Journal of Clinical Oncology最新文献

{"title":"Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial.","authors":"Nigel H Russell, Abin Thomas, Robert K Hills, Ian Thomas, Amanda Gilkes, Nuria Marquez Almuina, Sarah Burns, Lucy Marsh, Paresh Vyas, Marlen Metzner, Nicholas McCarthy, Georgia Andrew, Jennifer Byrne, Rob S Sellar, Richard Kelly, Paul Cahalin, Ulrik Malthe Overgaard, Priyanka Mehta, Mike Dennis, Steven Knapper, Sylvie D Freeman","doi":"10.1200/JCO.24.00259","DOIUrl":"10.1200/JCO.24.00259","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)-negative remission.</p><p><strong>Methods: </strong>Five hundred twenty-three patients with AML (median age, 67 years; range, 51-79) without a flow cytometric MRD-negative remission response after a first course of daunorubicin and AraC (DA; including 165 not in remission) were randomly assigned between up to two further courses of DA or intensified chemotherapy-either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) or DA with cladribine (DAC).</p><p><strong>Results: </strong>Overall survival (OS) was not improved in the intensification arms (DAC <i>v</i> DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; <i>P</i> = .054; FLAG-Ida <i>v</i> DA: HR, 0.86 [95% CI, 0.66 to 1.12]; <i>P</i> = .270); OS at 3 years was 34%, 46%, and 42% for DA, DAC, and FLAG-Ida, respectively. Early deaths and other adverse events were more frequent with FLAG-Ida (9% day 60 deaths <i>v</i> 4% after DA or DAC; <i>P</i> = .032). Of patients entering random assignment, 131 had MRD unknown status. In this subgroup of patients lacking evidence of residual leukemia by flow cytometry, there was no detectable survival advantage from intensification. A planned sensitivity analysis excluding these patients demonstrated a survival benefit for both DAC (HR, 0.66 [95% CI, 0.46 to 0.93]; <i>P</i> = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; <i>P</i> = .035); OS at 3 years was 30%, 46%, and 46% for DA, DAC, and FLAG-Ida, respectively. There was a concordant reduction in relapse (DAC <i>v</i> DA: HR, 0.66 [95% CI, 0.45 to 0.98]; <i>P</i> = .039; FLAG-Ida <i>v</i> DA: HR, 0.70 [95% CI, 0.49 to 0.99]; <i>P</i> = .042). DAC benefit was maintained when survival was censored for transplant (<i>P</i> = .042).</p><p><strong>Conclusion: </strong>In this study of older patients with AML considered fit and with evidence of residual disease after first induction, chemotherapy intensification improved survival. DAC intensification was better tolerated than FLAG-Ida.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"694-704"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials.","authors":"Jia Liu, Max Farrow, Lesley Seymour, Jayesh Desai, Herbert H Loong, Percy Ivy, Takafumi Koyoma, Natalie Cook, Sarah Blagden, Elena Garralda, Christophe Massard, Anthony W Tolcher, Jacob J Adashek, Li Zhang, Shen Zhao, Lin Shen, Razelle Kurzrock, Wafik S El-Deiry, Vivek Subbiah, Anthony M Joshua","doi":"10.1200/JCO-24-01534","DOIUrl":"10.1200/JCO-24-01534","url":null,"abstract":"<p><strong>Purpose: </strong>Over the past 15 years, the landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation of sites, trials, sponsors, and contract research organizations has surged exponentially, marking a significant shift in research conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety and the recommended phase II dose need to be established in a timely manner. Networks and consortia may overcome some of these challenges of enrolling suitable patients and streamlining start-up, particularly when distance and disease trajectory come into play.</p><p><strong>Design: </strong>In this article, we provide an overview of EPCT consortia in adult oncology across different continents assembled through systematic review of the literature and snowball sampling methodology. We illustrate their scope, structure, funding, and achievements.</p><p><strong>Results: </strong>Fifteen EPCT consortia were identified including two in the United States, three in Europe, five in Asia-Pacific, two intercontinental consortia, and three within private oncology networks. These consortia vary in their scope, funding, and structure from government-funded models such as the National Cancer Institute Experimental Therapeutics Clinical Trials Networks through charitably funded and private research organizations. EPCT consortia play a role in collaborative research, molecular tumor boards to provide patient-centric biomarker-matched treatments, and streamlining trial conduct to improve timelines and cost efficiency.</p><p><strong>Conclusion: </strong>The growth in EPCT activity and complexity has resulted in expansion in the number of EPCT consortia globally. By actively engaging with regulatory bodies and pharmaceutical and contract research organization industries, consortia have an opportunity to address the evolving challenges faced in this field and to accelerate the translation of scientific discoveries into clinical practice.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"735-747"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body Weight Gain Associated With Alectinib in Patients With ALK+ Non-Small Cell Lung Cancer: Pooled Analysis of Individual Patient Data From Four Prospective Clinical Trials.","authors":"Barend J Sikkema, Sara J Baart, Marthe S Paats, Egbert F Smit, Annemie M W J Schols, Ron H J Mathijssen, Elisabeth F C van Rossum, Anne-Marie C Dingemans","doi":"10.1200/JCO-24-01579","DOIUrl":"10.1200/JCO-24-01579","url":null,"abstract":"<p><strong>Purpose: </strong>Weight gain is a known adverse event (AE) of alectinib. This study evaluates the progression of actual weight gain over time and explores its association with baseline characteristics.</p><p><strong>Methods: </strong>A pooled analysis of individual patient data from four clinical trials (ALEX, J-ALEX, ALUR, and ML29453) was conducted. Actual weight gain was calculated as the percent change from baseline. A linear mixed model estimated weight change over time and associations between clinical characteristics and weight change.</p><p><strong>Results: </strong>Follow-up weights were available for three trials (J-ALEX, ALUR, and ML29453) and missing for ALEX. In total, 2,622 weights were recorded in the first year (N = 302). At baseline, 13.6% of the Japanese population were underweight and 5.0% in the Western population. Actual weight gain of any grade was substantially higher than reported AE rates (49% <i>v</i> 5%), with 18% experiencing ≥10% weight gain (from median 55.6 kg to 64.1 kg). Time on alectinib was positively associated with weight change (β = .37; 95% CI, 0.24 to 0.51; <i>P</i> < .001), corresponding to an average increase of 4.4% over 1 year. Baseline BMI was not associated with weight change in J-ALEX (β = -.090 [95% CI, -0.19 to 0.012]; <i>P</i> = .092) and ALUR/ML29453 (β = -.016 [95% CI, -0.077 to 0.044]; <i>P</i> = .59). Baseline albumin was positively associated with weight change in ALUR/ML29453 (β = .084 [95% CI, 0.027 to 0.14]; <i>P</i> = .0045), although not considered a clinically meaningful predictor.</p><p><strong>Conclusion: </strong>Weight gain is under-reported as AE in trials. Actual weights showed ≥10% weight gain in 18% of patients. Clinicians should be aware of this AE, emphasizing the importance of timely identification and monitoring weight. Identifying predictors for weight gain remains challenging.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"641-650"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Significance of Up-Front Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Patients With Brain Metastases in the Era of New Generation Tyrosine Kinase Inhibitors.","authors":"Chad G Rusthoven, Emily Miao, Lillian A Boe, Luke R G Pike","doi":"10.1200/JCO-24-02129","DOIUrl":"10.1200/JCO-24-02129","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"762-763"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Comment on the Definition and Interpretation of Complete Mesocolic Excision in the RELARC Trial.","authors":"Jun-Yang Lu, Yi Xiao","doi":"10.1200/JCO-24-02307","DOIUrl":"10.1200/JCO-24-02307","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"765"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Second Primary Cancer Risks After Breast Cancer in <i>BRCA1</i> and <i>BRCA2</i> Pathogenic Variant Carriers.","authors":"Isaac Allen, Hend Hassan, Yvonne Walburga, Catherine Huntley, Lucy Loong, Tameera Rahman, Sophie Allen, Alice Garrett, Bethany Torr, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Margreet Lüchtenborg, Joanna Pethick, Francesco Santaniello, Shilpi Goel, Ying-Wen Wang, Katrina Lavelle, Fiona McRonald, Diana Eccles, Eva Morris, Steven Hardy, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C Antoniou","doi":"10.1200/JCO.24.01146","DOIUrl":"10.1200/JCO.24.01146","url":null,"abstract":"<p><strong>Purpose: </strong>Second primary cancer (SPC) risks after breast cancer (BC) in <i>BRCA1/BRCA2</i> pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records.</p><p><strong>Methods: </strong>We followed 25,811 females and 480 males diagnosed with BC and tested for germline <i>BRCA1/BRCA2</i> PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks.</p><p><strong>Results: </strong>There were 1,840 <i>BRCA1</i> and 1,750 <i>BRCA2</i> female PV carriers. Compared with population incidences, <i>BRCA1</i> carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. <i>BRCA2</i> carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without <i>BRCA1/BRCA2</i> PVs on testing, <i>BRCA1</i> carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. <i>BRCA2</i> carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% (<i>BRCA1</i> carriers), 12%/3.0%/6.2% (<i>BRCA2</i> carriers), and 3.6%/0.4%/4.9% (noncarriers). Male <i>BRCA2</i> carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers.</p><p><strong>Conclusion: </strong>Survivors of BC carrying <i>BRCA1</i> and <i>BRCA2</i> PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"651-661"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma.","authors":"Christopher L Moertel, Angela C Hirbe, Hans H Shuhaiber, Kevin Bielamowicz, Alpa Sidhu, David Viskochil, Michael D Weber, Armend Lokku, L Mary Smith, Nicholas K Foreman, Fouad M Hajjar, Rene Y McNall-Knapp, Lauren Weintraub, Reuben Antony, Andrea T Franson, Julia Meade, David Schiff, Tobias Walbert, Prakash Ambady, Daniela A Bota, Cynthia J Campen, Gurcharanjeet Kaur, Laura J Klesse, Stefania Maraka, Paul L Moots, Kathryn Nevel, Miriam Bornhorst, Ana Aguilar-Bonilla, Sarah Chagnon, Nagma Dalvi, Punita Gupta, Ziad Khatib, Laura K Metrock, P Leia Nghiemphu, Ryan D Roberts, Nathan J Robison, Zsila Sadighi, Stacie Stapleton, Dusica Babovic-Vuksanovic, Timothy R Gershon","doi":"10.1200/JCO.24.01034","DOIUrl":"10.1200/JCO.24.01034","url":null,"abstract":"<p><strong>Purpose: </strong>Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults.</p><p><strong>Methods: </strong>ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m² twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging.</p><p><strong>Results: </strong>Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children.</p><p><strong>Conclusion: </strong>In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"716-729"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Human Leukocyte Antigen Mismatching and the Role of Killer Cell Immunoglobulin-Like Receptor Mismatch in Hematopoietic Cell Transplantation for Hematologic Malignancies.","authors":"Esteban Arrieta-Bolaños, Edouard F Bonneville, Annalisa Ruggeri, Katharina Fleischhauer","doi":"10.1200/JCO-24-02388","DOIUrl":"10.1200/JCO-24-02388","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"759-760"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Second MEK Inhibitor Shows Promise in Neurofibromatosis Type 1 With Symptomatic Plexiform Neurofibromas Signaling Hope for Other RASopathies.","authors":"Simon J Cook","doi":"10.1200/JCO-24-02375","DOIUrl":"10.1200/JCO-24-02375","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"730-734"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclin-Dependent Kinase 4/6 Inhibition as a Novel Therapy for Peritoneal Mucinous Carcinomatosis With GNAS Mutations.","authors":"Jonathan Weitz, Daisuke Nishizaki, Joy Liau, Jay Patel, Isabella Ng, Siming Sun, Dana Ramms, Jingjing Zou, Brian Wishart, Jordan Rull, Joel Baumgartner, Kaitlyn Kelly, Rebekah White, Jula Veerapong, Mojgan Hosseini, Hitendra Patel, Gregory Botta, J Sylvio Gutkind, Herve Tiriac, Shumei Kato, Andrew M Lowy","doi":"10.1200/JCO.24.00511","DOIUrl":"10.1200/JCO.24.00511","url":null,"abstract":"<p><strong>Purpose: </strong>Mucinous neoplasms of the gastrointestinal tract are characterized by a propensity for metastasis to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC). A subset of these tumors, most often originating in the appendix, harbor mutations in the <i>GNAS</i> oncogene. While the natural history of <i>GNAS</i>-mutant PMC varies, patient outcomes are generally poor, as is response to cytotoxic chemotherapy. The purpose of this study was to evaluate the clinical efficacy of single-agent palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, in patients with <i>GNAS</i>-mutant PMC.</p><p><strong>Patients and methods: </strong>We enrolled 16 patients with PMC in a single-arm personalized cancer therapy trial. For all patients, tumor tissue and/or circulating tumor DNA genomic profiling using next-generation sequencing and, when possible, PD-L1 expression, tumor mutational burden, and microsatellite instability status was assessed. Twelve of 16 patients had previous disease progression on at least one previous line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in two patients, and pancreas in one patient. Eleven cases were classified as low grade, and five as high grade.</p><p><strong>Results: </strong>In 13 of 16 patients, we observed a decrease in carcinoembryonic antigen (CEA), and in six patients, the CEA declined by >50%. As measured by clinical and modified peritoneal RECIST criteria, 50% of evaluable patients had stable disease after 12 months of palbociclib. At a median follow-up of 17.6 months, median survival has not been reached. Clinical response to CDK4/6 inhibition was mirrored in tumors with <i>GNAS</i> mutation and mucinous histology using an ex vivo preclinical platform.</p><p><strong>Conclusion: </strong>CDK4/6 inhibition with palbociclib had clinical activity in PMC characterized by mutations in <i>GNAS</i> that was superior to that previously reported with cytotoxic chemotherapy. CDK4/6 inhibition is a novel therapeutic strategy worthy of further evaluation in this subgroup of gastrointestinal neoplasms.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"705-715"},"PeriodicalIF":42.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}