzed DNA samples extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue sections of 470 lung adenocarcinoma patients, including 235 samples with activating EGFR mutations. Screening was performed using highly sensitive droplet digital PCR assay. No tumor samples with baseline C797S were identified. C797S does not occur in TKI-naïve NSCLCs and provide evidence that screening for this mutation before TKIs administration may not be necessary.

Dendritic cells (DCs) loaded with tumor-associated antigens (TAA) are known to be the important agents in antitumor response realization and still figure in lots of treatment schemes in cancer immunotherapy research. Here, we evaluated a cell-based protocol involving the use of original DNA constructs encoding the wide range of TAA epitopes expressed on different epithelial cancers. The constructs were transfected into ex-vivo-generated DCs of cancer patients (breast cancer, colorectal cancer, and non-small cell lung cancer). Direct cytotoxicity assay of effector cells, activated with the transfected DCs, showed a significant increase in the cytotoxicity against autologous tumor cells. The use of DNA-constructs encoding a large number of TAA’s for the in vitro DC loading to activate the T cell response could be a reliable and unified approach for immunotherapy and relapse prevention in patients with epithelial cancers.

Background Cosibelimab is a high affinity, fully-human IgG1 monoclonal antibody that directly binds to programmed death ligand-1 (PD-L1) and blocks its interaction with the programmed death receptor-1 (PD-1) and B7.1 receptors to restore an anti-tumor immune response. Cosibelimab has the additional benefit of a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against tumor cells. Study CK-301–101 is a global, multicenter, multicohort trial that is enrolling patients (pts) with select advanced cancers, including pivotal cohorts of pts with metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) and a cohort of pts with previously untreated advanced non-small cell lung cancer (NSCLC). Methods Eligible pts were aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1. The cSCC cohorts enrolled pts with histologically confirmed metastatic or locally advanced cSCC not amenable to local therapy. The NSCLC cohort enrolled previously untreated NSCLC pts with advanced disease and a PD-L1 tumor proportion score of at least 50%. Pts received a fixed dose of 800 mg cosibelimab administered intravenously every two weeks. Anti-tumor activity was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and were conducted every 8 weeks for the initial 32 weeks on study, and every 12 weeks thereafter. Results As of August 2020, 114 pts (73M/41F, median age 66 years) with diverse tumor types have been enrolled and treated with cosibelimab. Among these pts, 103 (90%) experienced ≥1 treatment-emergent adverse event (AE), 42 (37%) experienced a grade ≥3 AE, and 6 (5%) experienced a grade ≥3 drug-related AE. The most common AEs were fatigue (25%), anemia (21%), rash (18%) and nausea (16%) and the most common drug-related AEs were fatigue (15%) and rash (14%). In 42 cSCC pts evaluable for response, ORR based on investigator assessment of tumor response was 55% (95% confidence interval [CI]: 39, 70), including 5 (12%) complete responses, with 20/23 (87%) responses ongoing and 10 responses ≥6 months in duration as of data cutoff. In 25 NSCLC pts evaluable for response, ORR based on investigator assessment was 44% (95% CI: 24, 65), with 5/11 (45%) responses ongoing and 10 responses ≥6 months in duration. Conclusions Cosibelimab has a predictable and manageable safety profile and demonstrated robust clinical activity in cSCC and NSCLC pts, including durable complete and partial responses. Updated results will be presented. Trial Registration NCT03212404 Ethics Approval The study was approved by an appropriate ethics committee for each participating institution. Informed consent was obtained for all subjects. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

9017 Background: Although SCLC is highly responsive to initial therapy, most pts relapse < 1 y. Topotecan (T) and irinotecan (I) are used in 2LT of SCLC; however, treatment response is low: ≤10-25% and median survival is ~4-5 months. Preclinical studies support GD2 as an SCLC target. This study evaluated the combination of D+I vs. I alone or T alone in 2LT of SCLC pts. Methods: Pts with RR SCLC, Eastern Cooperative Oncology Group 0-1, were randomized 2:2:1 to receive D 16-17.5 mg/m2 intravenously (IV) plus I 350 mg/m2 IV (Day 1 q21d), I 350 mg/m2 IV (Day 1 q21d), or T 1.5 mg/m2 IV (Days 1-5 q21d). Randomization was stratified by duration of response to prior platinum therapy. Primary endpoint was overall survival (OS) in pts treated with D+I vs. I alone and was analyzed using stratified log-rank test and COX regression. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate, ORR + stable disease (CBR). Safety was assessed. Results: 471 pts were randomized to D+I (n = 187), I (n = 190), or T (n = 94). Baseline characteristics were balanced (24.2% women; mean ± SD age 61.6 ± 8.7 y). Median OS was similar in pts receiving D+I (6.9 [3.5,10.9] months) vs. I alone (7 [3.6,13.1] months) (HR [95% CI]: 1.12 [0.9,1.4]; P = 0.3132) or T alone (7.4 [3.8,12.8] months) (HR [95% CI]: 1.05 [0.8,1.37]; P = 0.7233). Median PFS was similar in pts receiving D+I (3.5 [1.5,6.2] months) vs. I (3 [1.4,5.7] months) or T (3.4 [1.6, 6.1] months) alone. ORR was similar in pts receiving D+I (17.1%) vs. I (18.9%) or T (20.1%) alone. CBR was similar in pts receiving D+I (67.4%) vs. I (58.9%) or T (68.1%) alone. Grade 3 or higher adverse events were experienced by 77% D+I, 69.5% I, and 86.4% T pts. Conclusions: Treatment with D+I was not superior to established 2LT for RR SCLC. Exploratory analyses are ongoing to evaluate GD2 expression in circulating tumor cells, select protein biomarkers, and any correlative impact on observed response. Clinical trial information: NCT03098030.

MDM2 inhibitors are promising anticancer agents that induce cell cycle arrest and tumor cells death via p53 reactivation. We examined the influence of Mycoplasma hyorhinis infection on sensitivity of human lung carcinoma cells NCI-H292 to MDM2 inhibitor Nutlin-3. In order to unveil possible mechanisms underlying the revealed effect, we investigated gene expression changes and signal transduction networks activated in NCI-H292 cells in response to mycoplasma infection. Sensitivity of NCI-Н292 cells to Nutlin-3 was estimated by resazurin-based cell viability assay. Genome-wide transcriptional profiles of NCI-H292 and NCI-Н292Myc.h cell lines were determined using Illumina Human HT-12 v3 Expression BeadChip. Search for key transcription factors and key node molecules was performed using the geneXplain platform. Ability for anchorage-independent growth was tested by soft agar colony formation assay. NCI-Н292Myc.h cells were shown to be 1.5- and 5.2-fold more resistant to killing by Nutlin-3 at concentrations of 15 and 30 µM than uninfected NCI-Н292 cells (P

Cancer is associated with a reduction in immature and mature circulating dendritic cells (DCs), and with an impaired migratory capacity, compared with healthy donors. Therefore, modern approaches to the in vitro generation of DCs loaded with tumor antigens and their use for inducing antitumor immune responses in vivo are being investigated. The purpose of the present study was to investigate the phenotypic and functional characteristics of peripheral blood DC subsets in patients with non-small cell lung cancer (NSCLC), and the development of an antitumor cytotoxic response by mononuclear cells (MNCs) from patients using in vitro generated antigen-primed DCs. Heparinized peripheral venous blood samples were obtained from 10 healthy donors and 20 patients with a histologically verified diagnosis of NSCLC. The ability of antigen-activated DCs to stimulate the activity of MNCs against autologous tumor cells was evaluated using a cytotoxic test. Peripheral blood DC subsets from patients with NSCLC were identified to be decreased and to exhibit an impaired ability to mature, compared with healthy donors. Furthermore, DCs generated from MNCs from patients with NSCLC were able to stimulate a specific cytotoxic response when loaded with autologous tumor lysates or RNA and matured, in vitro. A perforin and granzyme B-dependent mode of cytotoxicity was primarily induced. The ability of DCs loaded with tumor antigens to increase the cytotoxic activity of MNCs against NSCLC cells in vitro indicates the effective induction and co-stimulation of T lymphocytes by the generated DCs.

Cancer is associated with a reduction in immature and mature circulating dendritic cells (DCs), and with an impaired migratory capacity, compared with healthy donors. Therefore, modern approaches to the in vitro generation of DCs loaded with tumor antigens and their use for inducing antitumor immune responses in vivo are being investigated. The purpose of the present study was to investigate the phenotypic and functional characteristics of peripheral blood DC subsets in patients with non-small cell lung cancer (NSCLC), and the development of an antitumor cytotoxic response by mononuclear cells (MNCs) from patients using in vitro generated antigen-primed DCs. Heparinized peripheral venous blood samples were obtained from 10 healthy donors and 20 patients with a histologically verified diagnosis of NSCLC. The ability of antigen-activated DCs to stimulate the activity of MNCs against autologous tumor cells was evaluated using a cytotoxic test. Peripheral blood DC subsets from patients with NSCLC were identified to be decreased and to exhibit an impaired ability to mature, compared with healthy donors. Furthermore, DCs generated from MNCs from patients with NSCLC were able to stimulate a specific cytotoxic response when loaded with autologous tumor lysates or RNA and matured, in vitro. A perforin and granzyme B-dependent mode of cytotoxicity was primarily induced. The ability of DCs loaded with tumor antigens to increase the cytotoxic activity of MNCs against NSCLC cells in vitro indicates the effective induction and co-stimulation of T lymphocytes by the generated DCs.

e13109 Background: There is a little information of correlation between EGFRm rate in cytology and plasma samples in Russian NSCLC population. The interim analysis of the study aimed to evaluate the prevalence and types of EGFR mutations in paired cytology and plasma samples in treatment-naive patients with advanced NSCLC. Methods: ORTUS is a multicenter, non-interventional, prospective study to determine EGFR mutations rate in treatmentnaive Russian patients with advanced NSCLC. ClinicalTrials.gov identifier: NCT02321046. The study enrolled 426 patients in stage IIIB / IV of NSCLC. Interim analysis covered the data of 214 cytology verified patients (mean age - 62.6 (range 32-86) years, 58,4% of men) with EGFRm test results in paired cytology and ctDNA samples. 99.5% cases were adenocarcinoma. The proportion of non-smokers/smokers/exsmokers was 46.3%/36%/17.8% respectively. Stage IV disease was in 81% of cases; 84.1% of patients had symptoms. DNA isolation performed using QIAamp DNA FFPE Tissue Kit for cytology and Qiagen Circulating Nucleic Acid Kit for ctDNA according to the manufacturer’s instructions. EGFR gene mutations were analyzed using THerascreen RGQ EGFR PCR Kit in cytology samples and RGQ Plasma EGFR PCR kit in plasma (Qiagen). Results: EGFRm was identified in 17,8% cytology samples (38/214) that is close to 20,2% (1759/8716) in Russian tissue EGFRm study (Imyanitov et al., 2016). 10,3% of paired ctDNA samples were EGFRm positive. Sensitivity and specificity for ctDNA were 42.1%, and 97.1% respectively. The EGFRm rate was 3,9% and 2,6% in smokers, 5,3% and 0% in ex-smokers and 33,3% and 21,2% in nonsmokers in cytology and plasma samples respectively. EGFRm rate and concordance between cytology and ctDNA are presented in a table. EGFRm in ctDNA were detected more frequently in M1a/b groups (p = 0,028). Conclusions: Cytology samples are appropriate for EGFRm testing in NSCLC patients in comparison with tumor tissue ones. High tumor burden (positive metastatic status) is an important factor for successful mutation analysis in ctDNA. [Table: see text]