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A randomized, double-blind trial compared pembrolizumab with placebo in patients with advanced cervical cancer who were also receiving platinum-based chemotherapy with or without bevacizumab. The median progression-free survival was 10.4 months with pembrolizumab and 8.2 months with placebo. Overall survival at 2 years was 50.4% and 40.4%, respectively.

Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2–IIB node positive vs stage III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1—by investigator or by histopathologic confirmation of suspected disease progression—and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab–chemoradiotherapy group and 531 to the placebo–chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3–22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab–chemoradiotherapy group versus 57% in the placebo–chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55–0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab–chemoradiotherapy group and 81% in the placebo–chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49–1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab–chemoradiotherapy group and 69% in the placebo–chemoradiotherapy group. Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2–IIB with node-positive disease or stage III–IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2–IIB node positive vs III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab–chemoradiotherapy group and 531 patients in the placebo–chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3–34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4–86·1) in the pembrolizumab–chemoradiotherapy group and 74·8% (70·1–78·8) in the placebo–chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50–0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab–chemoradiotherapy group and 371 (70%) of 530 in the placebo–chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab–chemoradiotherapy group and 90 (17%) of 530 patients in the placebo–chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Introduction/BackgroundPembrolizumab has shown efficacy in patients with cervical cancer. The effect of chemoradiotherapy may be enhanced by immunotherapy. ENGOT-cx11/GOG-3047/KEYNOTE-A18 (NCT04221945) assessed efficacy and safety of pembrolizumab + concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC).MethodologyEligible patients with newly diagnosed, previously untreated, high-risk LACC (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA) were randomized 1:1 to receive 5 cycles of pembrolizumab 200 mg or placebo Q3W + CCRT, then 15 cycles of pembrolizumab 400 mg or placebo Q6W. The CCRT regimen included 5 cycles (with optional sixth dose) of cisplatin 40 mg/m2 Q1W + EBRT then brachytherapy. Patients were stratified by planned EBRT type (IMRT/VMAT vs non-IMRT/non-VMAT), stage at screening (stage IB2-IIB vs III-IVA) and planned total radiotherapy dose. Primary endpoints were PFS per RECIST v1.1 by investigator and OS.Results1060 patients were randomized to pembrolizumab+CCRT (n=529) or placebo+CCRT (n=531). At the protocol-specified first interim analysis (January 9, 2023, data cutoff), median follow-up was 17.9 mo (range, 0.9–31.0). Pembrolizumab+CCRT showed a statistically significant improvement in PFS vs placebo+CCRT. 24-mo PFS was 67.8% with pembrolizumab+CCRT vs 57.3% with placebo+CCRT; median PFS was not reached in either group (HR=0.70 [95% CI, 0.55–0.89; P=0.0020]); results were consistent across all prespecified subgroups. With only 103 events (42.9% maturity), the addition of pembrolizumab to CCRT showed a favorable trend in OS (HR=0.73 [95% CI, 0.49–1.07]); these data have not crossed the boundary of statistical significance. Grade ≥3 TRAE incidence was 67.0% in the pembrolizumab+CCRT group and 60.0% in the placebo+CCRT group.ConclusionPembrolizumab+CCRT showed a statistically significant and clinically meaningful improvement in PFS and a favorable trend in OS compared with placebo+CCRT in patients with high-risk locally advanced cervical cancer and had a manageable safety profile. These data suggest pembrolizumab+CCRT can be considered as a new standard of care for this population.DisclosuresDisclosures are provided via the ESGO COI Disclosure forms.

Background: Detection of left ventricular hypertrophy, atherosclerotic plaques of large arteries and renal injury in hypertension might provide more accurate risk classification, covering the underwater part of ICEBERG. Objectives: The primary purpose of Intensive / Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG) study protocol is to determine the impact of different laboratory tests on cardiovascular risk stratification of subjects with BP levels ≥130/85 mm Hg. Methods: ICEBERG is a healthcare organization-based epidemiological study, conducted at 217 centers (20 cardiology -1- and 197 primary healthcare centers -2-). Each protocol had two arms: (A) treated hypertensive patients and (B) subjects with BP ≥130/85 mmHg; under no medication for at least 3 months. Risk assessment of 10.313 subjects was performed. Results: The study subjects were 57.6±11.6 years old. In 1A, when evaluated by clinical data, only 26.0% of subjects were in very high added risk group (VH). Further 10.5% switched to VH, when routine laboratory tests were applied. In 1B, 49.4% of the subjects were in VH with baseline evaluation. Further 9.5% switched from lesser to VH with intensive risk evaluation. When H and VH are combined, the proportion of subjects in H or VH bounced from 57.9% to 89.6%. In 2B, 38.2% of the subjects were in VH with baseline evaluation. Further 7.2% switched from lesser to VH with initial risk evaluation. Conclusion: When different risk evaluation panels are applied, up to 30% percent of the subjects switch from lesser to H or VH. Thus, evaluation of people with high-normal and high BP should include intensive methods to detect occult vascular target organ damage. (See Table) Protocol/arm N Panel 1-A 765 Serum biochemistry, Quantitative microalbuminuria, Serum hs-CRP, ECG 1-B 178 1-A plus Echo and Carotid USG 2-A 8503 Qualitative microalbuminuria 2-B 936 same as 1-A

Background: The association between high blood pressure and end organ damage identifies high risk of future cardiovascular events. Microalbuminuria (MAlb) and high sensitive C-reactive protein (hs-CRP) tests for screening might improve risk classification. Objectives: The primary purpose of Intensive / Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG) study protocol is to determine the impact of different laboratory tests on cardiovascular risk evaluation and stratification of subjects with BP levels ≥130/85 mm Hg. This report focuses on the impact of MAlb and hs-CRP testing on risk evaluation. Methods: ICEBERG is a healthcare organization-based epidemiological study, with two sub-protocols: at 20 cardiology centers (1) and 197 primary healthcare centers (2). Each protocol had two arms: (A) treated hypertensive patients and (B) subjects with BP ≥130/85 mmHg; under no medication for at least 3 months. 1817 subjects were included in the analysis. Initial risk assessment was performed according to ESC-ESH 2003 guidelines and reassessment was done by using quantitative MAlb (urinary albumin/creatinine ratio ≥22 mg/g for male and 31 mg/g for female) and Hs-CRP levels (>1 mg/L). Results: Study subjects were 54.1±11.9 years old (female 57.6%). The frequency of MAlb were 21.2%, 22.3% and 23.5%, and the frequency of elevated hs-CRP were 86.9%, 85.3% and 82.4%, in groups 1A, 1B and 2B, respectively. 62.9%, 68.1% and 66.2% of the patients were in high (H) or very high (VH) added risk groups with initial evaluation, in groups 1A, 1B and 2B, respectively. When MAlb plus hs-CRP tests are taken into account, 15.6%, 14.1% and 16.9% switch from lesser to H/VH risk groups occurred. Conclusion: In people with high-normal and high BP, MAlb and hs-CRP measurement may improve risk stratification.

Background: Although microalbuminuria determined by quantitative methods seems to be more accurate, using dipstick is simpler and cheaper, thus making this qualitative method more suitable for screening in primary healthcare settings for hypertensive patients. Objectives: The primary purpose of Intensive / Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG) study protocol is to determine the impact of different laboratory tests on cardiovascular risk stratification of subjects with BP levels ≥130/85 mmHg. This report focuses on the comparison of the impact of quantitative and qualitative microalbuminuria detection on the risk evaluation. Methods: ICEBERG is a healthcare organization-based epidemiological study, conducted at 217 centers (20 cardiology -1- and 197 primary healthcare centers -2-). In group 1, microalbuminuria was calculated as urinary albumin/creatinine ratio in random urine samples (quantitative method) and in group 2, urine strips (Micral-test Microalbuminuria®, Roche Diagnostics GmBh) were used (qualitative method). 9268 patients were included in the analysis (765 and 8496 in groups 1 and 2, respectively). Initial risk assessment was performed according to ESC-ESH 2003 guidelines and reassessment was done by using quantitative and qualitative methods. Results: The study patients were 58.4±11.3 years old (female 65.3%). 53.8% and 54.5% of the patients were classified into high (H) or very high (VH) added risk group with baseline evaluation, in groups 1 and 2, respectively. Switching upwards to H/VH risk group was 6.2% and 6.6%, when quantitative and qualitative microalbuminuria tests were taken into account, respectively. Conclusion: Risk group switching upwards were found to be similar in both quantitative and qualitative microalbuminuria groups, thus demonstrating that dipstick microalbuminuria detection has almost the same effectiveness when compared with quantitative.

Background: Accurate detection of organ damage poses a problem in the management of hypertensive patients, and an important part of the patient's status remains hidden like the underwater part of an ICEBERG. The detection of left ventricular hypertrophy (LVH) by echocardiography (Echo) might provide a more accurate risk classification of the patients. Objectives: The primary purpose of Intensive / Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG) study protocol is to determine the impact of different laboratory tests on cardiovascular risk evaluation and stratification of subjects with blood pressure levels ≥130/85 mmHg. This report focuses on the impact of Echo on the detection of LVH. Methods: ICEBERG is a healthcare organization-based epidemiological study. This report includes the data of subjects with BP ≥130/85 mmHg, enrolled at 20 cardiology centers. The subjects were evaluated for the presence of LVH by ECG and Echo. All ECG and Echo recordings were evaluated centrally by two blinded experienced observers. A total of 164 subjects were included in the analysis. ECG criteria for LVH were the presence of Sokolow-Lyons (>38 mm) or Cornell (>2440 mm.ms) indexes. LVH was defined as left ventricular mass index (LVMI) ≥125 g/ m2 for male (M) and ≥110 g/m2 for female (F) by Echo. Results: The study subjects were 50.1±11.3 years old with a F/M ratio of 1.3. Only 0.7% and 2.7% of the subjects had positive Sokolow-Lyons and Cornell index, respectively. The proportion of subjects with LVH detected by ECG was 3.7%. On the other hand, 42.4% of the subjects were interpreted as having LVH when evaluated by Echo. LVH was detected by Echo in 40.2% of the subjects who had no LVH by ECG. Conclusion: Since the presence of any target organ damage including LVH changes the risk class of the people with high-normal or high blood pressure, screening with Echo might prevent them from being undertreated.