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Background: This study aimed to evaluate the vaccine effectiveness (VE) of mRNA-1273.815, a 2023-2024 Omicron XBB.1.5-containing mRNA COVID-19 vaccine, at preventing COVID-19-related hospitalizations and any medically attended COVID-19 in adults., Methods: In a linked electronic health record-claims dataset, we identified US adults (≥18 years) who received the mRNA-1273.815 vaccine (exposed cohort) between 12 September and 15 December 2023, matched 1:1 to individuals who did not receive a 2023-2024 updated COVID-19 vaccine (unexposed cohort). Cohorts were balanced using inverse probability of treatment weighting on demographics, vaccination and infection history, and underlying medical conditions. Study cohorts were followed until 31 December 2023 for COVID-19-related hospitalizations and medically attended COVID-19. Cox regression was used to estimate hazard ratios and VE. Subgroup analyses were performed for adults ≥50 years, adults ≥65 years, and individuals with underlying medical conditions., Results: Overall, 859 335 matched pairs of mRNA-1273.815 recipients and unexposed adults were identified. The mean (standard deviation) age was 63 (16) years. More than 60% of individuals in both cohorts had an underlying medical condition. Among the overall adult population, VE was 60.2% (95% confidence interval, 53.4-66.0) against COVID-19-related hospitalization and 33.1% (30.2-35.9) against medically attended COVID-19 over a median follow-up of 63 (interquartile range: 44-78) days. VE estimates by age and underlying medical conditions were similar., Conclusions: These results demonstrate the significant protection provided by mRNA-1273.815 against COVID-19-related hospitalizations and any medically attended COVID-19 in adults, regardless of vaccination history, and support Centers for Disease Control and Prevention recommendations to stay up-to-date with COVID-19 vaccination to prevent COVID-19-related outcomes, including hospitalizations., Competing Interests: Potential conflicts of interest. A.B.A., D.M., H.K., J.A.M., M.A.M., and T.L. are employees of and shareholders in Moderna Inc. A.B., J.P.W.-J., N.Z., I.H.W., and M.B. are employees of Veradigm, which was contracted by Moderna and received fees for data management and statistical analyses. V.H.N. is an employee of VHN Consulting, which was contracted by Moderna to help conduct this analysis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 + T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors., Methods: This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C)., Results: From July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 µg/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8 + T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs., Conclusions: Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing., Trial Registration Number: NCT02799095., Competing Interests: Competing interests: UNV declares research support from Bristol Myers Squibb and Merck; consulting fees from Alkermes, Novartis, Bristol Myers Squibb, Exelixis, Bayer, Gilead, Seattle Genetics, Pfizer, and Aveo; speaker honoraria fees from Exelixis, Bayer, and Pfizer. JM declares advisory board attendance and honoraria from Exelixis. IW declares participation in advisory board for GOG Partners; Travel/Honoraria fees from Regeneron and IIT Collaborative funding from Chimerix for trial purposes only. SDR declares stock ownership at Pfizer, Amgen, and Johnson & Johnson. CJH declares grants from Merck; consulting fees from Merck, Eisai, and Seagen; honoraria fees from Eisai, Seagen, and Astellas; and advisory board attendance for CRISPR and Seagen. AChauhan declares grants from Bristol Myers Squibb, Clovis, Tersera, and ECS Progastrin; consulting fees from Tersera, Novartis, Lexicon, Ipsen, Curium, and Seneca Therapeutics; and honoraria from Tersera, Novartis, Lexicon, and Ipsen. AS declares funding to the institution from Alkermes. KDL declares funding to the institution from Alkermes and Merck; and employment with Regeneron. DSB declares independent research grant (payments made to institution) from AstraZeneca; consulting fees from or advisory board attendance for Bristol Myers Squibb, Mirati Therapeutics, Novartis, Eli Lilly, Amgen, Merck, Novocure, Regeneron, Syneos Health, Tempus and Daiichi-Sankyo; honoraria fees from AstraZeneca; advisory board attendance or travel fees from Bristol Myers Squibb, Novocure, AstraZeneca, Mirati Therapeutics and Regeneron; leadership as panel member for non-small cell lung cancer, thymic malignancies and pleural and peritoneal mesothelioma for National Comprehensive Cancer Network (NCCN). OD and MSE declare no conflicts of interest. DFM declares consulting fees from or advisory board attendance for Roche/Genentech BioOncology, Guidepoint, Bristol Myers Squibb, Merck, Exelixis, Pfizer, Lovance, Werewolf Therapeutics, and Svnthekine; leadership at Beth Israel, Dana-Farber Harvard Cancer Center; committee service at Beth Israel, Dana-Farber Harvard Cancer Center; grant review for FDA, Dana-Farber Harvard Cancer Center, National Cancer Institute; and funding from Prometheus Laboratories, X4 Pharmaceuticals, Alkermes, NIH, and Dept of Defense. JFS declares consulting fees from Synlogic (institution) and Binhui Biopharmaceuticals (institution); leadership at Dialectic Therapeutics; stock ownership at AbbVie, Abbot, Bristol Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck, and Regeneron. QSC declares grants from AstraZeneca; consulting fees from AbbVie, Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; honoraria from AbbVie, Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; serving on data and safety monitoring board for Merck KgaA; and unpaid and medical advocacy leadership for Lung Cancer Canada. LG declares consulting fees from or advisory board attendance for Merck and GlaxoSmithKline; honoraria fees from Merck, AstraZeneca, Eisai, GlaxoSmithKline, Eisai-Merck, Novocure, and GOG; institutional research funding from Merck Sharp & Dohme, IMV, AstraZeneca, ImmunoGen, Tesaro/GlaxoSmithKline, Karyopharm Therapeutics, Alkermes, OncoQuest, Novocure, Esperas Pharma, Mersana, Roche, and K-Group Beta Inc. AChaudhry declares receiving grants or clinical trial contracts from Arcus, Boehringer Ingelheim, AbbVie, Exelixis, Medilink, Gilead, Seagen, BeiGene, Roche, Tvardi, Amgen, Bristol Myers Squibb, Henlius, Merck, Mersana, Eli Lilly, Zia Pharmaceuticals, and AstraZeneca. EC declares employment at START, HM Hospitales Group; leadership at START, PharmaMar, EORTC, Sanofi, BeiGene, Novartis, and Merus NV; stock and other ownership interests at START and Oncoart Associated; honoraria fees from HM Hospitales Group; consulting or advisory role at Nanobiotix, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics, Servier, Bristol Myers Squibb, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma, Syneos Health, Genmab, and Diaccurate; research funding to the company from START; other relationships as president and founder of Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences), not-for-profit foundation PharmaMar, and not-for-profit CRIS Cancer Foundation. RD declares previous employment at and stock ownership in Mural Oncology. VB declares institutional research funding from Sanofi, Seattle Genetics, Loxo, Novartis, CytomX Therapeutics, Puma Biotechnology, Kura, Tesaro, Roche/Genentech, Bristol Myers Squibb, Menarini, Synthon, Janssen Oncology, Merck, Lilly, Merus, Pfizer, Bayer, Incyte, AbbVie, Zenith Epigenetics, Genmab, AstraZeneca, Adaptimmune, Alkermes, Amgen, Array BioPharma, Boehringer Ingelheim, BioNTech AG, and Boston Biomedical; consulting fees from OncoArt, and Guidepoint Global; honoraria fees from Loxo, Ideaya Biosciences, Puma Biotechnology, Amunix, Guidepoint Global, and EMD Serono; speakers’ bureau fees from Solti, Lilly, and Tactics; advisory board attendance or travel fees from START and Bayer; leadership at Next Oncology (Institution); stock ownership at 1TRIALSP; and employment at Quironsalud, Next Oncology. VV declares serving as a consultant or in an advisory role for Bristol Myers Squibb, Merck, AstraZeneca, Regeneron, G1 Therapeutics, Amgen, GSK, and Novocure., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/objectives: This retrospective cohort study evaluated the relative vaccine effectiveness (rVE) of two bivalent (original/Omicron BA.4/BA.5) vaccines mRNA-1273.222 versus the BNT162b2 Bivalent in preventing COVID-19-related outcomes in adults with underlying medical conditions associated with increased risk for severe COVID-19., Methods: In a linked electronic health record/claims dataset, US adults (≥18 years) with ≥1 underlying medical condition of interest who received either the bivalent vaccine between 31 August 2022 and 28 February 2023 were identified. The inverse probability of treatment weighting was used to adjust for cohort differences. Cohorts were followed up for COVID-19-related hospitalizations and outpatient encounters until 31 May 2023. Hazard ratios and rVEs were estimated using Cox regression. Subgroup analyses were performed on individuals with pre-specified comorbid conditions., Results: 757,572 mRNA-1273.222 and 1,204,975 BNT162b2 Bivalent recipients were identified. The adjusted rVE over a median follow-up of 198 days was 10.9% (6.2%-15.2%) against COVID-19-related hospitalization and 3.2% (1.7%-4.7%) against COVID-19-related outpatient encounters. rVE estimates for COVID-19 hospitalizations among subgroups with comorbid conditions were as follows: diabetes 15.1% (8.7%-21.0%), cerebro- and cardiovascular disease 14.7% (9.0%-20.1%), chronic lung disease 11.9% (5.1%-18.2%), immunocompromised 15.0% (7.2%-22.2%), chronic kidney disease 8.4% (0.5%-15.7%)., Conclusions: Overall, among adults with underlying medical conditions, mRNA-1273.222 was more effective than BNT162b2 Bivalent, especially in preventing COVID-19-related hospitalizations.

Introduction: Cyclic vomiting syndrome (CVS) imposes a substantial burden, but epidemiological data are scarce. This study aimed to estimate the incidence and prevalence of CVS, comorbid conditions, and treatment patterns, using administrative databases in the United States., Methods: This cross-sectional study used claims data from Merative MarketScan Commercial/Medicare Supplemental and Medicaid databases in all health care settings. Incidence and prevalence rates for 2019 were calculated and stratified by age, sex, region, and race/ethnicity. Patient characteristics were reported among newly diagnosed patients with CVS (i.e., no documented claims for CVS before 2019). CVS was defined as having 1+ inpatient and/or 2+ outpatient CVS claims that were 7+ days apart., Results: The estimated prevalence of CVS was 16.7 (Commercial/Medicare) and 42.9 (Medicaid) per 100,000 individuals. The incidence of CVS was estimated to be 10.6 (Commercial/Medicare) and 26.6 (Medicaid) per 100,000 individuals. Both prevalence and incidence rates were higher among female individuals (for both Commercial/Medicare and Medicaid). Comorbid conditions were common and included abdominal pain (56%-64%), anxiety (32%-39%), depression (26%-34%), cardiac conditions (39%-42%), and gastroesophageal reflux disease (30%-40%). Despite a diagnosis of CVS, only 32%-35% had prescriptions for prophylactic treatment and 47%-55% for acute treatment within the first 30-day period following diagnosis., Discussion: This study provides the first population-level estimates of CVS incidence and prevalence in the United States. Comorbid conditions are common, and most patients with CVS do not receive adequate treatment. These findings underscore the need for improving disease awareness and developing better screening strategies and effective treatments., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD., Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions., Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions., Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD., Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center., Competing Interests: Declaration of interests ALa reports payment from Alexion, support from Servier and stock from Gilead, outside of the submitted work. AV is co-lead role of the Consortium for Childhood Cancer Predisposition, outside of the submitted work. BH reports payment and stock from Invitae, outside of the submitted work. BC reports participation as data safety and monitoring board member in ReRad Study, participation in the chapter advisory board for Make a Wish Canada Nova Scotia, and participation in the medical advisory committee for Make a Wish Canada, outside of the submitted work. CCP reports grants from St Baldrick's Foundation, outside of the submitted work. DSZ reports consulting fees for Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Alexion, Amgen, and Norgine, outside of the submitted work. DTB reports grants from MSD and Novocure, consulting fees from Nanocarry Therapeutics and Servier, and payment from Servier, outside of the submitted work. EO reports payment and support from Alexion for educational event, outside of the submitted work. EB reports grants from Roche and board participation for Novartis, Alexion and Gilead, outside of the submitted work. FC reports grants from Hall Hunter Foundation (UK), outside of the submitted work. HBF reports payments from Illumina and Sanofi Genzyme, support from Illumina, participation as scientific advisory committee for Sanofi Genzyme, International Gaucher Alliance and Igentify, stock from Igentify, and receipt of materials from Illumina, outside of the submitted work. IW reports grants from Chimerix and payment from COG Partners, outside of the submitted work. IS reports grants from Fondation Saint-Luc and FNRS-CDR, outside of the submitted work. JK reports other financial interests at Servier and PRA Health Sciences, outside of the submitted work. JRG-S reports participation on the board of the Philippine Society of Pediatric Oncology and Philippine Board of Pediatric Oncology, and stock in Macrogenics, Moderna, Mirati Therapeutics, CRISPR Therapeutics, Repligen, Quidelortho, and Shockwave Medical, outside of the submitted work. KJB reports consulting fees from US WorldMeds, Springworks Therapeutics, Alexion, and YmAbs, and payment from Alexion, outside of the submitted work. MS reports grants and support from the Swedish Childhood Cancer Fund, participation as a data safety and monitoring board member for clinical trial NCT05230758, and participation in the Swedish Pediatric CNS tumour group, outside of the submitted work. MAC reports financial support from SUNY Upstate Department of Pediatrics and board participation for Paige's Butterfly Run, outside of the submitted work. MO reports payment from Aptitude Health and participation on a data safety monitoring board or advisory board for Ultragenyx and Abeona, outside of the submitted works. MZ reports payment and support from and board participation for AstraZeneca. NW reports grants from CANSEARCH Foundation, Childhood Cancer Research Switzerland, and the Foundation for Children and Adolescents with Cancer; payment, support, and advisory board participation for Swedish Orphan Biovitrum; and board participation for Childhood Cancer Switzerland, outside of the submitted work. NH reports grants from the National Institutes of Health (NIH) and board participation for Incyte and Pfizer, outside of the submitted work. PCN reports grants from the Canadian Institutes for Health Research (CIHR) Foundation, US Department of Defense, and Garron Family Cancer Centre, outside of the submitted work. RP reports participation in the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, outside of the submitted work. RT reports consulting fees from Fennec Pharmaceuticals and Day One Biopharmaceuticals and payment from Fennec Pharmaceuticals, outside of the submitted work. SS reports payments from Sanofi Pharmaceuticals and Mylan Pharmaceutical, and board participation for Sanofi Pharmaceuticals, outside of the submitted work. SB reports consulting fees from Hoffmann-La Roche, YmAbs, MAP Biopharma and SERB SAS, and payment from Zschimmer & Schwarz Mohsdorf, outside of the submitted work. UI reports board participation in Pakistan Society of Pediatric Oncology, outside of the submitted work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 that depletes tumor-associated macrophages. In this study, the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC. Eligible patients had clear cell RCC with disease progression on prior CPI either in combination or sequentially with VEGF-TKI. Patients were treated with PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days. The primary objective was to assess safety and tolerability and secondary objectives included pharmacokinetics and anti-tumor activity by RECIST v1.1. Seventeen patients were enrolled with a median age of 67 years, 82% male, 100% had prior CPI, and 76% had received three or more prior lines of therapy. The combination of PY314 and pembrolizumab demonstrated an acceptable safety profile with 47.1% any grade treatment-related adverse events (AE) (including only 5.9% grade ≥ 3), the most common being fatigue, pyrexia, nausea, and infusion-related reactions. One patient achieved a partial response (6%), and four patients had stable disease (24%) as their best response. The median PFS was 1.4 months (95% CI 1.2- 3.8). The combination of PY314 and pembrolizumab was safe, but the limited anti-tumor effect observed suggests that TREM2 targeting in conjunction with PD-1 blockade may not overcome resistance to prior CPI. Further investigation is warranted to determine if improved efficacy can be achieved in IO-naïve settings. Trial Registration: NCT04691375., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours., Study Design: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1)., Results: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days., Conclusions: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings., (© 2024. The Author(s).)

The emergence of Omicron variants coincided with declining vaccine-induced protection against SARS-CoV-2. Two bivalent mRNA vaccines, mRNA-1273.222 (Moderna) and BNT162b2 Bivalent (Pfizer-BioNTech), were developed to provide greater protection against the predominate circulating variants by including mRNA that encodes both the ancestral (original) strain and BA.4/BA.5. We estimated their relative vaccine effectiveness (rVE) in preventing COVID-19-related outcomes in the US using a nationwide dataset linking primary care electronic health records and pharmacy/medical claims data. The study population (aged ≥18 years) received either vaccine between 31 August 2022 and 28 February 2023. We used propensity score weighting to adjust for baseline differences between groups. We estimated the rVE against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary) for 1,034,538 mRNA-1273.222 and 1,670,666 BNT162b2 Bivalent vaccine recipients, with an adjusted rVE of 9.8% (95% confidence interval: 2.6-16.4%) and 5.1% (95% CI: 3.2-6.9%), respectively, for mRNA-1273.222 versus BNT162b2 Bivalent. The incremental relative effectiveness was greater among adults ≥ 65; the rVE against COVID-19-related hospitalizations and outpatient visits in these patients was 13.5% (95% CI: 5.5-20.8%) and 10.7% (8.2-13.1%), respectively. Overall, we found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 Bivalent vaccine in preventing COVID-19-related hospitalizations and outpatient visits, with increased benefits in older adults.

Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies., Methods: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis., Results: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival., Conclusions: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To estimate the rate of concurrent surgery for locoregional gynecologic cancer and pelvic organ prolapse-urinary incontinence (POP-UI) and to assess the rate of surgery for POP-UI within 5 years for those who did not undergo concurrent surgery., Methods: This is a retrospective cohort study. The SEER-Medicare data set was used to identify cases of local or regional endometrial, cervical, and ovarian cancer diagnosed from 2000 to 2017. Patients were followed up for 5 years from diagnosis. We used χ 2 tests to identify categorical variables associated with having a concurrent POP-UI procedure with hysterectomy or within 5 years of hysterectomy. Logistic regression was used to calculate odds ratios and 95% CIs adjusted for variables statistically significant (α=.05) in the univariate analyses., Results: Of 30,862 patients with locoregional gynecologic cancer, only 5.5% underwent concurrent POP-UI surgery. Of those with a preexisting diagnosis related to POP-UI, however, 21.1% had concurrent surgery. Of the patients who had a diagnosis of POP-UI at the time of initial surgery for cancer and who did not undergo concurrent surgery, an additional 5.5% had a second surgery for POP-UI within 5 years. The rate of concurrent surgery remained constant over the time period (5.7% in 2000 and 2017) despite an increase in the frequency of POP-UI diagnosis in the same time frame., Conclusion: The rate of concurrent surgery for patients with an early-stage gynecologic cancer and POP-UI-associated diagnosis in women older than age 65 years was 21.1%. Of women who did not undergo concurrent surgery but had a diagnosis of POP-UI, 1 in 18 underwent surgery for POP-UI within 5 years of their index cancer surgery. Dedicated efforts must be made to identify patients who would most benefit from concurrent cancer and POP-UI surgery in those with locoregional gynecologic cancers and pelvic floor disorders., Competing Interests: Financial Disclosure: Carol Emi Bretschneider received payment from Boston Scientific. Ira Winer's institution received payment from Oncoceutics to complete an exploratory analysis for investigator initiated clinical trial. They also received payment from Regeneron. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Advanced clear cell gynecologic malignancies remain among the most challenging diseases to manage. We evaluated ovarian and endometrial clear cell carcinoma (OCCC and ECCC) specimens using comprehensive sequencing technology to identify mutational targets and compared their molecular profiles to histologically similar clear cell renal cell carcinoma (ccRCC)., Methods: Using next-generation sequencing (NGS), fragment analysis (FA), and in situ hybridization (ISH), 164 OCCC, 75 ECCC and 234 ccRCC specimens from 2015 to 2018 were evaluated and compared., Results: The highest mutation rates in ECCC and OCCC were noted in: ARID1A (75.0%, 87.5%), TP53 (34.8%, 11.1%), PIK3CA (25.0%, 46.8%), PPP2R1A (8.7%, 16.7%), MSI-high (8.8%, 6.4%) and PTEN (8.3%, 7.1%). Among these mutations, there was no significant difference between OCCC and ECCC mutation prevalence except in TP53, with higher mutation rates in ECCC versus OCCC (34.8 vs. 11.1%, respectively, p < 0.05). ccRCC demonstrated different mutation profiles with higher mutation rates in VHL (80.3%), PBRM1 (43.9%), SETD2 (31.1%), and KDM5C (29.2%). By contrast, VHL, PBRM1, and SETD2 mutations were not found in ECCC and OCCC (0.0%). Compared to ccRCC and ECCC, OCCC was found to have a significantly higher tumor mutation burden (TMB) (19.1%)., Conclusion: Gynecologic and renal CCC demonstrate separate and disparate somatic profiles. However, OCCC and ECCC are diseases with similar profiles. TMB and MSI analyses indicate that a subset of OCCC may benefit from immunotherapy. Prospective clinical trials are needed and are underway to examine targeted therapies in these gynecologic disease subtypes., Competing Interests: Declaration of Competing Interest David Arguello and Pilar Ramos are employees of Caris Life Sciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort., Methods: Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens., Results: Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent., Conclusion: BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents., Competing Interests: Declaration of Competing Interest David Arguello and Yasmin Baca are employees of Caris Life Sciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: This study aimed to estimate the extent of US health care resource use (HRU) and direct cost burden of cyclic vomiting syndrome (CVS)., Methods: We selected patients in the MarketScan Commercial and Medicare Supplemental databases with ≥1 inpatient (IP) or ≥2 outpatient (OP) claims for CVS between October 1, 2015 and June 30, 2019, and continuous insurance enrollment for ≥12 months before (baseline) and ≥3 months after first CVS diagnosis (index). Using propensity scores based on baseline characteristics, each patient with CVS was matched to ∼3 non-CVS controls. We annualized HRU and costs to accommodate varying follow-up periods. Multivariable regressions further balanced CVS and non-CVS groups, and differences in HRU and costs between the matched cohorts were compared to quantify the direct cost burden of CVS., Results: Patients with CVS incurred significantly higher average annualized HRU, with the largest differences in emergency room (1.9 vs 0.4) visits and hospital IP (0.9 vs 0.1) stays ( P < .001). Patients with CVS had significantly higher annual total health care costs ($57,140 vs $14,912), with IP spending as the primary driver ($28,522 vs $3250) of the cost difference (all P < .001). After multivariable regression adjustments, total health care costs remained 4.1 times higher for patients with CVS relative to non-CVS controls, with IP costs 12.3 times higher, emergency room costs 5.8 times higher, OP visit costs 2.9 times higher, and OP pharmacy costs 1.5 times higher (all P < .001)., Conclusion: Newly diagnosed patients with CVS have greater health care utilization and higher costs than matched non-CVS counterparts, suggesting substantial economic burden of CVS on the US health care system., (© 2022 The Authors.)

Background: Black women experience worse survival effects with high-grade endometrial cancer. Differences in adjuvant treatment have been proposed to be major contributors to this disparity. However, little is known about the differences in type or timing of adjuvant treatment as it relates to race and ethnicity in the Medicare population., Objective: This study aimed to examine patterns of adjuvant therapy and survival for non-Hispanic Black women vs non-Hispanic White women and Hispanic women who have undergone surgery for high-grade endometrial cancer in the Medicare population., Study Design: We used the Medicare-linked Surveillance, Epidemiology, and End Results database to identify women who underwent surgery as a primary treatment for uterine grade 3 endometrioid adenocarcinoma, carcinosarcoma, clear-cell carcinoma, or serous carcinoma between the years 2000 and 2015. Women who did not identify as White or Black race or Hispanic ethnicity were excluded. Multinomial logistic regression was used to estimate odds ratios and 95% confidence intervals for receiving a treatment delay or not receiving adjuvant treatment (compared with those who received adjuvant treatment within 12 weeks) adjusted for clinical and demographic characteristics. Overall survival was stratified by race and ethnicity, route of surgery, operative complications, and type and timing of adjuvant therapy, which were analyzed using the Kaplan-Meier method. Cox proportional-hazards regression was used to estimate the hazard ratio of death by race and ethnicity adjusted for known predictors and surgical outcomes and adjuvant therapy patterns., Results: A total of 12,201 women met the study inclusion criteria. Non-Hispanic Black patients had a significantly worse 5-year overall survival than Hispanic and non-Hispanic White patients (30.9 months vs 51.0 months vs 53.6 months, respectively). Approximately 632 of 7282 patients (8.6%) who received adjuvant treatment experienced a treatment delay. Delay in treatment of ≥12 weeks was significantly different by race and ethnicity (P=.034), with 12% of Hispanic, 9% of non-Hispanic Black, and 8% of non-Hispanic White women experiencing a delay. After adjustment for the number of complications, age, histology (endometrioid vs nonendometroid), International Federation of Gynecology and Obstetrics stage, marital status, comorbidity count, surgical approach, lymph node dissection, and urban-rural code, Hispanic women had a 71% increased risk of treatment delay (odds ratio, 1.71; 95% confidence interval, 1.23-2.38) for all stages of disease. In the same model, non-Hispanic Black race was independently predictive of decreased use of adjuvant treatment for the International Federation of Gynecology and Obstetrics stage II and higher (odds ratio, 1.32; 95% confidence interval, 1.04-1.68). Non-Hispanic Black race, number of perioperative complications, and nonendometrioid histology were predictive of worse survival in univariate models. Treatment delay was not independently predictive of worse 1- or 5-year survival at any stage., Conclusion: Non-Hispanic Black race was predictive of worse 5-year survival across all stages and was associated with omission of adjuvant treatment in International Federation of Gynecology and Obstetrics stage II or higher high-grade endometrial cancer. In unadjusted analyses, patients who experience treatment omission or delay experienced poorer overall survival, but these factors were not independently associated in multivariate analyses. This study suggests that race and ethnicity are independently associated with the type and timing of adjuvant treatment in patients with high-grade endometrial cancer. Further efforts to identify specific causes of barriers to care and timely treatment are imperative., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To evaluate risk of a second cancer and associated survival times in United States women with diagnosis of cancer., Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for 2 cohorts of women aged 18 - 89 with either an index gynecologic or non-gynecologic cancer diagnosed between 1992 - 2017. Index cases were followed to determine if a second primary cancer was subsequently diagnosed; defined according to SEER multiple primary and histology coding rules. Standard Incident Ratios (SIR) and latency intervals between index diagnosis and second primary diagnosis were evaluated. Among those who developed a second primary cancer, median survival times from diagnosis of second primary cancer were also calculated., Results: Between 1992 - 2017, 227,313 US women were diagnosed with an index gynecological cancer and 1,483,016 were diagnosed with an index non-gynecologic cancer. Among patients with index gynecologic cancer, 7.78% developed a non-gynecologic subsequent primary cancer. The risk of developing any non-gynecologic cancer following an index gynecologic cancer was higher than the risk in the general population (SIR 1.05, 95% CI 1.04 - 1.07). Organs especially at risk were Thyroid (SIR 1.45), Colon and Rectum (SIR 1.23), and Urinary System (SIR 1.33). Among women diagnosed with an index non-gynecologic cancer, 0.99% were diagnosed with a subsequent gynecologic cancer. The risk of developing a gynecologic cancer following a non-gynecologic cancer was also elevated compared to the average risk of the general population (SIR 1.05, 1.03 - 1.07), with uterine cancer having the highest SIR of 1.13., Conclusion: The risk of a developing a second primary cancer and the corresponding survival time is based on the order and site of the index and subsequent cancer. Surveillance guidelines should be examined further to optimize survivorship programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corey, Ruterbusch, Shore, Ayoola-Adeola, Baracy, Vezina and Winer.)