Favorable Risk-benefit Profile Research Articles

Aspirin Use and Incidence of Colorectal Cancer According to Lifestyle Risk

Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority. To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors. A prospective cohort study among women in the Nurses' Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023. A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week. Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores. The mean (SD) baseline age of the 107 655 study participants (63 957 women from the Nurses' Health Study and 43 698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3 038 215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P < .001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking. In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.

Trastuzumab deruxtecan versus trastuzumab emtansine in Asian patients with HER2-positive metastatic breast cancer.

The global phase 3 DESTINY-Breast03 study (ClinicalTrials.gov; NCT03529110) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan (T-DXd) over trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. Here, we report a subgroup analysis of Asian patients enrolled in DESTINY-Breast03. In total, 309 patients (149 in the T-DXd arm and 160 in the T-DM1 arm) from Asian countries and regions were randomized. At data cutoff (July 25, 2022), the median duration of follow-up in the Asian subpopulation was 29.0 months with T-DXd and 26.0 months with T-DM1. The PFS (determined by blinded independent central review) hazard ratio was 0.30 (95% confidence interval 0.22-0.41) favoring T-DXd over T-DM1 (median PFS 25.1 vs. 5.4 months). Median OS was not reached in the T-DXd arm and was 37.7 months in the T-DM1 arm. The median treatment duration was 15.4 months with T-DXd and 5.5 months with T-DM1. The incidence of grade ≥3 drug-related treatment-emergent adverse events was similar between both treatment arms (49.0% vs. 46.5%) and was consistent with the overall DESTINY-Breast03 population. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.9% of patients treated with T-DXd and 2.5% treated with T-DM1, with a higher incidence in Japanese patients; none of these were grade ≥4 events. These efficacy and safety data reinforce the favorable benefit-risk profile of T-DXd in HER2-positive mBC, including in the Asian subgroup.

Assessment of health-related quality of life (HRQoL) in triple-class–exposed patients with relapsed or refractory multiple myeloma (RRMM) treated with linvoseltamab in the LINKER-MM1 trial.

e23185 Background: Linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody, is being evaluated in LINKER-MM1, a Phase 1/2 study in patients with RRMM (NCT03761108). Early results over 36 weeks of treatment showed promising efficacy and a generally manageable safety profile (Jagannath et al., ASH 2023), and improvement or stability in patient-reported outcomes (PROs) including pain and fatigue (Hoffman et al., ASH 2023). We now report PRO data over a treatment period of 76 weeks. Methods: We evaluated patients in LINKER-MM1 who received the 5-25-200 mg dosing regimen in Phases 1 and 2 (n = 117). Patients ≥18 years old with triple-class exposed RRMM were administered linvoseltamab at Weeks 1 (5 mg), 2 (25 mg), and 3 (200 mg), followed by 200 mg once weekly through Weeks 14 (Phase 2) or 16 (Phase 1), then every 2 weeks until progression. Patients with a very good partial response by Week 24 in Phase 2 transitioned to dosing every 4 weeks. The EORTC QLQ-C30 was administered at baseline, Week 4, and then every 4 weeks. Least squares (LS) mean change from baseline and 95% confidence interval (CI) were estimated at each timepoint and overall on all scales using a mixed effects model for repeated measures. A 10-point change from baseline was considered clinically meaningful. Results were stratified by objective response status (at least partial response). No adjustment for multiplicity was performed; statistical significance is nominal, with LS mean change from baseline considered statistically significant if 95% CI did not cross 0. Results: PRO completion rates were generally ≥80% through Week 44 and dropped slightly after Week 44. LS mean change showed improvement in Global Health Status/QoL at Week 12, reaching the clinically meaningful threshold at Week 44; clinically meaningful improvements were observed on role and social functioning scales at Weeks 24 and 28, respectively. Pain and fatigue significantly improved and reached the clinically meaningful threshold at Weeks 20 and 44, respectively; the clinically meaningful improvement in pain was generally maintained through Week 76. Overall LS mean change in pain was clinically meaningful (-10.2; 95% CI -13.7, -6.7). Among treatment responders, statistically significant improvements were observed on all scales, including clinically meaningful improvement in pain (-11.2; 95% CI -14.7, -7.6). Non-responders had statistically significant worsening in fatigue (9.9; 95% CI 0.8, 19.1); overall change from baseline was not significant on other scales. Conclusions: Over 76 weeks of treatment, improvements in measures of HRQoL including pain and fatigue were reported in patients with triple-class exposed RRMM receiving linvoseltamab; responders showed significant improvements on all scales. These PRO results support a favorable benefit–risk profile of linvoseltamab. Clinical trial information: NCT03761108 .

Melphalan/hepatic delivery system versus best available care in patients with unresectable metastatic uveal melanoma: Randomized FOCUS trial results.

9556 Background: Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. The purpose of the FOCUS study, an open label, multicenter randomized Phase 3 study, was to assess efficacy and safety of melphalan/HDS versus best alternative care (BAC). Methods: Eligible patients with unresectable mUM were randomized 1:1 to treatment with melphalan/HDS (3.0 mg/kg ideal body weight) once every 6-8 weeks for a maximum of 6 cycles or BAC. The primary endpoint was overall survival (OS). The planned study size was 240 patients; due to slow enrollment and patient reluctance to receive BAC treatment, the study design was amended to a single-arm melphalan/HDS study, and all efficacy analyses of the randomized study were treated as exploratory. Results: From February 2016 to October 2018 a total of 129 patients were screened and 85 were enrolled at 22 centers in the US and Europe; eligible patients were randomized to receive melphalan/HDS (N=43) or BAC (N=42) and 72 patients received study treatment. Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the melphalan/HDS arm vs. BAC (median OS: 18.5 vs 14.5 months; median progression free survival: 9.1 vs 3.3 months; objective response rate: 27.5% vs 9.4%; and disease control rate: 80.0% vs 46.9%). Serious adverse events (SAEs) occurred in 51.2% of melphalan/HDS and in 21.9% of BAC patients. Most common (&gt;5%) SAEs included thrombocytopenia (19.5%), and neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed. Conclusions: Treatment with melphalan/HDS shows clinically meaningful efficacy and demonstrates a favorable benefit-risk profile in patients with unresectable mUM as compared to best alternative care. Clinical trial information: NCT02678572 .

Benefit-risk profile of P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis

BackgroundRefractory or unexplained chronic cough disrupts quality of life and burdens healthcare systems around the world. The P2X3 receptor antagonist gefapixant is approved in many countries for its antitussive effects, but taste disturbances are a common adverse effect. Four newer, more selective P2X3 receptor antagonists have been developed to address this problem. Research QuestionHow does the benefit-risk profile vary across the five available P2X3 receptor antagonists? Study Design and MethodsA systematic review and network meta-analyses were conducted to evaluate the efficacy of P2X3 receptor antagonists, including gefapixant, sivopixant, eliapixant, camlipixant, and filapixant. Primary outcomes were a reduction rate in 24-hour cough frequency and incidence of taste disturbance. Dose-response curves, and median effective dose (ED50) were calculated. Effect size at ED50 was ranked according to SUCRA. The confidence was evaluated by CINeMA. ResultsSixteen randomized controlled trials involving 4,904 participants were analyzed. The gefapixant regimen demonstrated an ED50 of 90.7 mg/day for cough frequency reduction. Gefapixant showed the highest antitussive effectiveness at ED50 (reduction rate in 24-h cough frequency, median 28.1%; 95% Credible Interval 21.0 to 35.6%; ranked 1/5; moderate certainty) but the highest prevalence of taste disturbance (absolute risk difference per 100 patients, median 38; 95%CrI 27 to 51; ranked 5/5; high certainty) and the highest prevalence of discontinuation. Camlipixant had a well-balanced profile (reduction rate in 24-h cough frequency, median 14.7%; 95%CrI 5.4 to 26.0%; ranked 3/5; low certainty; and taste disturbance, absolute risk difference per 100 patients, median 2; 95%CrI 1 to 6; ranked 2/5; low certainty). Placebo had a mean of 33.1% reduction in 24-h cough frequency. InterpretationWhen used at safe doses, gefapixant had a favorable risk-benefit profile compared to the other four agents. Camlipixant showed initial promise, which may be further investigated by phase III trials currently underway. Clinical Trial RegistrationUMIN000050622

First-line treatment preferences for advanced melanoma among oncologists and patients in the US: A discrete choice experiment.

9539 Background: NCCN guidelines recommend nivolumab + ipilimumab, nivolumab + relatlimab, and anti-PD-1 monotherapy as category 1 preferred first-line (1L) treatments (txs) for advanced melanoma. These immunotherapies (IOs) however differ in administration, efficacy, and safety. Given these differences, this study examines oncologists (oncs) and patients (pts) preferences when choosing 1L tx. Methods: Pts with self-reported unresectable or metastatic melanoma and oncs completed an online cross-sectional survey. A discrete choice experiment assessed preferences for three efficacy attributes, three safety attributes, and dosing schedule. Attributes (shown in table) were identified via literature and qualitative research. Each attribute had two or three levels based on clinical trial data of recommended IOs. Participants completed 12 tasks; each task showed two tx options with varying levels for each attribute. Hierarchical Bayesian modeling was used to estimate preference weights for each level and relative importance estimates, based on the range between levels, were computed. Results: 75 oncs (male 76%; mean age 46 years; community-based 51%) and 62 pts (male 68%; mean age 43 years) were analyzed (pt recruitment ongoing; target n = 75). For both oncs and pts, improvements in safety attributes was more important than improvements in efficacy attributes (pts: 50.3 vs. 33.9; oncs: 48.6 vs. 40.9). For safety, a decrease in risk of discontinuation due to treatment-related adverse events (TRAEs) was most important in oncs (24.7); while for pts, lower risk of grade 3/4 TRAEs was most important (22.6). For efficacy, an increase in overall survival (OS) was most influential for oncs (21.0); pts had similar estimates within efficacy. Dosing schedule was third most important for pts (15.8), while it was among the least important for oncs. Conclusions: Oncs and pts prioritize minimizing the risk of serious AEs when efficacy differences are minimal in 1L advanced melanoma tx choice. These findings highlight that oncs and pts value an IO with an efficacy benefit while ensuring a favorable risk-benefit profile. This information can inform tx counseling and selection discussions among oncs and pts. [Table: see text]

#2434 Literature review on the burden of herpes zoster in patients with kidney disease—a need for earlier prevention

Abstract Background and Aims Kidney disease (KD), including end stage renal disease (ESRD), is a global health problem. Both are associated with impaired immune systems, which can lead to infections. Complications such as cardiovascular disease and various infections are leading causes of morbidity and mortality in KD patients. Notably, patients with KD have an increased risk of herpes zoster (HZ). While the link between ESRD and renal transplant with increased HZ risk is understood, knowledge gaps regarding the burden of HZ across the KD spectrum still exist. This review aims to describe the risk and impact of HZ across the KD spectrum in order to guide preventive care strategies for patients with renal diseases. Method A structured literature review was conducted in PubMed using a combination of keywords and Medical Subject Heading (MeSH) terms to identify studies related to HZ risk in adult KD patients aged ≥18 years published in the English language between 01/11/2003–31/10/2023. Data extracted from published studies included the burden of HZ infection in patients with KD (risk of HZ and related complications), impact of HZ on underlying KD, and the efficacy/effectiveness of HZ vaccines among patients with KD. Results A total of 47 studies were identified (Randomized controlled trials [RCT] = 2; observational studies = 45) in this review (Fig. 1). Included studies presented evidence from regions in Europe (n = 18), Asia (n = 17), North America (n = 7), South America (n = 1), multinational (n = 2) and Australia (n = 1); country not reported in one study. Evidence from observational studies (n = 37) reported a high risk of HZ infection and related complications, such as disseminated HZ, and recurrent HZ across the KD spectrum, including chronic KD, polycystic KD, hemodialysis, peritoneal dialysis and kidney transplant patients. Infection with HZ was reported to accelerate KD progression and increased the risk of ESRD and cardiovascular events. In general, for ESRD patients with an inpatient HZ diagnosis, mortality increased with age, followed by malnutrition and bacteremia/septicemia. Studies reporting vaccine efficacy (n = 2) and effectiveness results (n = 8) suggest that HZ vaccination was associated with a reduced risk of HZ when compared to unvaccinated individuals. Furthermore, the recombinant zoster vaccine (RZV) was found to be immunogenic in kidney transplant recipients, with immunogenicity persisting through 12 months post-vaccination. An RCT post-hoc analysis showed high vaccine efficacy in patients aged ≥50 years with medical conditions at enrollment, including KD, which was consistent with the overall population. A favorable benefit-risk profile was reported in randomized and observational studies. Studies evaluating the effectiveness of the zoster live-attenuated vaccine (ZVL) found a lower risk of HZ in patients with ESRD immunized against HZ compared to unvaccinated individuals. In many countries, vaccination guidelines specifically recommended immunization of people with KD to protect against HZ. However, ZVL is contraindicated for immunocompromised (e.g. kidney transplant) patients. Conclusion Findings indicate that HZ has a significant HZ burden across the KD spectrum, which may negatively impact renal disease progression. With effective vaccines offering durable protection against HZ and its complications, the immunization of renal patients at earlier stages could enhance healthcare management and patient outcomes.

#1419 A single, easy-to-use question to assess pruritus intensity in daily dialysis practice

Abstract Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) has been shown to negatively impact certain clinical outcomes and quality of life (QoL) in patients with kidney failure. However, regular screening for CKD-aP is not yet routine dialysis practice and no consensus on the preferred instrument exists. To facilitate implementation of regular screening for CKD-aP we assessed the performance of two different instruments validated in patients with CKD-aP. Method The Worst Itching Intensity Numerical Rating Scale (WI-NRS) asks patients to indicate the worst itch intensity in the past 24 hours (range 0 [no itch] to 10 [worst itch imaginable]). The 5-D Itch scale assesses itch-related QoL (range 5-25 where higher values indicate worse QoL) and includes one question on itch intensity over the past 2 weeks (5-D ‘degree’ domain, range 1 [not present] to 5 [unbearable]). Both instruments were included in two phase-3 clinical trials, KALM-1 and KALM-2, that established the favourable benefit-risk profile of difelikefalin over placebo in patients on haemodialysis with moderate to severe CKD-aP. WI-NRS was collected daily during the trial and 5-D Itch at the first dialysis visit in weeks 5, 9, 11 and 13. We assessed the correlations between both the 5-D total score and degree domain and a) the single WI-NRS measurement collected on the same day and b) the average of daily WI-NRS scores collected over the previous 2 weeks in all patients independent of treatment exposure. Results The two instruments demonstrated moderate to strong correlations (range 0.5635-0.7039, p &amp;lt; 0.0001) independent of whether the total 5-D Itch score or the 5-D itch degree question were compared with a single, same-day WI-NRS measurement or with the mean WI-NRS scores over the 2-week recall period of the 5-D Itch (Table). In addition, correlations remained consistent over time, supporting the reliability of the findings. Conclusion Using the WI-NRS to ask patients about their worst itch in the past 24 hours is a simple and swift approach for reliably identifying those with bothersome pruritus that also affects their itch-related QoL.

Upadacitinib in Active Non-radiographic Axial Spondyloarthritis: 1-Year Data From a Double-Blind, Randomized, Placebo-Controlled, Phase 3 Trial.

Upadacitinib improved the signs and symptoms of non-radiographic axial spondyloarthritis (nr-axSpA) versus placebo over 14 weeks in the primary analysis of the SELECT-AXIS 2 nr-axSpA study. Here, we evaluated the efficacy and safety of upadacitinib through 1 year in patients with nr-axSpA in SELECT-AXIS 2. Patients aged at least 18 years diagnosed with nr-axSpA who fulfilled the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria and were receiving stable background therapy were randomized to upadacitinib 15 mg once daily or placebo for the 52-week double-blind period. Efficacy was assessed using non-responder imputation incorporating multiple imputation (NRI-MI) and as-observed analyses for binary endpoints, and mixed-effects model repeated measures for continuous endpoints. Of 314 randomized patients, 259 (upadacitinib, n = 129; placebo, n = 130) completed 52 weeks of treatment. More patients receiving upadacitinib versus placebo achieved ≥40% improvement in ASAS at week 52 (63% vs 43%, NRI-MI; nominal P < 0.001). Similar treatment effects were observed for the achievement of axSpA Disease Activity Score inactive disease (33% v 11%, NRI-MI; nominal P < 0.001). Overall, patients receiving upadacitinib versus placebo showed greater improvement in disease activity, inflammation, pain, function, enthesitis, and quality of life through 52 weeks. Adverse events were generally comparable between the treatment groups. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, inflammatory bowel disease, or deaths were reported in those receiving upadacitinib. Treatment with upadacitinib showed sustained efficacy versus placebo with no new safety findings identified through 1 year. These results support the continued favorable benefit-risk profile of upadacitinib treatment for nr-axSpA.

Transcatheter Mitral Valve Repair With the MitraClip Device for Prior Mitral Valve Repair Failure: Insights From the GIOTTO-FAILS Study.

Minimally invasive mitral valve repair has a favorable risk-benefit profile in patients with significant de novo mitral regurgitation. Its role in patients with prior mitral valve repair is uncertain. We aimed to appraise the outcome of patients undergoing transcatheter edge-to-edge repair (TEER) with prior transcatheter or surgical mitral valve repair (SMVR). We queried the Italian multicenter registry on TEER with MitraClip, distinguishing naïve patients from those with prior TEER or (SMVR). Inhospital and long-term clinical/echocardiographic outcomes were appraised. The primary outcome was the occurrence of death or rehospitalization for heart failure. A total of 2238 patients were included, with 2169 (96.9%) who were naïve to any mitral intervention, 29 (1.3%) with prior TEER, and 40 (1.8%) with prior SMVR. Several significant differences were found in baseline clinical and imaging features. Respectively, device success was obtained in 2120 (97.7%), 28 (96.6%), and 38 (95.0%, P=0.261) patients; procedural success in 2080 (95.9%), 25 (86.2%), and 38 (95.0%; P=0.047); and inhospital death in 61 (2.8%), 1 (3.5%), and no (P=0.558) patients. Clinical follow-up after a mean of 14 months showed similar rates of death, cardiac death, rehospitalization, rehospitalization for heart failure, and their composite (all P>0.05). Propensity score-adjusted analysis confirmed unadjusted analysis, with lower procedural success for the prior TEER group (odds ratio, 0.28 [95% CI, 0.09-0.81]; P=0.019) but similar odds ratios and hazard ratios for all other outcomes in the naïve, TEER, and SMVR groups (all P>0.05). In carefully selected patients, TEER can be performed using the MitraClip device even after prior TEER or SMVR.

The Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Elderly Breast Cancer Patients: What Do We Know?

Breast cancer (BC) incidence increases with age, particularly in HR-positive/HER2-negative subtypes. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6is) alongside endocrine therapy (ET) have emerged as promising treatments for HR-positive/HER2-negative advanced and early BC. However, their efficacy, safety, and impact on quality of life (QoL) in older and frail patients remain underexplored. This position paper assesses the existing literature from 2015 to 2024, focusing on CDK4/6is use in patients aged 65 years and older with HR-positive/HER2-negative BC. Our analysis methodically addresses critical questions regarding the utilization of CDK4/6is in the elderly BC patient population, organizing findings from the metastatic and adjuvant settings. In the metastatic setting, CDK4/6is significantly improve progression-free survival (PFS), paralleling benefits observed in younger patients, and suggest potential overall survival (OS) benefits, warranting further investigation. Despite an increased incidence of grade ≥ 3 adverse events (AEs), such as neutropenia and asthenia, CDK4/6is present a markedly lower toxicity profile compared to traditional chemotherapy, with manageable side effects. QoL analysis indicates that integrating CDK4/6is into treatment regimens does not significantly impact elderly BC patients' daily life and symptom management. Special attention is given to frail subgroups, and personalized approaches are recommended to balance efficacy and adverse effects, such as starting with ET alone and introducing CDK4/6is upon progression in patients with a low disease burden. Transitioning to the adjuvant setting, early results, particularly with abemaciclib, indicate positive effects on disease-free survival (DFS), emphasizing the need for continued analysis to validate these findings and assess long-term implications. However, data on older patients are insufficient to conclude whether they truly benefit from this treatment. Overall, CDK4/6is present a favorable benefit-risk profile in older BC patients, at least in advanced BC; however, further research is warranted to optimize treatment strategies and improve outcomes in this population.

Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study

BackgroundUveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM.MethodsEligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS).ResultsThe study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44–47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed.ConclusionTreatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Abstract PO4-04-11: Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer

Abstract BACKGROUND Giredestrant (GIR) is a highly potent, nonsteroidal, oral, selective estrogen receptor antagonist and degrader (SERD). The Phase Ia/b GO39932 study (NCT03332797) investigated GIR ± palbociclib (palbo) and ± a luteinizing hormone-releasing hormone agonist for patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer who had disease progression on prior endocrine therapies. In the single-agent dose-escalation stage, patients received 10, 30, 90, or 250 mg of once-daily (QD) GIR. In the dose-expansion stage, patients received 30, 100, or 250 mg of QD GIR. Safety and tolerability of 100 mg GIR + 125 mg palbo was also explored in the dose-escalation and -expansion stages. Results showed that GIR was well tolerated and potentially clinically active as a single agent and in combination with palbo, including in patients with ESR1-mutated tumors. To inform the selection of the clinical dose for GIR late-stage development based on risk–benefit considerations, exposure–response (E–R) analyses for efficacy and safety endpoints were conducted using single-agent GIR data. METHODS Exposure metrics included maximum concentration at steady state and area under the concentration–time curve at steady state. The association between the exposure metrics and efficacy endpoints (objective response rate [ORR] and clinical benefit rate [CBR]) or safety endpoints (all adverse events [AEs], Grade ≥ 3 AEs, selected AEs of interest [sAEIs], including all-grade hepatotoxicity, and bradycardia) were evaluated. RESULTS Data cutoff was September 17, 2021. A total of 111 patients were enrolled in the single-agent GIR cohort. Of these 111 patients, 107 were pharmacokinetic-evaluable and included in the analysis. ORR in patients with measurable disease at baseline was 20% (16/81 patients) and CBR was 49% (54/111). No significant associations were observed between exposure and ORR or CBR, including in patients with ESR1-mutated tumors and those with no mutation detected (p &amp;gt; 0.05). There were 92/107 patients (86%) with AEs of any grade, overall. Seventy-two (67%) had sAEIs, 19 (18%) experienced hepatotoxicity (all events were reported as liver function test abnormalities), 11 (10%) had bradycardia, and 20 (19%) had Grade ≥ 3 AEs. Increasing exposure did not significantly increase the incidence of all AEs, Grade ≥ 3 AEs, sAEIs, or bradycardia at the dose range of 10 to 250 mg (p &amp;gt; 0.05). For hepatotoxicity, the analysis suggested that higher exposure may lead to a higher probability of events (p = 0.0065); however, at the clinically relevant exposure range for the 30 mg dose, the incidence of hepatotoxicity was low and the predicted exposures were at the shallower slope of the relationship. CONCLUSIONS Single-agent GIR did not exhibit a significant association between exposure and efficacy endpoints at a dose range of 10 to 250 mg, regardless of ESR1 mutation status, indicating that the efficacy of GIR might have reached a plateau at low dose levels. At the clinically relevant exposure range of the 30 mg dose, GIR exposure was not associated with an appreciable increase in the incidence of AEs. The Phase Ia/b study design and subsequent E–R results enabled dose selection to be based on risk–benefit considerations, rather than the traditional maximum tolerated dose paradigm, in line with the United States Food and Drug Administration’s oncology dose optimization recommendations. The E–R results also indicate that GIR may have a relevant wide therapeutic window. Overall, these data support the 30 mg clinical dose of GIR that was selected, with a favorable risk–benefit profile, for further clinical studies. Citation Format: Komal Jhaveri, Yi Ting (Kayla) Lien, Nicholas Turner, Elgene Lim, Maureen Cannon, Richard Anziano, Jurgen Langenhorst, Kenta Yoshida, Vikram Malhi, Mary Gates, Jennifer Eng-Wong, Chunze Li, Mona Shah, Pablo Perez-Moreno, Jiajie Yu, Aditya Bardia. Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-11.

Long-term safety and efficacy of upadacitinib versus adalimumab in patients with rheumatoid arthritis: 5-year data from the phase 3, randomised SELECT-COMPARE study

ObjectivesTo assess the safety and efficacy of upadacitinib versus adalimumab from SELECT-COMPARE over 5 years.MethodsPatients with rheumatoid arthritis and inadequate response to methotrexate were randomised to receive upadacitinib 15 mg...

Structured benefit-risk assessment for enoxaparin, in the context of its label extension, for the extended treatment of deep vein thrombosis and pulmonary embolism, and prevention of its recurrence in patients with active cancer.

Guidelines recommend low-molecular-weight heparins (LMWHs) for patients with cancer-associated thrombosis. However, until recently, only dalteparin and tinzaparin were approved in the European Economic Area (EEA) for these patients. This study compares the benefit-risk profile of enoxaparin with dalteparin and tinzaparin for the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence in adult patients with active cancer. A semi-quantitative structured benefit-risk assessment was conducted for the label-extension application of enoxaparin based on the benefit-risk action team descriptive framework: define decision context; determine key benefit and risk outcomes; identify data sources; extract data; interpret results. The key benefits were defined as reduced all-cause mortality and venous thromboembolism (VTE) recurrence (including symptomatic DVT, fatal PE or non-fatal PE); the key risks were major and non-major bleeding of clinical significance, and heparin-induced thrombocytopenia (HIT). Enoxaparin demonstrated comparable effects for the reduction of VTE recurrence and all-cause mortality versus other EEA-approved LMWHs (dalteparin, tinzaparin). There was no evidence of a significant difference between enoxaparin and the comparator groups with regard to incidence of major and non-major bleeding. The data on HIT were too limited to assess the difference between the two groups. The assessment demonstrated a favourable benefit-risk profile for enoxaparin similar to that of other EEA-approved LMWHs for the treatment of DVT and PE and the prevention of recurrence in patients with active cancer and thus supported the label-extension approval.

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma.

This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Janus kinase inhibitors and the changing landscape of vitiligo management: a scoping review.

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne-related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk-benefit profile.

Outcomes After Left Atrial Appendage Clip Placement During Cardiac Surgery: A Nationwide Analysis

This study evaluated the nationwide associations between concomitant left atrial appendage clip (LAAC) placement during cardiac surgery and postoperative outcomes. We identified 1,260,999 patients who underwent coronary artery bypass grafting, valve, and aortic surgeries in the 2016 to 2020 Nationwide Readmissions Database and stratified by concomitant LAAC versus no LAAC placement. Patients who underwent surgical ablation were excluded. Mortality and complications were compared during index admissions and for patients readmitted within 30 and 90 days of the index discharge date for unmatched and propensity score-matched groups. Overall, 6.7% (84,293) of patients underwent cardiac surgery and concomitant LAAC placement without surgical ablation. After propensity score matching, the index admission mortality and overall complications were not different in patients with LAAC versus patients without LAAC. LAAC placement was associated with increased any-cause 30-day readmissions (15% vs 13%, p <0.01). In patients with LAAC, within 30 days, there were no differences in mortality (3.9% vs 3.8%, p = 0.60) or overall complications (64% vs 63%, p = 0.20), whereas stroke was lower (5.3% vs 6.5%, p <0.01) and heart failure was higher (35% vs 30%, p <0.01). For patients readmitted within 90 days, similar findings were observed for any-cause readmissions, mortality, overall complications, stroke, and heart failure. In conclusion, concomitant LAAC placement during cardiac surgery was associated with lower early postdischarge incidence of stroke and a favorable overall risk-benefit profile. Given these short-term findings in a real-world population of all patients who underwent cardiac surgery, longer-term studies with more granular data are needed to evaluate the potential benefit of this practice.

Abstract CT039: Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: Data from the iMATRIX Alectinib Phase I/II open-label, multi-center study

Abstract Background Alectinib is a central nervous system (CNS)-penetrant, oral, inhibitor of ALK-fusion proteins that has demonstrated durable responses in adults with ALK-positive non-small cell lung cancer. In children and adolescents there remains a significant unmet clinical need for patients with tumors harboring ALK-fusions, including infantile high grade gliomas and inflammatory myofibroblastic tumors at diagnosis and relapse. Here we present updated safety and efficacy data from the iMATRIX Alectinib phase I-II study (NCT04774718). Methods Patients with ALK fusion-positive solid or CNS tumors for whom prior treatment has proven to be ineffective or for whom there is no satisfactory treatment available, less than 18 years of age, were eligible. Patients were recruited to the Part 1, safety run-in to confirm the recommended phase 2 dose and monitor drug pharmacokinetics. Investigators reported responses according to RANO (CNS tumors), RECIST (solid tumors) or INRC (neuroblastoma) criteria with a data cut off of June 12, 2023. Results In total 8 patients at a median age of 11 years (range 6 months - 17 years), diagnosed with inflammatory myofibroblastic tumor (n=2), high grade glioma (n=3), renal cell carcinoma (n=2), and anaplastic large cell lymphoma (n=1, protocol deviation) were enrolled. Among 7 patients evaluable for efficacy, 6 had not received prior systemic therapy. ALK fusion partners were KIF5C in 2 patients and TPM3, CLTC, PLEKHA7, DCTN1 and HNRNPA3 in 1 patient each. Median treatment duration was 12 months (range 1-21). No Dose Limiting Toxicities were reported. Seven patients experienced a related Adverse Event (AE) including 2 patients with Grade ≥ 3 related AE. There were no AE-related deaths, and no new safety signals detected. Investigators reported Best Overall Responses as follows: in 4 patients (57.1%; 1 CR, 3 PR), 2 patients (28.6%) with Stable Disease and 1 patient had not undergone a tumor assessment at the time of data cut off. Conclusions Alectinib was generally well tolerated in pediatric patients with ALK-fusion positive solid or CNS tumors. In this hard-to-treat population, efficacy results are promising with the majority of patients experiencing a response, demonstrating a favorable benefit-risk profile. Citation Format: Francois Doz, Michela Casanova, Kyung-Nam Koh, Karsten Nysom, Adela Canete, Hyoung Jin Kang, Matthias Karajannis, Darren Hargrave, Nadege Corradini, Yeming Wu, Thorsten Ruf, Johannes Noe, Gabriele Manzella, Tao Xu, Nastya Kassir, Yachun Tai, Francis Mussai, Clare Devlin, Amar Gajjar. Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: Data from the iMATRIX Alectinib Phase I/II open-label, multi-center study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT039.

Utilization of Ocrelizumab within Different Treatment Strategies for Multiple Sclerosis: A 5-Year Population-Based Study.

We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences. We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs. The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; p < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; p < 0.01); adherence was lower for other highly active DMTs (Coeff = -0.07; 95%CI = -0.10, -0.04; p < 0.01) and low-/medium-efficacy DMTs (Coeff = -0.16; 95%CI = -0.19, -0.14; p < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; p < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = -772.31; 95%CI = -816.95, -727.66; p < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations. From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit-risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs.