Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first‑line treatment of ER+/HER2− advanced breast cancer (PALOMA‑1, TRIO‑18)

Purpose Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole signifcantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748; P=0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the fnal overall survival (OS) and updated safety results. Methods Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. Results A total of 165 patients were randomized. At the data cutof date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratifed hazard ratio for OS was 0.897 (95% CI 0.623–1.294; P=0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to frst subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Conclusions Palbociclib plus letrozole treatment led to a numerical but not statistically signifcant improvement in median OS. Pfzer Inc (NCT00721409

Modern education technologies: 21

Since modern technologies produce new global education trends, education prospects redesign, and new opportunities and threats assessments are needed. The new educational technology development phase was researched as an answer to modern world challenges. The strategic priorities of education in the EU are analyzed. New technologies, practices, and related needs: financing, digital integration, accessibility, informational security were studied and generalized. Higher education key trends and their transformation in the context of the COVID-19 crisis new opportunities and threats were researched. The analysis of the seven years of NMC Horizon and other research emerging educational technologies adoption forecasts provided in the research shows significant discrepancies related to extreme uncertainty. Five educational trend groups from the NMC Horizon report 2020 were reviewed. The author defined the remote education tools and their importance on the example of the university providing online/mixed learning. The anonymous polls among lecturers and students performed in the spring of 2020 (just after the COVID-19 quarantine announcement) show the most highly demanded tools are Google Meet, email, specific learning systems such as Moodle. The barriers to fully-fledged remote education are technical problems and occasionally poor Internet connectivity. The participants are quite ready to learn and to use digital tools for education. However, the absence of live communication increases workload during online learning, and other factors arise as the factors lowering student activity. During severe transformation, the main tasks of education are accessibility and diversity

Cluster analysis of decarbonisation of the regional economy in the context of the potential of united territorial communities and the alter global vector of development

Research background: The article examines the peculiarities of the economy decarbonisation in Ukraine’s regions using cluster analysis, which helped to determine the composition of clusters of regions with a similar level of the economy decarbonisation and common features. The study takes into account specific indicators. Close attention is paid to the study of the dynamics of carbon dioxide emissions into the atmosphere from stationary sources per unit of gross regional product in certain clusters and to the identification of factors and measures to reduce them. The development of energy innovations is identified as a key area for decarbonisation of regional economies. The role of decentralization reform is analysed and regarded as a factor in the growth of decarbonisation and development of energy projects in united territorial communities, which, in general, increases the level of effectiveness of the regional policy on innovative development of the energy sector. Purpose of the article: to identify key factors in the growth of decarbonisation of the economy of the regions. Methods: general scientific methods were used, the main of which are: cluster analysis – to identify clusters of regions with a similar level of decarbonisation of the economy, system analysis – to apply a comprehensive approach to the study of factors influencing the growth of decarbonisation of the economy and determining an effective balanced regional policy towards innovative development of the energy sector. Findings & Value added: The directions of balancing the regional policy towards ensuring innovative development of the energy sector of the national economy in the conditions of Industry 4.0 are determined

Створення багатоконтурної системи безпеки інформаційних взаємодій у соціокиберфізичних системах

The object of the study is a multi-loop security system of information interactions in socio-cyberphysical systems. The dynamic nature of physical environments inherently challenges the ability of socio-cyber-physical systems to perform adequate control actions for physical assets in many contexts. However, adaptation and evolution actions must be evaluated before implementation in the control system to ensure fault tolerance while minimizing risks. Therefore, the design of socio-cyber-physical systems must ensure not only reliable autonomy, but also operational fault tolerance and safety. The proposed approach is based on the integration of targeted (mixed) threats based on the synthesis of technical cyber threats with social engineering methods. This approach allows forming a dynamic security model based on the analysis of the interaction of various agents in socio-cyberphysical systems, which makes it possible to increase the level of counteraction to targeted (mixed) cyber threats. The results of modeling are based on the proposed classification of threats using social engineering methods, which allows cyberattackers to ensure the probability of implementing targeted threats up to 95–98 %. The proposed classification of threats based on social engineering methods will allow forming an additional parameter for the objectivity of target threats, taking into account their integration and synergy. At the same time, the presented model will make it possible to timely provide knowledge about the possibility of implementing a targeted attack and timely take preventive countermeasures. This approach will improve the set of protection measures, as well as promptly create an increase in the level of resistance of the company's personnel (organization, enterprise, etc.) to threats of social engineeringОб’єктом дослідження є многоконтурная система безпеки інформаційних взаємодій у соціокіберфізичних системах. Динамічний характер фізичних середовищ за своєю природою ставить під сумнів здатність соціокіберфізичних систем виконувати адекватні дії з управління керованими фізичними активами у багатьох контекстах. Однак дії з адаптації та еволюції повинні бути оцінені до їх реалізації в керованій системі, щоб забезпечити стійкість до відмови при мінімізації ризиків. Отже, дизайн соціокіберфізичних систем повинен забезпечувати не тільки надійну автономність, а й експлуатаційну стійкість до відмов і безпеку. Пропонований підхід ґрунтується на комплексуванні цільових (змішаних) загроз на основі синтезу технічних кіберзагроз із методами соціальної інженерії. Такий підхід забезпечує можливість формувати динамічну модель безпеки на основі аналізу взаємодії різних агентів у соціокіберфізичних системах, що дозволяє підвищити рівень протидії цільовим (змішаним) кіберзагрозам. Наведені результати моделювання ґрунтуються на запропонованій класифікації загроз методів соціальної інженерії, що дозволяє кіберзловмисникам забезпечити ймовірність реалізації цільових загроз до 95–98 %. Запропонована класифікація загроз на основі методів соціальної інженерії дозволить сформувати додатковий параметр об'єктивності цільових загроз з урахуванням їхнього комплексування та синергії. При цьому представлена модель дозволить своєчасно забезпечити знання про можливість реалізації цільової атаки та своєчасно вжити превентивних заходів протидії. Такий підхід дозволить покращити комплекс заходів захисту, а також своєчасно сформувати підвищення рівня протидії персоналу компанії (організації, підприємства тощо) загрозам соціальної інженері

Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN):updated results from a randomised, controlled, open-label, phase 3 trial

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.</p

Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer

BACKGROUND Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.METHODS We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety.RESULTS A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events.CONCLUSIONS Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis