دورية أكاديمية
Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.
| العنوان: | Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors. |
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| المؤلفون: | Corcoran RB; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Do KT; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Kim JE; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Cleary JM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Parikh AR; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Yeku OO; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Xiong N; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Weekes CD; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Veneris J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Ahronian LG; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Mauri G; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, and Department of Hematology Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy., Tian J; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Norden BL; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Michel AG; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Van Seventer EE; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Siravegna G; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Camphausen K; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Chi G; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Fetter IJ; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Brugge JS; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts., Chen H; National Institute of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Bethesda, Maryland., Takebe N; National Institute of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Bethesda, Maryland., Penson RT; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Juric D; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Flaherty KT; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Sullivan RJ; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Clark JW; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Heist RS; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts., Matulonis UA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Liu JF; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Shapiro GI; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 May 01; Vol. 30 (9), pp. 1739-1749. |
| نوع المنشور: | Journal Article; Clinical Trial, Phase I; Clinical Trial, Phase II; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Pyridones*/administration & dosage , Pyridones*/adverse effects , Pyridones*/therapeutic use , Aniline Compounds*/administration & dosage , Aniline Compounds*/adverse effects , Aniline Compounds*/therapeutic use , Pyrimidinones*/administration & dosage , Pyrimidinones*/adverse effects , Proto-Oncogene Proteins p21(ras)*/genetics , Mutation* , Neoplasms*/drug therapy , Neoplasms*/genetics , Neoplasms*/pathology , bcl-X Protein*/antagonists & inhibitors , bcl-X Protein*/genetics , Sulfonamides*/administration & dosage , Sulfonamides*/adverse effects, Humans ; Female ; Male ; Middle Aged ; Aged ; Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Aged, 80 and over ; GTP Phosphohydrolases/genetics ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/therapeutic use ; Treatment Outcome |
| مستخلص: | Purpose: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. Patients and Methods: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. Results: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. Conclusions: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population. (©2024 The Authors; Published by the American Association for Cancer Research.) |
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| معلومات مُعتمدة: | P50 CA240243 United States CA NCI NIH HHS; U54 CA224068 United States CA NCI NIH HHS; UM1 CA186709 United States CA NCI NIH HHS |
| المشرفين على المادة: | 33E86K87QN (trametinib) XKJ5VVK2WD (navitoclax) 0 (Pyridones) 0 (Aniline Compounds) 0 (Pyrimidinones) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) 0 (bcl-X Protein) 0 (Sulfonamides) 0 (KRAS protein, human) EC 3.6.1.- (GTP Phosphohydrolases) 0 (BCL2L1 protein, human) 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240308 Date Completed: 20240501 Latest Revision: 20240531 |
| رمز التحديث: | 20240601 |
| مُعرف محوري في PubMed: | PMC11061595 |
| DOI: | 10.1158/1078-0432.CCR-23-3135 |
| PMID: | 38456660 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-23-3135 |