دورية أكاديمية
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.
| العنوان: | Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. |
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| المؤلفون: | Desai J; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. jayesh.desai@petermac.org., Alonso G; Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain., Kim SH; Seoul National University Bundang Hospital, Seongnam, South Korea., Cervantes A; Hospital Clinico Universitario De Valencia, Valencia, Spain., Karasic T; Abramson Cancer Center, University Of Pennsylvania, Philadelphia, PA, USA., Medina L; Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain., Shacham-Shmueli E; Sheba Medical Center, Sackler School of Medicineó, Tel Aviv University, Tel Aviv, Israel., Cosman R; The Kinghorn Cancer Centre, St. Vincent's Hospital and School of Medicine, University of New South Wales, Sydney, Australia., Falcon A; Hospital Universitario Virgen del Rocio, Sevilla, Spain., Gort E; Universitair Medisch Centrum Utrecht, Utrecht, Netherlands., Guren T; Oslo University Hospital Radiumhospitalet, Oslo, Norway., Massarelli E; City of Hope - Comprehensive Cancer Center, Duarte, CA, USA., Miller WH Jr; Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Quebec, Canada., Paz-Ares L; Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain., Prenen H; University Hospital Antwerp, Edegem, Belgium., Amatu A; Haematology and Oncology Division, Grande Ospedale Metropolitano Niguarda, Milan, Italy., Cremolini C; University of Pisa, Pisa, Italy., Kim TW; Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea., Moreno V; START MADRID-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain., Ou SI; University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA., Passardi A; Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy., Sacher A; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, Department of Medicine & Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Santoro A; Humanitas University and IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy., Stec R; Biokinetica, Przychodnia Jozefow, Józefów, Poland.; Warsaw Medical University, Warsaw, Poland., Ulahannan S; Stephenson Cancer Center, Oklahoma City, OK, USA.; Sarah Cannon Research Institute, Nashville, TN, USA., Arbour K; Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Lorusso P; Yale Cancer Center, Yale University, New Haven, CT, USA., Luo J; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Patel MR; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA., Choi Y; Genentech, South San Francisco, CA, USA., Shi Z; Genentech, South San Francisco, CA, USA., Mandlekar S; Genentech, South San Francisco, CA, USA., Lin MT; Genentech, South San Francisco, CA, USA., Royer-Joo S; Genentech, South San Francisco, CA, USA., Chang J; Genentech, South San Francisco, CA, USA., Jun T; Genentech, South San Francisco, CA, USA., Dharia NV; Genentech, South San Francisco, CA, USA., Schutzman JL; Genentech, South San Francisco, CA, USA., Han SW; Seoul National University Hospital and Seoul National University Cancer Research Institute, Seoul, South Korea. saewon1@snu.ac.kr. |
| مؤلفون مشاركون: | GO42144 Investigator and Study Group |
| المصدر: | Nature medicine [Nat Med] 2024 Jan; Vol. 30 (1), pp. 271-278. Date of Electronic Publication: 2023 Dec 05. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York Ny : Nature Publishing Company Original Publication: New York, NY : Nature Pub. Co., [1995- |
| مواضيع طبية MeSH: | Proto-Oncogene Proteins p21(ras)*/genetics , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/pathology, Humans ; Cetuximab/adverse effects ; Cetuximab/genetics ; ErbB Receptors/genetics ; Progression-Free Survival ; Mutation/genetics |
| مستخلص: | KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874. (© 2023. Crown.) |
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| معلومات مُعتمدة: | P30 CA008748 United States CA NCI NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS |
| سلسلة جزيئية: | ClinicalTrials.gov NCT04449874 |
| المشرفين على المادة: | PQX0D8J21J (Cetuximab) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) EC 2.7.10.1 (ErbB Receptors) 0 (KRAS protein, human) |
| تواريخ الأحداث: | Date Created: 20231205 Date Completed: 20240124 Latest Revision: 20240312 |
| رمز التحديث: | 20240312 |
| مُعرف محوري في PubMed: | PMC10803265 |
| DOI: | 10.1038/s41591-023-02696-8 |
| PMID: | 38052910 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1546-170X |
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| DOI: | 10.1038/s41591-023-02696-8 |