Combination Arm Research Articles

Response-Adaptive Surgical Timing in neoadjuvant immunotherapy demonstrates enhanced pathologic treatment response in Head and Neck Squamous Cell Carcinoma.

We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response. Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing. Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p<0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV- cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response. Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

Promoting Influenza Vaccination Uptake Among Chinese Older Adults Based on Information–Motivation–Behavioral Skills Model and Conditional Economic Incentive: Protocol for Randomized Controlled Trial

Background: Influenza poses a substantial health burden, especially among older adults in China. While vaccination is one of the most effective preventions, influenza vaccine uptake rates among Chinese older adults remain low. This study examines the individual and combined effects of behavioral interventions based on the Information–Motivation–Behavioral Skills (IMB) model and economic incentives in promoting influenza vaccine uptake among older adults living in China. Methods: The study will recruit 640 older adults living in eight communities that have not been covered by the free influenza vaccination policy. These eight communities (as clusters), stratified by urban and rural, will be randomized to four parallel arms, including a usual care arm, an IMB-based behavioral intervention arm, a conditional economic incentive arm, and a combined behavioral-economic arm. The interventions will start from the beginning of the flu season and last for about one month. Specifically, the IMB-based behavioral intervention encompasses health education brochures, healthcare provider-led lectures, interactive quizzes, and personalized consultations. The exact number of economic incentives is conditional on the timing of vaccination (a higher amount for early immunization) and the number of people within a household to be vaccinated at the same appointment (a higher amount for more people). The primary outcome is the influenza vaccination rate. Data will be gathered through vaccination records and questionnaires covering IMB-based vaccination cognitions. Mixed-effects models will be used to analyze the outcome of vaccination rate, reporting difference-in-differences estimates with 95% confidence intervals. Conclusions: The results of this study have the potential to inform influenza vaccination program scaleup among older adults who are not yet covered by the free influenza vaccination policy. Ethics and dissemination: Ethics approval has been granted by the ethics commission of Peking University Health Science Centre (IRB00001052-24090). Participants will be required to sign a written consent form. Findings will be reported in conferences and peer-reviewed publications in accordance with the recommendations of the Consolidated Standards of Reporting Trials. Registration number: This study was registered at the Chinese Clinical Trial Registry (ChiCTR2400090229).

Combination Prostatic Artery Embolization Prior to Water-Jet Ablation (Aquablation) for Benign Prostatic Hypertrophy: A Propensity Score Analysis.

Objectives: To compare post-operative bleeding measures in patients who underwent prostatic artery embolization (PAE) prior to water-jet ablation (aquablation) vs. water-jet ablation alone. Methods: A retrospective review identified 145 patients treated with water-jet ablation for benign prostatic hyperplasia from December 2018 to June 2021. Patients were divided into two groups: water-jet ablation alone (n = 56) vs. pre-operative PAE and water-jet ablation (n = 89). Patient demographics, pertinent laboratory values, operative reports, and hospital courses were reviewed. Results: PAE was technically successful in all patients (n = 89), and all 89 patients underwent successful water-jet ablation within a median time of 2 days. Compared to water-jet ablation alone, pre-operative PAE resulted in a significant reduction in post-operative bleeding as measured via lower rates of continuous bladder irrigation, hemostatic measures, and hematuria. Pre-operative PAE was also associated with lower rates of post-operative urinary retention (odds ratio 17, p = 0.02) and less likely to require reoperation 30 days after the procedure (p = 0.003). There were no major PAE-related adverse events reported in the combination arm. Conclusions: Compared to water-jet ablation alone, pre-operative PAE resulted in fewer bleeding-related complications and urinary retention.

CTNI-59. TUMOUR VOLUMES PREDICT PROGNOSIS AND RESPONSE TO TREATMENT WITH DEPATUXIZUMAB MAFADOTIN

Abstract BACKGROUND Preclinical data demonstrates that tumor volumes predicted response to the anti-EGFR ADC Depatuxizumab mafadotin (Depatux-M) because of reduced drug delivery in large tumors. We investigated the impact of tumor volumes on outcomes with Depatux-M in the EORTC randomized phase 2 Intellance 2 study on recurrent glioblastoma (NeuroOncol 22(5):684). METHODS 260 patients were randomized to Depatux-M, Depatux-M with temozolomide, or control treatment (lomustine/temozolomide). Manual segmentation of enhancing tumor on baseline MRI scans was performed and compared with OS and PFS using SPSS Version 29.0: Kaplan-Meier survival analysis including log rank test and Cox regression analyses; categorical data were compared with Fishers’ exact test; correlation between 2D and 3D measurements with Pearson’s correlation. RESULTS MRI scans and data from 240/260 (92%) patients were available. Firstly, we confirmed that tumor volumes were a significant prognostic variable. Significant differences were seen in OS between the 0-20 vs 20-40 ml groups (321 vs 216 days, p&amp;lt;0.001) and between the 20-40ml vs 40+ groups (216 vs 150 days, p&amp;lt;0.001) with corresponding differences in PFS. Tumor volumes were also predictive of benefit from Depatux-M, with only patients with smaller tumors benefiting from Depatux-M. Patients in the 0-20 ml and 20-40 ml group group had superior OS when treated with Depatux-M compared to controls (356 vs 309 days, p=0.011 and 229 vs 178 days, p=0.028 respectively). Conversely, the 40 ml + group had no benefit (146 vs 152 days, p=0.875) as predicted. The benefit was maximal in the combination arm, with OS improvement in the 0-20 ml group (437 vs 309 days, p=0.007) and 20-40ml groups (225 vs 178 days, p=0.009). The impact of tumor volumes was confirmed in multi-variate analysis and superior to similar analysis with 2D RANO measurements. CONCLUSIONS Tumor volumes are an important prognostic variable in recurrent glioblastoma and modulate survival to large molecules like Depatux-M.

Effects of home-based exercise alone or combined with cognitive training on cognition in community-dwelling older adults: A randomized clinical trial

BackgroundStructured and supervised physical exercise and cognitive training are two efficient ways to enhance cognition in older adults. Performing both within a combined intervention could maximize their effect on cognition due to their potential synergy on brain functions. During the COVID-19 pandemic, these interventions were particularly relevant due to the collateral impact of social restrictions regarding physical activity and the level of cognitive stimulation. However, the benefits of remotely monitored intervention combining physical exercise and cognitive training for older adult cognition remain to be demonstrated. Methods127 older adults (age: 65.20 ± 7.95) were randomized in two arms, encouraging self-engagement in six months of home-based physical exercise alone or combined with cognitive training, monitored by phone once a week. Neuropsychological assessment was performed under videoconference supervision at baseline and after three and six months. Composite Z-scores were calculated for processing speed, executive functioning, working, and episodic memory to assess changes after three and six months of training. The weekly metabolic expenditure of self-reported activities was estimated using the compendium of physical activity to distinguish participants performing higher and lower doses of exercise (median split). Results106 participants (83.46 %) completed the 6-month training. Results showed a greater Z-score change in executive functioning for participants in the combined arm than those who only exercised (F = 4.127, p = 0.046, ηp2 = 0.050). Group x Exercise dose interaction was observed for episodic memory Z-score change (F = 6.736, p = 0.011, ηp2 = 0.070), with a greater improvement for participants performing higher doses of exercise compared to those who performed a lower dose, only in exercise alone arm. Performing a higher dose of exercise increased the working memory Z-score change in both intervention arms compared to a lower dose (F = 7.391, p = 0.008, η p2 = 0.076). ConclusionRemote combined training may lead to larger improvement in executive functioning than exercise alone. Physical exercise showed a dose-related improvement in working and episodic memory performances. The combination of cognitive interventions mitigated the effects of exercise on episodic memory. These results suggest that home-based exercise and cognitive training may help improve older adults' cognition. Trial registrationCOVEPIC was retrospectively registered on December 03, 2020. Clinical trials Identifier: NCT04635462 - https://clinicaltrials.gov/ct2/show/record/NCT04635462?term=NCT04635462&draw=2&rank=1

Improving follow-up survey completion rates through pilot interventions in the All of Us Research Program: Results from a non-randomized intervention study.

Retention to complete follow-up surveys in extensive longitudinal epidemiological cohort studies is vital yet challenging. All of Us developed pilot interventions to improve response rates for follow-up surveys. The pilot interventions occurred from April 27, 2020, to August 3, 2020. The three arms were: (1) telephone appointment [staff members calling participants offering appointments to complete surveys over phone] (2) postal [mail reminder to complete surveys through U.S. Postal Service], and (3) combination of telephone appointment and postal. Controls received digital-only reminders [program-level digital recontact via email or through the participant portal]. Study sites chose their study arm and participants were not randomized. A total of 50 sites piloted interventions with 17,593 participants, while 47,832 participants comprised controls during the same period. Of all participants, 6,828 (10.4%) completed any follow-up surveys (1448: telephone; 522: postal; 486: combination; 4372: controls). Follow-up survey completions were 24% higher in the telephone appointment arm than in controls in bivariate analyses. When controlling for confounders, telephone appointment and combination arms increased rates of completion similarly compared to controls, while the postal arm had no significant effect (odds ratio [95% Confidence Interval], telephone appointment:2.01[1.81-2.23]; combination:1.91[1.66-2.20]; postal:0.92[0.79-1.07]). Although the effects of the telephone appointment and combination arms were similar, differential effects were observed across sub-populations. Telephone appointments appeared to be the most successful intervention in our study. Lessons learned about retention interventions, and improvement in follow-up survey completion rates provide generalizable knowledge for similar cohort studies and demonstrate the potential value of precision reminders and engagement with sub-populations of a cohort.

Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the ‘CAVARLY TRIAL’

ObjectivesBeta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk...

Beyond bedwetting: How successful treatment is observed in sleep macrostructure

IntroductionSleep enuresis (SE), commonly known as bedwetting, refers to involuntary urination during sleep. It is a prevalent condition affecting approximately 15 % of children at age 5, 10 % by age 7, and 5 % by age 10. This condition can significantly impact both children and their families. The pathophysiology of SE is complex and not yet fully understood. There are several established treatment methods, but limited information on their sleep dynamics. ObjectiveThis study aimed to evaluate differences in sleep structure before and after treatment in patients with monosymptomatic SE (MSE), focusing on alarm therapy, desmopressin, and a combination of both. The analysis compared pre- and post-treatment differences within each treatment arm. The analysis was conducted for both successful and unsuccessful treatment outcomes. Methods/resultsThis was a prospective study with MSE patients, aged 6–16 years, diagnosed by multidisciplinary assessment. Of the 140 initial applicants 75 were initially included in the study and randomized for therapeutic intervention in three treatment arms, namely: alarm, desmopressin and alarm + desmopressin. Therapeutic response was evaluated 12 months after treatment discontinuation. Polysomnographic evaluation pre and post treatment was carried out. 51/75 completed the entire protocol. 42/51 were successfully treated and had a median age of 10 [8–12] and the non-success, 8 [7–10]. Among the successful patients, the percentage of N2 sleep decreased from a median of 55.7 %–48.5 % (p = 0.0004) in the alarm arm, from 58.8 % to 50 % (p = 0.002) in the desmopressin arm, and from 54.7 % to 50.9 % (p = 0.044) in the combined arm. The percentage of N3 sleep increased from 25.7 % to 30.1 % (p = 0.004) in the alarm arm, from 21.6 % to 26 % (p = 0.032) in the desmopressin arm, and from 23.7 % to 28.3 % (p = 0.014) in the combined arm. The arousal index significantly increased from pre-to post-treatment in all arms: in the alarm arm, from 1.25 to 2.8 (p = 0.002); in the desmopressin arm, from 1.3 to 2.7 (p = 0.019); and in the combined treatment arm, from 1 to 4 (p = 0.003). No significant differences were observed in the non-successful arm or among those who experienced complete resolution of the enuresis without treatment. ConclusionThe observed increase in N3 sleep and arousal and decrease in N2 sleep following successful treatment, regardless of the specific interventions, underscores the role of sleep in the pathophysiology of enuresis. Conversely, the lack of sleep differences in the non-successful arm further highlights the importance of sleep, beyond developmental factors, in influencing the clinical outcomes of enuresis, especially since all children were assessed 12 months after the start of treatment.

Femoral versus Acetabular Containment Procedures in Perthes Disease: A Systematic Review and Meta-analysis

Abstract Background Perthes disease is a rare childhood condition that affects the hip. It occurs when the blood supply to the rounded head of femur is temporarily disrupted. Without an adequate blood supply, the bone cells die, a process called avascular necrosis. There is limited data about surgical options in treatment of Perthes disease. The authors conducted this systematic review and meta-analysis to compare between femoral versus acetabular containment in the management of Perthes disease in terms of efficacy and complications, however there is a debate about the ideal way of treatment in Perthes disease. Objective To compare between femoral varus and acetabular containment osteotomies in children with Perthes disease, regarding the efficacy, long-term outcomes and complications. Methods This systematic review and meta-analysis examined studies that compared FVO and Pelvic Osteotomy. The authors searched the Medline database via PubMed, EMBASE, and Cochrane Library for studies published between 2012 and 2022. Results A total of 1051 patients were analyzed for different procedures, including 429 patients in the pelvic arm, 459 patients in FVO arm, and 163 patients in the combined arm. The number of hips included in the current analysis was 1069 hips, including 437 in pelvic arm, 469 in FVO arm, and 163 in the combined arm. The mean age for the included patients was 9.5±7.74 years, with 859 (81.8%) males and 192 (18.2%) females. There was an apparent predominance in males vs. females in all arms. The mean follow-up of the included studies was 8.6±8.32 years. We compared between the three procedures clinically, radiographic and complications. (FVO: Femoral varus osteotomy). Conclusion Femoral varus osteotomy and Pelvic osteotomy have shown comparable clinical and radiological improvement in treatment of perthes disease. The FVO group has shown higher rate than pelvic or combined osteotomies regarding post-operative arthritis and decrease range of motion. The pelvic group has shown higher rate than FVO and combined osteotomies regarding post-operative impingement and leg length discrepancy. There was no significant difference between the pelvic, femoral and combined osteotomies regarding range of motion, Trendelenberg, limping, post-operative pain and secondary knee deformity. In summary, this review provides evidence that femoral and pelvic osteotomies are safe, effective methods in treatment.

Health-related quality of life in patients with progressive glioblastoma treated with combined bevacizumab and lomustine versus lomustine only: Secondary outcome of the randomized phase III EORTC 26101 study

Abstract Background Progression-free survival, but not overall survival, was prolonged with bevacizumab and lomustine compared to lomustine only in the randomized phase 3 European Organization for Research and Treatment of Cancer (EORTC) 26101 study. Objective To evaluate the impact of treatment on health-related quality of life (HRQoL) in progressive glioblastoma patients participating in the EORTC 26101 study. Methods Patients with progressive glioblastoma, after standard radio-chemotherapy, were 2:1 randomized to either BEV/LOM or LOM. HRQoL was a secondary trial outcome and assessed using the EORTC QLQ-C30 and QLQ-BN20 questionnaires at baseline, and subsequently every 12 weeks. Predefined scales for analysis were global health status (GH), physical functioning, social functioning (SF), motor dysfunction, and communication deficit. The primary endpoint was HRQoL during the last assessment up to week 36. Moreover, time to HRQoL deterioration (TTD) and HRQoL deterioration-free survival (DFS) were calculated. Results Out of 437 patients, 402 (92%) patients had a baseline HRQoL assessment, which dropped to 66% at week 36. During the last assessment up to week 36, no differences were observed for predefined scales, apart from SF being clinically relevant lower in the combination arm (mean 66.0 versus 81.0, p = .001). Of note, the baseline SF score was 66.4 for patients in the combination arm, showing stable SF. Median DFS was significantly longer in the combination arm (12.4 weeks) compared to lomustine alone (6.7 weeks), reflecting the difference in time to progression between arms. TTD, not including progression as an event, was not different between treatment arms (median 13.0 versus 12.9 weeks). Conclusion The addition of bevacizumab to lomustine did not negatively affect HRQoL during the progression-free period.

Experimental demonstration of the combined arm- and cavity-locking system for LISA

Experimental demonstration of the combined arm- and cavity-locking system for LISA

CtDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial.

The ETOP 10-16 BOOSTER study was a randomized phase II trial of osimertinib and bevacizumab therapy versus osimertinib therapy in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously. Next-generation sequencing (Guardant360) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored, and molecular alterations at progression were described. A total of 136 patients (88% of 155 randomized) had plasma samples at baseline (68 per arm), 110 (71%) at week 9, and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found to differ by smoking status (interaction P = 0.046), with the effect of smoking also differing by baseline EGFR T790M (interaction P = 0.033), whereas both TP53 at baseline and the tissue EGFR exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (P = 0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (P = 0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arms, respectively. The differential effect of treatment by smoking was not explained by TP53 mutations or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected, but no novel molecular alterations were identified in the combination arm.

Mediating effects of inequitable gender norms on intimate partner violence and contraceptive use in a cluster randomized control trial in Niger.

Previous research has demonstrated that the Reaching Married Adolescents intervention (RMA) was associated with changes in inequitable gender norms, intimate partner violence (IPV), and modern contraceptive use. This study seeks to understand if changes in inequitable gender norms mediate the RMA intervention's effects on contraceptive use and intimate partner violence (IPV). A four-arm cluster randomized control trial was conducted to evaluate effects of the RMA intervention (household visits, small groups, combination, control) on married adolescent girls and their husbands in Dosso, Niger (baseline: 1042 dyads; 24m follow-up: 737 dyads; 2016-2019). Mediation was assessed using inverse odds ratio weighting. In the small group intervention, of the total effect on IPV prevalence (8% reduction), indirect effects via inequitable gender norms is associated with a 2% decrease (95% CI: -0.07, 0.12) and direct effects with a 6% decrease (95% CI: -0.20, -0.02). For household visits, of the total effect on contraceptive use (20% increase), the indirect effect accounts for an 11% decrease (95% CI: -0.18, -0.01) and direct effect, a 32% increase (95% CI: 0.13, 0.44); similar to findings for the combination arm. This experimental evidence informs the value of changing underlying social norms to reduce IPV and increase contraception use.

5 A Phase 1b, Open-Label, Safety, Tolerability, and Efficacy Study of HC-7366 in Combination with Belzutifan (WELIREGTM) in Patients with Advanced or Metastatic Renal Cell Carcinoma, NCT06234605

Abstract Background HC-7366 is a novel, orally administered, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Activation of GCN2 promotes cell survival, whereas prolonged activation induces apoptosis. GCN2 activation also suppresses general protein synthesis and induces cell cycle arrest, thereby preventing cell growth during nutrient scarcity. Additionally, HC-7366 decreases HIF expression and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function. HC-7366 also inhibits HIF expression in immunosuppressive myeloid cells, including macrophages. These effects of HC-7366 on metabolism, HIF signaling, and immune suppression suggest therapeutic benefit in ccRCC with clear rationale for combinations with HIF2a antagonists and immune checkpoint inhibitors. HC-7366 (0.5-1 mg/kg), combined with belzutifan (1 mg/kg), exhibited combination benefit in HIF-2 dependent A-498 and 786-O RCC xenografts, yielding 90% tumor growth inhibition and a three-fold increase in complete responses, respectively. Additionally, HC-7366 drives significant monotherapy antitumor activity in PDX models that demonstrated belzutifan resistance. Mechanism of action studies have identified several pathway engagement and potential efficacy biomarkers (Stokes, et al., 2024). Trial design/schema This multicenter, open-label phase 1b study will identify the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd, in patients with advanced or metastatic RCC with renal cell histology irrespective of VHL gene mutation. Monotherapy HC-7366 will be evaluated in parallel. The monotherapy arm, HC-7366, 60 mg p.o. qd, includes patients who have relapsed after 1 to 4 prior lines of standard of care that may include belzutifan or another HIF-2α inhibitor. The combination arm includes patients who have received 1 to 3 prior lines of standard of care and are belzutifan or HIF-2α naïve. HC-7366 dose escalation arm evaluates combination fixed dose belzutifan, 120 mg po qd plus HC-7366 at 20, 40, or 60 mg po qd. Enrollment will start with the HC-7366 monotherapy arm. Subsequently, patients will begin to enroll in the combination therapy HC-7366 dose escalation arm, while the monotherapy arm will continue to enroll. Expansion will evaluate the combination of fixed dose belzutifan with two doses of HC-7366 selected from escalation. Assessments include safety, PK, and anti-tumor activity. The study will enroll up to 80 patients at US study sites. Significance and vision Combination HC-7366 plus belzutifan, supported by preclinical evidence, is being studied to assess antitumor activity in the RCC relapsed setting. Determining safety and evaluation of dose are foundational to this study. Reference Stokes M, Tameire F, Wojnarowicz P, et al. HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models. Meeting of the American Association for Cancer Research; 2024 Apr 5-10; San Diego (CA); AACR; 2024. Abstract 4615. This study is in collaboration with Merck Sharp &amp; Dohme LLC, a subsidiary of Merck &amp; Co., Inc., Rahway, NJ, USA

8 Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable risk patients from the phase 3 CheckMate 214 trial

Abstract Background First-line nivolumab plus ipilimumab (NIVO+IPI) has provided substantial long-term survival benefits over sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC) in CheckMate 214. With a median follow-up of 8 years, the longest follow-up to date for any phase 3 trial of immune checkpoint inhibitor combination therapy in patients with aRCC, we report survival, response per independent radiology review committee (IRRC), and safety in all randomized patients (intent-to-treat [ITT] population) and in patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk. Methods Patients with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W×4 doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Key study endpoints included overall survival (OS), IRRC-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (primary), ITT (secondary), and favorable-risk (exploratory) patients. Cancer-specific survival was evaluated in ITT patients by censoring all causes of death other than RCC. Post hoc exploratory analyses in patients with favorable risk were performed. Results With 8 years (99.1 months) median follow-up, OS with NIVO+IPI versus SUN remained superior in ITT patients (hazard ratio [HR], 0.72; Table). The HR for PFS with NIVO+IPI versus SUN was 0.88. ORR was higher with NIVO+IPI versus SUN (Table), with more complete responses (12% vs 3%) and a longer median duration of response (DOR) in the combination arm versus SUN. In patients with favorable risk, OS benefits were similar between arms (HR, 0.82; Table). The HR for PFS favored SUN (HR, 1.76). ORR was lower with NIVO+IPI versus SUN, yet more patients achieved complete responses (13% vs 6%, respectively) and median DOR was longer with NIVO+IPI. Median cancer-specific survival (95% CI) in ITT patients was 73.7 (62.8-91.2) months with NIVO+IPI versus 45.1 (37.8-53.3) months with SUN (HR, 0.69; 95% CI 0.59-0.82). In exploratory post hoc analyses of patients with favorable risk, 75/125 (60.0%) patients in the NIVO+IPI arm and 85/124 (68.5%) patients in the SUN arm died over 8 years of follow-up. Of these patients, 31 in the NIVO+IPI arm and 27 in the SUN arm died within 3 years of randomization; the primary reason for death was disease in either arm (71.0% and 85.2%, respectively). Furthermore, among 27 patients in the NIVO+IPI arm with favorable risk who died after disease progression within 3 years, 12 patients did not receive second-line systemic therapy. Beyond 3 years, only 2 of 43 patients who died after disease progression did not receive subsequent systemic therapy. Among all treated patients, incidence of any-grade and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. Table Conclusions With a median follow-up up of 8 years, NIVO+IPI continues to demonstrate sustained survival and more durable response benefits versus SUN in the ITT population, including a further reduction in the risk of death with NIVO+IPI as measured by cancer-specific survival. Long-term exploratory data in patients with favorable risk have shown a steady improvement in the HR for OS, and a marked improvement in median DOR and complete response rates with NIVO+IPI versus SUN, thus contributing to the survival and response benefits reported in the ITT population. Furthermore, the disproportionate number of patients with favorable risk who died within 3 years of randomization after documented progression without receiving subsequent therapy may have affected the HR for OS in this patient population early on. NIVO+IPI offers the potential for positive long-term outcomes, regardless of IMDC risk, and with no emergence of new safety signals.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study

BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%.MethodsECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsTarget enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35–48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67–29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent.ConclusionsEpacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted.Trial registrationClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Baseline biomarkers of efficacy and on-treatment immune-profile changes associated with bempegaldesleukin plus nivolumab

In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.

The effect of vitamin E and docosahexaenoic acid ethyl ester on Metabolic Dysfunction-Associated steatotic Liver Disease (MASLD)-A randomised, double-blind, placebo-controlled, parallel-group clinical trial (PUVENAFLD).

We conducted a clinical trial to determine the efficacy of the combination of vitamin E and/or docosahexaenoic acid (DHA) versus placebo in reducing liver fat content after 6 months of intervention in adults with MASLD. Adults with MASLD were randomised to one of four treatment arms (vitamin E 1000 mg/daily + DHA 1.89 g/daily or combination arm, vitamin E 1000 mg alone, DHA 1.89 g alone or placebo) following a 2:1:1:2 randomisation. The primary objective was to determine the efficacy of DHA + vitamin E versus placebo in reducing hepatic fat fraction (%) relative to baseline after 6 months of intervention. Secondary objectives were to determine the effect of vitamin E or DHA alone versus placebo on reducing liver fat at 6 months. Our cohort consisted of 203 subjects with a mean age of 51 years, 53% female, 91% White, 59% Hispanic ethnicity. The combination of vitamin E + DHA had no effect on the primary endpoint of reducing hepatic steatosis as determined by MRI-PDFF (p = 0.98). Neither vitamin E alone (p = 0.91) nor DHA alone (p = 0.14) significantly reduced hepatic steatosis compared to placebo. However, the trial was not powered adequately for this analysis. Compared with placebo, no statistically significant differences were detected in the 3-month or 6-month levels for ALT (U/L) or AST (U/L) in all three intervention groups. The combination of DHA + vitamin E or either agent alone did not demonstrate efficacy on reducing liver fat or aminotransferases in the studied population.

Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.

Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.

Clinician- and Patient-Directed Communication Strategies for Patients With Cancer at High Mortality Risk

Serious illness conversations (SICs) that elicit patients' values, goals, and care preferences reduce anxiety and depression and improve quality of life, but occur infrequently for patients with cancer. Behavioral economic implementation strategies (nudges) directed at clinicians and/or patients may increase SIC completion. To test the independent and combined effects of clinician and patient nudges on SIC completion. A 2 × 2 factorial, cluster randomized trial was conducted from September 7, 2021, to March 11, 2022, at oncology clinics across 4 hospitals and 6 community sites within a large academic health system in Pennsylvania and New Jersey among 163 medical and gynecologic oncology clinicians and 4450 patients with cancer at high risk of mortality (≥10% risk of 180-day mortality). Clinician clusters and patients were independently randomized to receive usual care vs nudges, resulting in 4 arms: (1) active control, operating for 2 years prior to trial start, consisting of clinician text message reminders to complete SICs for patients at high mortality risk; (2) clinician nudge only, consisting of active control plus weekly peer comparisons of clinician-level SIC completion rates; (3) patient nudge only, consisting of active control plus a preclinic electronic communication designed to prime patients for SICs; and (4) combined clinician and patient nudges. The primary outcome was a documented SIC in the electronic health record within 6 months of a participant's first clinic visit after randomization. Analysis was performed on an intent-to-treat basis at the patient level. The study accrued 4450 patients (median age, 67 years [IQR, 59-75 years]; 2352 women [52.9%]) seen by 163 clinicians, randomized to active control (n = 1004), clinician nudge (n = 1179), patient nudge (n = 997), or combined nudges (n = 1270). Overall patient-level rates of 6-month SIC completion were 11.2% for the active control arm (112 of 1004), 11.5% for the clinician nudge arm (136 of 1179), 11.5% for the patient nudge arm (115 of 997), and 14.1% for the combined nudge arm (179 of 1270). Compared with active control, the combined nudges were associated with an increase in SIC rates (ratio of hazard ratios [rHR], 1.55 [95% CI, 1.00-2.40]; P = .049), whereas the clinician nudge (HR, 0.95 [95% CI, 0.64-1.41; P = .79) and patient nudge (HR, 0.99 [95% CI, 0.73-1.33]; P = .93) were not. In this cluster randomized trial, nudges combining clinician peer comparisons with patient priming questionnaires were associated with a marginal increase in documented SICs compared with an active control. Combining clinician- and patient-directed nudges may help to promote SICs in routine cancer care. ClinicalTrials.gov Identifier: NCT04867850.