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The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double-blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4-35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs. [ABSTRACT FROM AUTHOR]

1 The renal antimineralocorticoid potency of single doses of thirteen compounds with properties in animals compatible with competitive aldosterone antagonism was compared to that of spironolactone in healthy men. 2 Twelve compounds showed significant activity when compared to placebo but only one, prorenoate potassium, was significantly more potent than spironolactone on a weight basis. 3 The results allowed ranking of the compounds in order of potency relative to spironolactone and general observations on structure activity relationships in man. 4 Animal bioassays and in vitro aldosterone binding studies are unreliable predictors of the human activity of competitive mineralocorticoid antagonists. [ABSTRACT FROM AUTHOR]

The plasma potassium responses to 1 week's treatment with metolazone 0.625 mg, 1.25 mg and 2.5 mg in combination with spironolactone 50 mg, and metolazone 2.5 alone were examined in a double-blind, crossover study in twelve healthy subjects. Spironolactone attenuated the hypokalaemia induced by metolazone-addition of spironolactone 50 mg to metolazone 2.5 mg raised plasma potassium by 0.18 mmol/l (P less than 0.025). In the presence of spironolactone, a linear log metolazone dose- plasma potassium response relationship (P less than 0.01) was demonstrated. Spironolactone was unable to compensate fully for metolazone's hypokalaemic effect although in combination with metolazone 0.625 mg and 1.25 mg, plasma potassium concentration was maintained close to pretreatment levels. The human bioassay employed provided conveniently quantitative information which allows the rational development of a fixed dose diuretic-spironolactone combination tablet. [ABSTRACT FROM AUTHOR]

Tarlatamab is a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 (DLL3) and the cluster of differentiation 3 (CD3) molecule. In the phase 2 DeLLphi-301 trial of tarlatamab for patients with previously treated small cell lung cancer, tarlatamab 10 mg every 2 weeks achieved durable responses and encouraging survival outcomes. Analyses of updated safety data from the DeLLphi-301 trial demonstrated that the most common treatment-emergent adverse events were cytokine release syndrome (53%), pyrexia (38%), decreased appetite (36%), dysgeusia (32%), and an emia (30%). Cytokine release syndrome was mostly grade 1 or 2 in severity, occurred primarily after the first or second tarlatamab dose, and was managed with supportive care, which included the administration of antipyretics (e.g., acetaminophen), intravenous hydration, and/or glucocorticoids. Other treatment-emergent adverse effects of interest included neutropenia (16%) and immune effector cell-associated neurotoxicity syndrome and associated neurologic events (10%). Given that tarlatamab is the first T-cell engager approved for the treatment of small cell lung cancer, raising awareness with regard to the monitoring and management of tarlatamab-associated adverse events is essential. Here, the authors describe the timing, occurrence, and duration of these adverse events and review the management and risk-mitigation strategies used by clinical investigators during the DeLLphi-301 trial., (© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a "3 + 3" schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103. Secondary objectives included describing objective response rate, progression-free survival and overall survival. Dose escalation cohorts included GT103 given intravenously at 0.3, 1, 3, 10, and 15 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. Thirty one patients were enrolled across 3 institutions. Two dose-limiting adverse events were reported: grade 3 acute kidney injury (0.3 mg/kg) and grade 2 colitis (1 mg/kg). No dose-limiting toxicities were noted at the highest dose levels and the MTD was not reached. No objective responses were seen. Stable disease occurred in 9 patients (29%) and the median overall survival was 25.7 weeks (95% confidence interval [CI], 19.1-30.6). Pharmacokinetic analysis confirmed an estimated half life of 6.5 days. The recommended phase 2 dose of GT103 was 10 mg/kg every 3 weeks, however further dose optimization is needed given the absence of an MTD. The study achieved its primary objective of demonstrating safety and tolerability of GT103 in refractory NSCLC., Competing Interests: Competing interests: This research was supported by Grid Therapeutics. Drs. Patz, Campa, and Gottlin have affiliation with both Grid Therapeutics and Duke University. JMC reports trial funding from Bristol-Myers Squibb, Genentech, Spectrum, Adaptimmune, AbbVie, Moderna, GlaxoSmithKline, Array, AstraZeneca, Grid Therapeutics, Abel Zeta, Pfizer; advisory/consulting from AstraZeneca, Merck, Pfizer, Spectrum, Genentech, Novartis, Turning Point, G1 Therapeutics, Vivacitas, Omega, Amgen, Corbus, Sanofi; speaking and travel from Merck and Amgen; DSMB from BioThera and G1 Therapeutics. GS reports speaking for Astra-Zeneca, consulting for Daiichi Sankyo, board member for Florida chapter of ASCO, and stock Options and consulting compensation for Onc.AI. HM reports advisory board for AstraZeneca, Genentech, and Daiichi Sankyo; and research funding from AstraZeneca. TS reports clinical trial funding from AstraZeneca, Seagen, Mirati Therapeutics, Genentech/Roche, Nuvalent, Inc.; consulting from Takeda, G1 Therapeutics, Spectrum Pharmaceuticals, Gilead Sciences, AstraZeneca, Coherus Biosciences, Blueprint Medicines, Boehringer Ingelheim, Pfizer, Abbvie; travel funding from Pfizer; DSMB participation from Genentech. NR reports advisory compensation from BMS, Merck, Jazz, Genentech, Daiichi, Regeneron, ABBVIE, research funding Merck, Regeneron, and speaking from Jazz. JC reports Scientific Advisor from Actimed, Enzychem, Gen Sci, Pfizer, Tensegrity; DSMB Member of BioAtla, G1 Therapeutics; PI/Institutional Research Funding for AstraZeneca, Helsinn, Pfizer, NCI/NCTN; Publications Committee of Amgen, Frensenius-Kabi, G1, Pfizer. GS reports advisory board from EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo; Consultant/Scientific Advisory Board (SAB)/trial steering committee: Syapse, Merck, Servier, Syncorp, Ellipses; Research Support to institution from EMD Serono, Jazz Therapeutics, Bayer, Sumitomo Pharma, Blue Earth Diagnostics; Speaker from Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, Merck; Data safety monitoring committee (honorarium) from Mereo; Employment: Spouse employed by Myriad, Exact Sciences; and Travel: BMS, Astellas. SB receives support from the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), serves on an NIH DSMB, and consults for UCB (Morrisville, NC, USA), CARRA, and Rutgers University. Stephen Balevic is a member of the American College of Rheumatology, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), Alpha Omega Alpha, the American Society of Clinical Investigators, and the Society for Pediatric Research, and served as the Assistant Scientific Director for CARRAAN reports funding from Genentech, Genmab, MedImmune/AstraZeneca, Seattle Genetics; consulting from Sanofi, Promega; SAB from Leap Therapeutics; NCI Chair, Core Correlatives Sciences Committee (NCTN-CCSC); and patents of No 925592 and No. 62/337,633. MC is a founder of Grid Therapeutics, LLC and is on the advisory board. EBG is a founder of Grid Therapeutics, LLC. SA reports being member of scientific advisory boards for Cellepus Therapeutics (and Co-founder), Leap Therapeutics, Guardian Bio, Immutep, Shoreline Therapeutics, Tubulis, Xilis, Glympse Bio, Achilles Therapeutics, Memgen, RAPT Biotherapeutics. EFP is a founder, CEO and on the BOD of Grid Therapeutics, LLC. All other authors report no competing interests., (© 2024. The Author(s).)

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021., (©2024 American Association for Cancer Research.)

The Philippine Society of Hypertension (PSH) took part again in the annual May Measurement Month 2021 (MMM21) blood pressure (BP) campaign to raise awareness of hypertension. The MMM standard protocol designed by the MMM coordinating centre was used during screening. These included the collection of basic data on demography, lifestyle, and environmental factors. Standardized sitting BP measurements were taken three times, using automated BP apparatus and were either entered via MMM21 app, MMM@Home, and Google Forms or recorded on paper and transferred to Excel spreadsheets by PSH encoders. Hypertension was defined either as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or on antihypertensive medication. A total of 59 655 participated through opportunistic convenience sampling. After multiple imputation, a total of 26 813 (44.9%) participants were identified as having hypertension. Of these, 14 449 (53.9%) were aware and 12 978 (48.4%) were on antihypertensive medication. Of those who were treated, 5644 (43.5%) had controlled BP (<140/90 mmHg) and 7334 (56.5%) were uncontrolled. These latest local data showed that BP awareness is still low with BP control achieved in less than half of treated patients. Continued collaboration is needed to improve BP screening programmes in the country., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Direct comparison of tumor microenvironment of matched lung cancer biopsies and pleural effusions (PE) from the same patients is critical in understanding tumor biology but has not been performed. This is the first study to compare the lung cancer and PE microenvironment by single-cell RNA sequencing (scRNA-seq)., Methods: Matched lung cancer biopsies and PE were obtained prospectively from ten patients. We isolated CD45 + cells and performed scRNA-seq to compare the biopsies and PE., Results: PE had a higher proportion of CD4 + T cells but lower proportion of CD8 + T cells (False detection rate, FDR = 0.0003) compared to biopsies. There was a higher proportion of naïve CD4 + T cells (FDR = 0.04) and naïve CD8 + T cells (FDR = 0.0008) in PE vs. biopsies. On the other hand, there was a higher proportion of Tregs (FDR = 0.04), effector CD8 + (FDR = 0.006), and exhausted CD8 + T cells (FDR = 0.01) in biopsies. The expression of inflammatory genes in T cells was increased in biopsies vs. PE, including TNF, IFN-ɣ, IL-1R1, IL-1R2, IL-2, IL-12RB2, IL-18R1, and IL-18RAP (FDR = 0.009, 0.013, 0.029, 0.043, 0.009, 0.013, 0.004, and 0.003, respectively). The gene expression of exhaustion markers in T cells was also increased in tumor biopsies including PDCD1, CTLA4, LAG 3, HAVCR2, TIGIT, and CD160 (FDR = 0.008, 0.003, 0.002, 0.011, 0.006, and 0.049, respectively)., Conclusions: There is a higher proportion of naïve T cells and lower proportion of exhausted T cells and Tregs in PE compared to lung cancer biopsies, which can be leveraged for prognostic and therapeutic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Few series report on using fat grafting as the primary form of breast reconstruction. A 9-year experience with absorbable biosynthetic scaffolds, used in place of silicone implants, for breast reconstruction is reviewed., Methods: A clinical quality improvement approach was used to evaluate real-world data on a single plastic surgeon's experience treating breast reconstruction patients over a 7-year period., Results: Fifty-three patients had 74 breasts reconstructed, (following 51 therapeutic mastectomies and 23 prophylactic). Five of the 51 breasts (9.80 %) developed a local recurrence (mean follow-up of 4.5-5.5 years). This compared favorably with the practice's previous 6 years of silicone reconstructions. The most common complications were benign fat necrosis and oil cysts. More than 100 radiologic examinations were performed without interference by the absorbable implants. By 12-18 months post implantation, very little immune response was seen on histologic examinations of the biosynthetic scaffold constructs. Mature collagen and robust vascularity characterized the "mesh zone," whereas regenerated adipose tissue was seen in between and on top of the folded sheets of the implants. The average number of fat graft sessions in immediate reconstructions was 2.3, with a mean total fat graft volume of 551 mL, to restore an average mastectomy defect volume of 307 mL. Aesthetic outcomes were much better in the immediate reconstruction of nipple-sparing mastectomy group, which saw 68% achieve an A/B grade; 19%, C grade; and 13%, D/F on subjective grading., Conclusion: This composite strategy, using biosynthetic scaffold and autologous fat grafting, yielded outcomes equivalent to flap reconstructions with the ease of implants., Competing Interests: Dr. Rehnke is a paid consultant for Becton Dickinson (BD) and has sold intellectual property on absorbable implants to BD. Dr. Rehnke is also a paid consultant for Ricoh, USA, related to their three-dimensional modeling technology, used in preoperative planning for surgical treatment of patients with breast cancer. Dr. Badylak has received research funding from BD. Drs. Clarke and Goodrum have no financial interest to declare in relation to the content of this article. This work received no outside private or public funding., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies., Competing Interests: T.W., J.-M.N., S.R., C.K., M.C., R.B., K.H., A.L., A.C., R.W., L.Q., J.P.S., C.M., F.B., E.E., P.B., and D.W. are or were employees of Adaptimmune at the time of the study and may own stock/stock options in Adaptimmune. M.V.K., S.V.R., K.S., and K.A. are employees of CellCarta NV, Antwerp, Belgium, and were involved in the development and validation of the MAGE-A4 IHC assay. G.B.J. received consulting fees from AbbVie, Daiichi Sankyo, Eli Lilly, Genzyme, Gilead, Merck Sharp & Dohme, Novartis, Regeneron; expenses from Regeneron; research funding from AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Exelixis, Genentech, Incyte, Merck Sharp & Dohme, Novartis, Regeneron. M.O.B. received grant support from Merck, Takara Bio; quality improvement support from Novartis; is on the advisory board of Adaptimmune, Bristol Myers Squibb, GlaxoSmithKline, IDEAYA, Instil Bio, Iovance, La Roche Possey, Medison, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma; oral presentations given for Bristol Myers Squibb, Merck, Novartis, Pfizer, Sanofi. J.M.C. received grant/research support from AbbVie, Adaptimmune, Array, AstraZeneca, Bayer, Bristol Myers Squibb, CBMG, Genentech, GlaxoSmithKline, Grid Therapeutics, Medpacto, Moderna, Spectrum; consultant for Amgen, Corbus, G1 Therapeutics, Novartis, Omega, Sanofi, Turning Point, Vivacitas; speaker’s bureau for AstraZeneca. J.F.G. was compensated consultant or received honoraria from AI Proteins, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Curie Therapeutics, Genentech/Roche, Gilead, iTeos, Jounce, Karyopharm, Loxo/Lilly, Merck, Merus Pharmacueticals, Mirati, Moderna, Novartis, Novocure, Nuvalent, Pfizer, Silverback Therapeutics, Takeda; research support from Genentech/Roche, Novartis, Takeda; institutional research support from Adaptimmune, Alexo, Array Biopharma, Bristol Myers Squibb, Blueprint Medicines, Jounce, Merck, Moderna, Novartis, Palleon, Tesaro; equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. V.M. received consulting fees from Affimed, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Roche, Syneos; was principal investigator – institutional funding from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, Bristol Myers Squibb, Boehringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GlaxoSmithKline, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith. M.J. received research funding (institutional) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Eli Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics; had a consulting/advisory role (institutional) for AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Black Diamond, Boehringer Ingelheim, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, Gilead Sciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Normunity, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics. D.S.H. received travel, accommodations, expenses from AACR, ASCO, CLCC, Bayer, Genmab, SITC, Telperian; had consulting, speaker, or advisory role with 28Bio, AbbVie, Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Affini-T, Astellas, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, CARSgen, CLCC, COG, COR2ed, Cowen, EcoR1, Erasca, Fate Therapeutics, F. Hoffmann-La Roche, Genentech, Gennao Bio, Gilead, GLG, Group H, Guidepoint, HCW Precision Oncology, Immunogenesis, InduPro, Janssen, Liberium, MedaCorp, Medscape, Numab, Oncologia Brasil, ORI Capital, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Projects in Knowledge, Quanta, RAIN, Ridgeline, SeaGen, Stanford, STCube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; has other ownership interests in Molecular Match (advisor), OncoResponse (founder, advisor), Telperian (founder, advisor); received institutional research/grant funding from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, AstraZeneca, Bayer, Biomea, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Infinity, Kyowa Kirin, Merck, Mirati, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Revolution Medicine, SeaGen, STCube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology., (© 2024 The Authors.)

Background: Although serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in 3 groups: Isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs., Methods: Patients with a Guardant360 ctDNA profile with ( n  = 253) and without BrMs ( n  = 449) from the Duke Molecular Registry between January 2014 and December 2020 were identified. Actionable alterations were defined as FDA-recognized or standard-of-care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection., Results: Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC; 12.0%) and non-small cell lung cancer (NSCLC; 76.4%) were the most common tumor types. ESR1 (60% vs 25%, P  < .001) and BRCA2 (17% vs 5%, P  = .022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, P  = .08) and in patients with BrMs (36% vs 17%, P  < .001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations., Conclusions: This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions., Competing Interests: No disclaimers. No funding., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone., Methods and Materials: Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence., Results: Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts., Conclusions: The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs., (Copyright © 2023 Elsevier Inc. All rights reserved.)