Benefit In Subgroups Research Articles

Efficacy and Safety of Systematic Corticosteroids treatment among HIV-Positive Patients with Tuberculosis: a systematic review and meta-analysis of randomized controlled trials.

The efficacy and safety of corticosteroids in patients with human immunodeficiency virus (HIV) and tuberculosis (TB) remain controversial. PubMed, Embase, Web of Science, and the Cochrane Database were searched on September 19, 2024. The primary outcome was all-cause mortality, while secondary outcomes included serious adverse events. A random-effects model calculated risk ratios (RR) with 95% confidence intervals (CIs). Seven RCTs involving 1,410 HIV-positive TB patients were included. Corticosteroid use was not significantly reduce all-cause mortality (RR = 0.91, 95% CI: 0.79-1.04, P = 0.17) and did not significantly increase serious adverse events (RR = 0.96, 95% CI: 0.82-1.13, P = 0.63). This meta-analysis of seven RCTs involving 1,410 HIV-positive TB patients found that corticosteroid treatment neither significantly reduced all-cause mortality nor increased serious adverse events. Further large-scale RCTs with extended follow-up are needed to explore potential benefits in subgroups, optimize treatment protocols, and inform clinical guidelines.

Does Remdesivir Lower COVID-19 Mortality? A Subgroup Analysis of Hospitalized Adults Receiving Supplemental Oxygen.

The first Adaptive COVID-19 Treatment Trial (ACTT-1) showed that remdesivir improved COVID-19 recovery time compared with placebo in hospitalized adults. The secondary outcome of mortality was almost significant overall (p = 0.07) and highly significant for people receiving supplemental oxygen at enrollment (p = 0.002), suggesting a mortality benefit concentrated in this group. We explore analysis methods that are helpful when a single subgroup benefits from treatment and apply them to ACTT-1, using baseline oxygen use to define subgroups. We consider two questions: (1) is the remdesivir effect for people receiving supplemental oxygen real, and (2) does this effect differ from the overall effect? For Question 1, we apply a Bonferroni adjustment to subgroup-specific hypothesis tests and the Westfall and Young permutation test, which is valid when small cell counts preclude normally distributed test statistics (a frequently unexamined condition in subgroup analyses). For Question 2, we introduce Qmax, the largest standardized difference between subgroup-specific effects and the overall effect. Qmax simultaneously tests whether any subgroup effect differs from the overall effect and identifies the subgroup benefitting most. We demonstrate that Qmax strongly controls the familywise error rate (FWER) when test statistics are normally distributed with no mean-variance relationship. We compare Qmax to a related permutation test, SEAMOS, which was previously proposed but not extensively applied or tested. We show that SEAMOS can have inflated Type 1 error under the global null when control arm event rates differ between subgroups. Our results support a mortality benefit from remdesivir in people receiving supplemental oxygen.

Effectiveness of the MyDiaMate application in reducing diabetes distress in adults with type 1 diabetes: Study protocol of the multi-national, randomised-controlled MyREMEDY trial.

Diabetes distress is common among people with type 1 diabetes (T1D), negatively affecting quality of life, self management, and diabetes outcomes. E-health-based interventions could be an effective and low-cost way to improve the psychological care for people with T1D experiencing diabetes distress. The MyREMEDY study aims to test the effectiveness of the online unguided self-help intervention MyDiaMate in decreasing diabetes distress in adults with T1D. MyDiaMate is based on Cognitive Behavioural Therapy and consists of eight modules, each focusing on a different aspect of living with T1D that is often experienced as burdensome (e.g. hypoglycaemia, fatigue). The effectiveness of MyDiaMate will be tested through a randomised-controlled trial across four European countries (the Netherlands, Germany, Spain and the United Kingdom). Six hundred and sixty adults (N = 165 per country) with T1D will be recruited and randomised with a balance of 2:1 into the intervention and care as usual groups. Intervention group members receive access to MyDiaMate for 6 months, care as usual group members receive access after 3 months for 3 months. Participants fill in questionnaires at 0 (baseline), 3 (effectiveness) and 6 months (follow-up). Primary outcome is diabetes distress at 3 months. Secondary outcomes are emotional well-being, psychological self-efficacy in relation to diabetes, social engagement, fatigue, and glycaemic outcomes. Moreover, logdata of MyDiaMate use is passively collected. Linear mixed model analyses will be used to test the effectiveness of MyDiaMate along with identifying which user subgroup benefits most from MyDiaMate use. Clinicaltrials.gov NCT06308549.

Prophylactic ICD Survival Benefit Prediction: Review and Comparison between Main Scores.

Current guidelines advocate for the use of prophylactic implantable cardioverter defibrillators (ICDs) for all patients with symptomatic heart failure (HF) with low ejection fraction (EF). As many patients will never use their device and some are prone to device-related complications, scoring systems for delineating subgroups with differential ICD survival benefits are crucial to maximize ICD benefit and mitigate complications. This review summarizes the main scores, including MADIT trial-based Risk Stratification Score (MRSS) and Seattle Heart Failure Model (SHFM), which are based on randomized trials with a control group (HF medication only) and validated on large cohorts of 'real-world' HF patients. Recent studies using cardiac MRI (CMR) to predict ventricular arrhythmia (VA) are mentioned as well. The review shows that most scores could not delineate sustained VA incidence, but rather mortality without prior appropriate ICD therapies. Multiple scores could identify high-risk subgroups with extremely high probability of early mortality after ICD implant. On the other hand, low-risk subgroups were defined, in whom a high ratio of appropriate ICD therapy versus death without prior appropriate ICD therapy was found, suggesting significant ICD survival benefit. Moreover, MRSS and SHFM proved actual ICD survival benefit in low- and medium-risk subgroups when compared with control patients, and no benefit in high-risk subgroups, consisting of 16-20% of all ICD candidates. CMR reliably identified areas of myocardial scar and 'channels', significantly associated with VA. We conclude that as for today, multiple scoring models could delineate patient subgroups that would benefit differently from prophylactic ICD. Due to their modest-moderate predictability, these scores are still not ready to be implemented into clinical guidelines, but could aid decision regarding prophylactic ICD in borderline cases, as elderly patients and those with multiple co-morbidities. CMR is a promising technique which might help delineate patients with a low- versus high-risk for future VA, beyond EF alone. Lastly, genetic analysis could identify specific mutations in a non-negligible percent of patients, and a few of these mutations were found to predict an increased arrhythmic risk.

Does Adjuvant Chemotherapy Benefit Patients with T4 N0 Colon Cancer?

Background and Objectives: Colorectal cancer (CRC) poses a major global health challenge, with high incidence rates and ongoing treatment debates. Adjuvant chemotherapy benefits for high-risk subgroups, particularly stage II disease, remain controversial. This study seeks to clarify this issue by specifically examining the impact of adjuvant chemotherapy on disease-free survival (DFS) and overall survival (OS) in patients diagnosed with T4 colon cancer. Materials and Methods: This retrospective study analyzed patients undergoing radical surgery for T4 colon cancer between 2002 and 2023. Results: Our study of 184 pT4 pN0 colon cancer patients revealed that 79.3% received adjuvant chemotherapy. Multivariate analysis demonstrated significant DFS improvement: a 60% reduction in risk for those who received adjuvant therapy (0.40 95% CI: 0.25-0.62, p < 0.001). Lymphovascular invasion (LVI) and adjuvant treatment were also significantly associated with OS. Adjuvant treatment reduced mortality by 60% (HR: 0.40, 95% CI: 0.23-0.68, p = 0.001). Patients with LVI had a 1.9-fold increase in mortality (HR: 1.94, 95% CI: 1.17-3.20, p = 0.011). These findings underscore the potential value of adjuvant chemotherapy and highlight the importance of treatment completion in managing T4 colon cancer. Conclusions: Our study identifies LVI and adjuvant chemotherapy as key prognostic factors in T4 colon cancer patients. These results support the consideration of adjuvant chemotherapy in this patient population.

Differential Impact of Virtual Family-Centered Rounds in the Neonatal Intensive Care Unit by Social Factors: A Post Hoc Subgroup Analysis.

Background: Barriers to attending family-centered rounds (FCR) exist for socially disadvantaged families. Using telehealth to conduct virtual FCR could potentially promote equitable parent/guardian FCR access. The objective of this work was to assess whether the effects of a virtual FCR intervention on parent FCR attendance varied by subgroups defined by social factors. Methods: We conducted a post hoc analysis of a randomized controlled trial of virtual FCR in the neonatal intensive care unit. Parents of intervention arm infants were invited to participate in virtual FCR plus usual care; control arm infants received usual care. Participants were analyzed according to the assigned group and by race/ethnicity, insurance, mother's education, and neighborhood health conditions. We used Poisson regression to estimate and compare FCR parent attendance rates. Heterogeneity of intervention effects was assessed using interaction terms to evaluate the relative benefit of the intervention in increasing parent FCR attendance. Results: We included all enrolled trial subjects (74 intervention, 36 control). Intervention arm infants had 3.36 (95% confidence interval [CI]: 2.66-4.23) times the FCR parent attendance rate of subjects in the control arm. Compared with the corresponding reference subgroup, intervention benefits were 2.15 times (95% CI: 1.30-3.56) better for racial/ethnic minorities, 3.08 times (95% CI: 1.59-5.95) better for those with private insurance, 2.68 times (95% CI: 1.12-6.40) better for those whose mother reported no college education, and 4.14 times (95% CI: 2.07-8.25) better for those from a neighborhood with worse health conditions. Conclusions: Virtual FCR improved parent FCR attendance overall, with even greater benefits for certain subgroups. Further research is needed to mitigate the differential benefit demonstrated for privately insured subjects.

Generating the Evidence Base for Convalescent Plasma Use for a New Infectious Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swept across the world in the waning months of 2019 and emerged as the cause of the coronavirus disease 19 (COVID-19) pandemic in early 2020. The use of convalescent plasma (CP) for prior respiratory pandemics provided a strong biological rationale for the rapid deployment of COVID-19 convalescent plasma (CCP) in early 2020 when no validated treatments or prior immunity existed. CCP is an antiviral agent, with its activity against SARS-CoV-2 stemming from specific antibodies elicited by the virus. Early efforts to investigate the efficacy of CCP in randomized clinical trials (RCTs) that targeted hospitalized patients with COVID-19 did not demonstrate the overall efficacy of CCP despite signals of benefit in certain subgroups, such as those treated earlier in disease. In contrast, studies adhering to the principles of antibody therapy in their study design, choice of patient population, and product qualification, i.e., those that administered high levels of specific antibody during the viral phase of disease in immunocompromised or very early in immunocompetent individuals, demonstrated benefits. In this chapter, we leverage the knowledge gained from clinical studies of CCP for COVID-19 to propose a framework for future studies of CP for a new infectious disease. This framework includes obtaining high-quality CP and designing clinical studies that adhere to the principles of antibody therapy to generate a robust evidence base for using CP.

Epidemiology and Risk Factors of Actinic Keratosis. What is New for The Management for Sun-Damaged Skin.

Actinic keratosis (AK) is considered a chronic skin disease mostly caused by long-term exposure to UV radiation and other risk factors such as immunosuppression, leading to an individual susceptibility for skin cancer manifestation. The treatment of AK is laborious and costly, and the incidence of skin cancer is forecasted to double until the year 2030 in an aging society.Risk factors in AK for malignant transformation in cutaneous squamous cell carcinoma (cSCC) are not fully understood, but studies suggest that histological features, such as atypia in the basal epidermal third and basal proliferation (PRO score) in AK play a pivotal role for development of malignancy. As the clinical appearance of AK does not correlate with the risk for malignancy, guidelines suggest treating every single AK lesion upon diagnosis. Skin imaging techniques, such as line-field confocal optical coherence tomography (LC-OCT) can help to provide an individual holistic follow-up for AK lesions by non-invasive visualization of atypia and basal proliferation. A follow-up for patients with AK may be critical for treatment success in terms of strengthening therapy adherence. When AK presents therapy refractory, cSCC manifests in nearly 30% of the cases after several years. Patients with AK suffering from field cancerization and immunosuppression are susceptible for a severe course of disease including metastasis and high mortality rates. Those vulnerable subgroups benefit from close skin cancer screening, early adequate treatment and chemoprevention, such as niacinamide or acitretin. Skin cancer prevention is substantial. Primary prevention should include chemical and physical UV-light protection and avoidance of indoor tanning. Secondary prevention is essential in high-risk populations, such as fair skin type elderly men and STORs. Tertiary prevention should comprise adequate treatment strategies to prevent therapy resistance, reoccurrence and cSCC, especially when field cancerization and immunosuppression are present.

Optimal candidates and surrogate endpoints for HAIC versus Sorafenib in hepatocellular carcinoma: an updated systematic review and meta-analysis.

Hepatic artery infusion chemotherapy (HAIC) has been a long-standing intervention for hepatocellular carcinoma (HCC). Despite positive clinical outcomes, its inclusion in guidelines remains limited due to a lack of evidence-based support. This study aims to identify optimal target populations for HAIC and validate associations between intermediate endpoints with overall survival (OS). Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The primary search strategy was based on medical subject headings terms (MeSH) using "Hepatic arterial infusion chemotherapy", "HAIC", "Sorafenib", "Nexavar", "hepatocellular carcinoma", "HCC", "Liver cancer", combined with free text words. Data extraction, quality assessment, and analysis were performed according to pre-registered protocol. A total of 26 studies, 6456 HCC patients were included for analysis (HAIC, n=2648; Sorafenib, n=3808). Pooled outcomes revealed that Sorafenib demonstrated better OS only in patients who were refractory to trans-arterial chemoembolization (TACE) (HR=1.32,95%CI [1.01-1.73]), in other subgroups or overall HCC population HAIC consistently outperformed Sorafenib in patients' survival. Radiologically, higher response rates in the HAIC group does not necessarily translate into survival improvement, but the hazard ratios (HRs) of 1y-OS (R2=0.41, P=0.0044) and 1y-progression free survival (1y-PFS) (R2=0.77, P=0.0002) strongly correlated with the patients OS. Meanwhile, larger tumour size (HR=1.86,95%CI [1.12-3.1, 95%), heavier tumour burden (HR=2.32, 95%CI [1.33-4.02), existence of MVI or EHS (HR=1.65,95%CI[1.36-2]; HR=1.60,95%CI[1.19-2.14]), and AFP >400ng/mL (HR=1.52, 95%CI [1.20-1.92]) were identified as independent risk factors for OS, while HAIC treatment (HR=0.54, 95%CI[0.35-0.82]) and lower BCLC stage (HR=0.44, 95%CI[0.28-0.69]) were potential protective factors for HCC patients. HAIC monotherapy appears noninferior to Sorafenib in HCC treatment, with potential benefits in specific subgroups. The robust correlation between 1y-OS/1y-PFS and OS, alongside identified risk and protective factors from the present study, offers valuable insights for designing future large prospective studies in this field.

P-681 LH priming before ovarian stimulation in POSEIDON-4 patients: effects on oocyte recovery and post ICSI/IVF pregnancy rates

Abstract Study question Can a seven-day long LH priming treatment preceding ovarian stimulation (OS) improve follicular responses, oocyte yields and ICSI/IVF outcomes of POSEIDON-4 patients? Summary answer A seven-day long LH priming can substantially increase pregnancy rates through specific benefits in different subgroups of POSEIDON-4 patients. What is known already The combination of advanced maternal age (AMA) with diminished ovarian reserve (DOR) has become one of the most relevant and complex topics in the field of reproductive medicine. AMA/DOR patients appear to be refractory to increased gonadotropin dose and may benefit from strategies specifically capable of increasing the population of FSH-responsive small follicles before the onset of ovarian stimulation (OS). Androgen mediated LH intra-ovarian activity stimulates early follicular development. Pre-treatment with LH has been suggested to improve ICSI/IVF outcomes in normal responders but has not been assessed in AMA/DOR patients, despite the prevalence and relevance of this population. Study design, size, duration Retrospective cohort study from 2022 to 2023, including 235 POSEIDON-4 patients stimulated with FSH+LH in a flexible antagonist protocol with oestradiol pre-treatment (n = 129) or with the same stimulatory treatment preceded by a seven-day LH priming (150 IU/day) combined with GnRH agonist downregulation (n = 106). Follicular responses, oocyte recovery and ICSI/IVF outcomes were compared between treatment-groups in overall POSEIDON-4 patients and in a subgroup of patients with AMH &amp;lt;0.75 ng/mL (n = 77/Control, n = 59/LH priming). Participants/materials, setting, methods All participants were POSEIDON-4 caucasian patients aged 35 to 44 years undergoing a single homologous ICSI/IVF cycle in our clinic. Outcomes in the form of percentages were compared with the Fisher’s exact test, whereas differences in continuous variables were assessed with the Wilcoxon sum rank test. A multivariate analysis was performed to control for the interference of unequal variations in maternal age, AMH, insemination method and presence of male subfertility. Main results and the role of chance Patients in different treatment groups did not differ (p &amp;gt; 0.05) regarding maternal age (39.2±2.5 vs. 39.3±2.5), basal FSH serum concentrations (11.0±4.6 vs. 10.1±4.3) and antral follicle count (6.3±3.0 vs. 6.4±3.3, for patients stimulated with and without LH priming, respectively), but patients treated with LH priming presented slightly lower AMH serum levels (0.56±0.3 vs. 0.63±0.3; p = 0.05). Nevertheless, patients treated with LH priming achieved a twice higher clinical pregnancy rate per cycle (19.8% vs. 9.3%; p = 0.02), accompanied by a 40% reduction in cycle cancellation (32.1% vs. 45.0%; p = 0.03) and increased production of viable embryos (transferred fresh + frozen) per cycle (1.22±1.09 vs. 0.94±1.07; p = 0.02) and per oocyte inseminated (48.3% vs. 38.5%; p = 0.01), but did not differ regarding follicular outputs or oocyte yield. The multivariate analysis indicated a robust association between LH priming and pregnancy achievement, independently of potential confounding variables (OR = 2.52; p = 0.02). A two-fold increase in pregnancy achievement was also observed in severely restricted POSEIDON 4 patients (AMH &amp;lt;0.75 ng/mL) subjected to the LH priming (p = 0.05), which in this case was accompanied by higher oocyte yields per cycle (3.3±2.8 vs. 2.2±2.0; p = 0.04) and per pick (3.9±2.6 vs. 2.3±2.0; p &amp;lt; 0.01). Limitations, reasons for caution This study is limited by its retrospective nature and the data may be potentially influenced by the use of different downregulation strategies in the treatment-groups, even if the literature indicates equivalent performance for these strategies in the population under analysis. Wider implications of the findings The present data strongly suggest that a seven-day LH priming preceding OS can markedly improve ICSI/IVF outcomes of POSEIDON-4 patients, while indicating that this strategy benefits in different ways subgroups of this increasingly prevalent patient category. These findings thus represent new valuable parameters for the progress of ovarian stimulation. Trial registration number NA

HGG-42. COMBINED PRECLINICAL AND CLINICAL INVESTIGATION OF WHICH PEDIATRIC HIGH-GRADE GLIOMA SUBTYPES BENEFIT FROM CCNU/TEMOZOLOMIDE

Abstract BACKGROUND The only chemotherapy regimen that has shown a clear survival benefit in pediatric high-grade glioma (pHGG) is combining temozolomide (TMZ) and lomustine (CCNU) with RT per COG ACNS0423. However, which pHGG subgroups benefit from this treatment is unknown. METHODS Through the Children’s Brain Tumor Network (CBTN) database, we found 20 pHGG patients treated with RT-TMZ-CCNU, along with 95 control patients who received other treatment. We compared overall (OS) and event-free survival (EFS) using the Log-rank test for the respective pHGG subtype. We used a patient-derived xenograft (PDX) model, representing newly diagnosed hemispheric pHGG (diffuse hemispheric glioma, G34R-mutant (DHG), to test the effects of combining TMZ-CCNU. RESULTS From our clinical (CBTN) data, we found that median OS for the RT-TMZ-CCNU group was significantly greater compared to the control cohort (990 days (d) vs. 427d, p=0.011), as was EFS (510 vs. 215d, p=0.0041). For patients with hemispheric tumors, median OS and EFS were significantly increased for the RT-TMZ-CCNU group (n=8) vs. controls (n=47) (OS 5,274 vs. 496d, p=0.018; EFS 903 vs. 271d, p=0.018). For patients with midline pHGG, median OS and EFS were not significantly different between the RT-TMZ-CCNU group (n=11) and controls (n=43). In our PDX model, we found that TMZ-CCNU led to long-term survival compared to vehicle control and single-agent treatment (p&amp;lt;0.001). DISCUSSION: Patients with hemispheric pHGG had a significant survival benefit from RT-TMZ-CCNU treatment, while those with midline pHGG did not. Hemispheric pHGG, which are enriched for H3G34 and IDH mutations, may be more likely to respond to RT-TMZ-CCNU. These findings are supported by preclinical data showing that mice with DHG, G34R-mutant were cured after TMZ-CCNU treatment. Given our results and those from ACNS0423, RT-TMZ-CCNU should be strongly considered for treatment of patients with hemispheric pHGG and as a backbone for future clinical trials in this population.

Onco-functional outcome after resection for eloquent glioblastoma (GLIOFO): A propensity-score matched analysis of an international, multicentre, cohort study.

e14017 Background: Minimizing residual volume and preventing functional loss are the main goals in glioblastoma resections in eloquent areas. However, their combined impact on patient outcomes remains poorly understood. We therefore developed a novel onco-functional outcome (OFO) classification and evaluated its benefit in subgroups based on age, preoperative neurological morbidity (NIHSS), and Karnofsky Performance Score (KPS). Methods: Propensity-score matching was used to match OFO 1 (gross total resection, no functional loss) vs. OFO 2-3-4, OFO 2 (no gross total resection, no functional loss) vs. OFO 1-3-4, OFO 3 (gross total resection, functional loss) vs. OFO 1-2-4, and OFO 4 (no gross total resection, no functional loss) vs. OFO 1-2-3 for the overall cohort and subgroups. Cox proportional-hazard regressions and logistic regressions were performed to analyze the association between OFO class and postoperative outcomes, and the predictive value of perioperative factors on OFO class, respectively. Results: Between 2010 and 2020, 3919 patients were recruited, of whom 858 were included as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised of 512 patients, of whom 256 had OFO 1 and 256 had OFO 2-3-4. Overall survival differed significantly between OFO groups: 21.0 months [19.0-25.0] (OFO 1) versus 14.0 months [13.0-16.0] (OFO 2) versus 12.0 [11.0-15.0] (OFO 3) versus 8.5 months [7.0-10.0] (OFO 4) (p&lt;0.0001). In the overall matched cohort, OFO 1 versus OFO 2-3-4 resulted in fewer neurological deficits at 6 weeks (26 [10.2%] of 256 vs. 66 [25.8%] of 256, p &lt;0.001), 3 months (30 [12.7%] of 237 vs. 69 [29.9%] of 231, p &lt;0.001), and 6 months postoperatively (48 [21.0%] of 229 vs. 72 [35.1%] of 205, p = 0.0010), lower frequencies of KPS deterioration at 3 months (34 [14.2%] of 239 vs. 121 [52.4%] of 231, p &lt;0.001), and 6 months postoperatively (61 [26.5%] of 230 vs. 110 [52.9%] of 208, p&lt;0.001), longer overall survival (median 21.0 months [19.0-25.0] vs. 13.0 months [12.0-15.5], p&lt;0.001), and longer progression-free survival (median 10.0 months [9.0-11.0] vs. 7.5 months [6.0-8.0], p&lt;0.001). OFO 1 was associated with higher frequencies of receipt of adjuvant chemotherapy and radiotherapy, and longer overall survival and progression-free survival in all subgroups except the KPS 90-100 subgroup. Awake craniotomy more often led to OFO 1 compared to asleep resection (43.0% vs. 26.9%, p&lt;0.001; OR 1.91, p = 0.0080). Conclusions: OFO 1 was associated with improved survival outcomes, neurological outcomes, and receipt of adjuvant therapy in all glioblastoma patients. Awake craniotomy was significantly associated with achieving this more often. Aggressive and safe resections (OFO 1) were superior to resections that were defensive but safe (OFO 2), aggressive but unsafe (OFO 3), or defensive but unsafe (OFO 4).

Camrelizumab plus apatinib and temozolomide as first-line therapy for advanced acral melanoma: 2-year survival results from CAP 03.

9547 Background: Acral melanoma is the predominant subtype in Asia, which presents with aggressive biological behavior. First-line immunotherapy yields modest efficacy in advanced acral melanoma, suggesting the need of combination therapy. Our CAP 03 study investigated the combination of anti-PD-1 antibody plus antiangiogenic agent and chemotherapy for the first-line treatment of advanced acral melanoma, and the primary analysis has been published on JAMA Oncology in June 2023 (objective response rate [ORR], 64%; median progression-free survival [PFS], 18.4 months). Here we updated the efficacy results with a median follow-up of 30.3 months (95% CI, 28.9-32.5; reverse Kaplan-Meier method) at data cutoff date on January 8, 2024. Methods: In this single-center phase 2 trial (NCT04397770), patients with pathologically confirmed unresectable stage III or IV acral melanoma and without prior systemic therapy for advanced disease were recruited. Patients received first-line intravenous camrelizumab (200 mg once every 2 weeks) plus oral apatinib (250 mg once a day) and intravenous temozolomide (200 mg/m2 once a day on days 1-5 every 4 weeks) until disease progression or intolerable toxicity. The primary endpoint was ORR per Response Evaluation Criteria In Solid Tumors, version 1.1. Imaging assessment was performed after 4 weeks, then every 8 weeks until one year, and every 3 months thereafter. Overall survival (OS) was followed every 3 months. Results: Between May 2020 and August 2021, a total of 50 patients were enrolled. The confirmed ORR was 66.0% (33 of 50; 95% CI, 51.2%-78.8%). The median PFS was 21.2 months (95% CI, 10.1-27.1). The median OS was not reached, and the 1-year and 2-year OS rates were 88.0% (95% CI, 75.2%-94.4%) and 64.8% (95% CI, 49.5%-76.5%), respectively. Further analyses indicated comparable PFS benefit in subgroups by age (&lt;65 years vs ≥65 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), NRAS status (variant vs wild-type), stage, lactic dehydrogenase (LDH) level, and PD-L1 combined positive score (&lt;5 vs ≥5). Regarding OS, similar trends were observed in these subgroups, except that patients with normal LDH had better median OS than those with elevated LDH (not reached vs 22.6 months, log-rank nominal P=0.033). Conclusions: This first-line triplet combination shows encouraging survival benefits in patients with advanced acral melanoma, regardless of NRAS status or PD-L1 expression level. Follow-up is still ongoing to obtain mature OS data. Clinical trial information: NCT04397770 .

LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer.

1052 Background: Following promising outcomes in hormone receptor (HR)-positive, HER2-negative endocrine-resistant advanced breast cancer (BC) with lerociclib plus fulvestrant, this study assesses the efficacy and safety of lerociclib and letrozole in HR+/HER2- advanced or metastatic BC. Methods: This randomized, double-blind, placebo-controlled phase III study involved HR+/HER2- advanced or metastatic BC patients without prior systemic therapy for advanced disease. Participants were allocated 1:1 to either lerociclib (150mg twice daily) with letrozole or placebo with letrozole. The primary endpoint was progression-free survival (PFS) as assessed by investigators. Secondary endpoints included PFS (assessed by Blinded Independent Central Review (BICR)), response rates, overall survival (OS), and safety. The interim analysis was planned approximately 80 PFS events. Results: By September 20, 2023, 279 patients were randomized (137 to lerociclib + letrozole, 142 to placebo + letrozole), with a median follow-up of 12.91 months. Baseline characteristics were comparable across groups. At the data cutoff, 83 PFS events were reported. The lerociclib significantly improved PFS versus placebo (median: not reached (NR) versus 16.56 months; hazard ratio: 0.464; 95% CI: 0.293-0.733; p=0.0004). BICR analysis confirmed these results (median: NR versus NR; hazard ratio: 0.457; 95% CI: 0.274-0.761; p=0.0011). Subgroup benefits were consistent, including in patients with visceral metastases, extensive metastatic sites and previous (neo)adjuvant endocrine therapy, etc. For patients with measurable disease, lerociclib plus letrozole showed a higher objective response rate (62.3%) compared to placebo group (48.5%). OS data were immature at the cutoff. Adverse events were primarily hematological toxicity, with higher incidences of grade 3/4 neutropenia (grade 3: 41.6% vs. 0.7%; grade 4: 5.1% vs. 0%) and leucopenia (grade 3: 27.0% vs. 0%; grade 4: 1.5% vs. 0%) in the lerociclib group. All of neutropenia and leukopenia were considered to be treatment related. Grade 3 diarrhea was infrequent, only 1 case (0.7%) was reported in lerociclib group. QTc prolongation was reported comparable between lerociclib group (4.4%, Grade 3:1.5%) and placebo group (3.5%, Grade 3:0.7%). No venous thromboembolism was reported. Serious AEs were slightly higher in the lerociclib group (13.1% vs. 7.7%). Treatment discontinuation due to AEs was rare (1 patient [0.7%]) with lerociclib. Conclusions: Lerociclib with letrozole had an excellent safety profile and significantly prolonged PFS in HR+/HER2- advanced or metastatic BC patients. This benefit was consistent across all clinically relevant subgroups, suggesting lerociclib as a viable first-line therapeutic option with a favorable benefit-risk balance. Clinical trial information: CTR20212139; NCT05851014.

DREAMM-7 update: Subgroup analyses from a phase 3 trial of belantamab mafodotin (belamaf) + bortezomib and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM).

7503 Background: Patients (pts) with RRMM and poor prognostic features, such as high-risk cytogenetics or disease refractory to major drug classes, have an unmet need. In DREAMM-7 (NCT04246047), BVd demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit vs standard-of-care (SOC) DVd in pts with RRMM and ≥1 prior line of treatment (LOT). We present further analyses from DREAMM-7 to better understand efficacy in key subgroups. Methods: Pts with ≥1 prior LOT were randomized (1:1) to BVd, B 2.5 mg/kg IV Q3W + V 1.3 mg/m2 (D1, 4, 8, 11 of 21-day cycles [C]; up to 8 C) and d 20 mg (D1, 2, 4, 5, 8, 9, 11, 12; up to 8 C), or DVd, D 16 mg/kg (21-day C: C1-3, Q1W; C4-8, Q3W; Q4W from C9 on)—V and d schedules were the same. The primary endpoint was independent review committee–assessed PFS. Secondary endpoints include overall survival (OS), duration of response, and overall response rate (ORR). Pts with high-risk cytogenetics had ≥1 of t(4;14), t(14;16), or del(17p13). Results: The intent to treat (ITT) included 494 pts: BVd, n=243; DVd, n=251. Median PFS (mPFS) in the ITT was 36.6 mo with BVd vs 13.4 mo with DVd (HR, 0.41; 95% CI, 0.31-0.53; P&lt;.00001). ORR in the ITT was 82.7% (95% CI, 77.4%-87.3%) with BVd and 71.3% (65.3%-76.8%) with DVd. BVd had a higher complete response rate vs DVd (34.6% vs 17.1%). At baseline, 79 pts (33%) in the BVd arm and 87 pts (35%) in the DVd arm were refractory to lenalidomide (LEN). In the LEN-refractory subgroup, mPFS favored BVd (25.0 mo; 95% CI, 18.1 mo to NR) vs DVd (8.6 mo; 6.4-13.5 mo) (HR, 0.31; 95% CI, 0.19-0.48). A higher ORR was reported with BVd (84%; 95% CI, 73.5%-90.9%) vs DVd (61%; 49.9%-71.2%) in LEN-refractory pts. In the BVd and DVd arms, 67 (28%) and 69 (27%) pts had ≥1 high-risk cytogenetic abnormality. In the high-risk cytogenetic subgroup, the mPFS was 33.2 mo (95% CI, 20.3 mo to NR) with BVd vs 10.5 mo (7.6-13.4 mo) with DVd (HR, 0.31; 95% CI, 0.18-0.52). ORR favored BVd (85%; 95% CI, 74.3%-92.6%) vs DVd (67%; 54.3%-77.6%) in this subgroup. Additional data including other subgroup analyses will be presented. More deaths occurred with DVd (35%) than BVd (22%) in the ITT; neither arm reached median OS (HR, 0.57; 95% CI, 0.40-0.80; nominal P=.00049). In the ITT, all pts in both arms had ≥1 AE, and 95% (exposure-adjusted rate [exp-adj], 69 per 100 person-years [PY]) of BVd pts and 76% (exp-adj, 62 per 100 PY) of DVd pts reported grade 3/4 AEs. Serious AEs were reported in 50% (exp-adj, 36 per 100 PY) of BVd pts vs 37% DVd (exp-adj, 30 per 100 PY) pts. Ocular AEs were more frequent with BVd vs DVd (79% vs 29%). Conclusions: In DREAMM-7 BVd demonstrated PFS benefit over DVd with an mPFS improvement of 23 mo in pts with RRMM and ≥1 prior LOT. These results, demonstrating efficacy benefit in key subgroups with a high unmet need, support BVd as a potential new SOC in this setting. Clinical trial information: NCT04246047 .

Comparison of adjuvant targeted and anti-PD1 immunotherapy in BRAF-mutated stage III cutaneous melanoma: Retrospective, single center cohort study.

e21558 Background: Targeted therapy (TT) and anti-PD1 immunotherapy (IT) are standard of adjuvant stage III melanoma treatment. However, no comparative prospective randomized trials (head-to-head) were conducted. Data limited to a few retrospective studies. Both treatment regimens were registered in Russia in 2019. We aimed to compare adjuvant options in Russian melanoma pts. Methods: We conducted a single-center retrospective observational study approved by the IRB. We included all pts age 18 and older (one patient, female, was 14) with BRAF-mutated stage III melanoma who were treated at the N.N.Blokhin NMRC of Oncology MoH and received adjuvant therapy between Jan 2019 and Dec 2022. The primary endpoint was RFS, the secondary endpoint - OS. Cox regression analysis was used to identify prognostic factors for RFS (including substage, thickness and ulceration of primary tumor). Results: A total of 209 pts were included, mostly BRAF V600E/K, 92 (44%) male and 117 (56%) female. Median age was 50,6 years (range: 14-81). 93 (44,4%) pts received TT, 103 (49,3%) pts received IT and 13 (6,3%) didn’t receive adjuvant therapy (observation only). The observation group wasn’t analyzed due to a small number of pts. At a median follow-up of 27 mo, median RFS was 30 mo (95% CI 23-56) in TT group and wasn’t reached in IT group; median OS wasn’t reached in both groups. There weren’t statistical differences between TT and IT groups in RFS (HR 0,84, 95% CI 0,53-1,34, p = 0,47) and OS (HR 0,59, 95% CI 0,26-1,34, p = 0,21), even though at 12 mo, the rate of RFS was higher in the TT group (91.4%) compared IT group (67%), at 18 mo – 79,5% and 63,1%, 24 mo – 68,8% and 61,1% respectively. TT group had numeric but not significant RFS benefit in most subgroups. HR values for substage, thickness and ulceration are presented in the table below. Tx+T0 pts (TT, n = 7; IT, n = 13) and unknown status of ulceration (TT, n = 7; IT, n = 16) was not presented for some pts. Conclusions: Differences between TT and IT wasn't reached at a median follow-up of 27 mo. But IT-treated pts had more and earlier recurrences than TT pts. In BRAF mutated pts, adjuvant TT might prevent early recurrences more effectively than IT. These results need to be interpreted with caution given its retrospective and non-randomized nature and potential selection biases. Additional time to follow-up and biomarker analysis was planned. [Table: see text]

Temporal Considerations in Brain Metastases Radiation Therapy: The Intersection of Chronobiology and Patient Profiles.

The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assessed circadian timing's impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. The aim of the study was to evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes and to identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities. An IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017-2021), receiving over 80% of treatments in the morning or afternoon, was performed. Survival analyses utilized Kaplan-Meier curves. This was a single-institution study involving patients receiving whole-brain radiotherapy. Demographic, disease, and socioeconomic parameters from electronic medical records were collected. Morning treatment (n = 158) showed a trend toward improved overall survival vs. afternoon (n = 79); the median survival was 158 vs. 79 days (p = 0.20, HR = 0.84, CI95% 0.84-0.91). Subgroup benefits for morning treatment in females (p = 0.04) and trends in controlled primary disease (p = 0.11) and breast cancer metastases (p = 0.08) were observed. Black patients exhibited diminished circadian influence. The present study emphasized chronobiological factors' relevance in brain metastases radiation therapy. Morning treatment correlated with improved survival, particularly in specific subgroups. Potential circadian influence disparities were identified, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

The effect of laser-assisted hatching on vitrified/warmed blastocysts: the ALADDIN randomized controlled trial

ObjectiveTo evaluate whether laser-mediated assisted hatching (AH) performed on vitrified/warmed blastocysts before embryo transfer can improve live birth rate. DesignThe “pArtiaL zonA pelluciDa removal by assisteD hatchINg of blastocysts (ALADDIN)” is a 2-center comparative study with a parallel randomized controlled design. SubjectsParticipants were recruited between September 2018 and November 2021. They were aged 18 to 39 years, underwent non-donor IVF cycles, and were scheduled for elective single embryo transfer with vitrified/warmed blastocysts. Those with uterine abnormalities, BMI >35 kg/m2, severe male factor infertility, or performing preimplantation genetic testing were excluded. InterventionAssisted hatching was performed using a 1480 nm diode laser, removing approximately one-third of the zona pellucida with continuous 0.2 ms pulses applied from the 1 to 5 o’clock positions. Main Outcome MeasuresThe primary outcome was the live birth rate. Secondary endpoints included clinical pregnancy, miscarriage, multiple pregnancies, preterm births, obstetrical and neonatal complications, and congenital anomalies. ResultsOverall, 698 participants met the inclusion criteria and were randomized: 352 patients were assigned to the AH arm and 346 to the control arm. One-hundred and five (29.8%) and 101 (29.2%) participants achieved a live birth following treatment, respectively (p=0.87). The relative risk of live birth in patients with vitrified/warmed blastocysts treated with AH was 1.02 (95%CI: 0.86-1.19). Exploratory subgroup analyses for women’s age, recruiting centers, indications for IVF, method of insemination, blastocyst quality, and days of blastocyst development failed to highlight any clinical situation that could benefit from AH in thawed blastocysts. ConclusionIn patients undergoing frozen embryo transfer with vitrified/warmed blastocysts, laser AH does not improve the live birth rate. Further studies are required to rule out milder but potentially interesting benefits in specific subgroups of patients.

Nivolumab (NIVO) plus (+) chemotherapy (chemo) or ipilimumab (IPI) vs chemo as 1L treatment for advanced esophageal squamous cell carcinoma (ESCC): First comprehensive biomarker analyses from CheckMate 648.

252 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in previously untreated patients with advanced ESCC in CheckMate 648 (NCT03143153), resulting in approvals in many countries. We present first comprehensive exploratory biomarker analysis results from this trial. Methods: Whole exome sequencing (WES) of baseline tumor tissue and matching blood was performed to assess tumor mutational burden (TMB) and select gene alterations. TMB-high tumors were defined as ≥ 199 mutations/exome. RNA sequencing of baseline tumor tissue was used to assess gene expression signatures (GES). GES subgroups were defined by signature score tertiles. Results: In total, 60% (191/321) of patients receiving NIVO + chemo were both WES- and GES-evaluable; 62% (200/325) and 58% (188/325) of patients receiving NIVO + IPI and 59% (190/324) and 59% (192/324) receiving chemo were WES- and GES-evaluable, respectively. In the NIVO + chemo arm, patients with TMB-high tumors had numerically longer median OS (mOS) compared with TMB-low tumors, whereas mOS was similar between TMB subgroups treated with NIVO + IPI, although the number of patients with TMB-high tumors was small (Table). Higher inflammation and lower β-catenin GES scores were associated with improved OS benefit of NIVO + chemo or IPI vs chemo (Table). Lower fibroblast GES scores were associated with improved OS benefit of NIVO + IPI vs chemo (Table). Additional biomarker analyses, including select gene alterations and GES in tumor cell PD-L1 subgroups, will be presented. Conclusions: These results further support the clinical efficacy of NIVO + chemo and NIVO + IPI in 1L ESCC and suggest enhanced OS benefit in multiple biomarker subgroups. The clinical utility of these biomarkers should be validated in future trials. Clinical trial information: NCT03143153 . [Table: see text]

Reconstruction of unreported subgroup survival data with PD-L1-low expression in advanced/metastatic triple-negative breast cancer using innovative KMSubtraction workflow

BackgroundAmong patients with advanced/metastatic triple-negative breast cancer (TNBC) with high/positive programmed death-ligand 1 (PD-L1) expression, a superior survival outcome has been demonstrated with immune checkpoint inhibitors (ICIs). However, it remains...