Academic Journal
Avutometinib, Abemaciclib, and Fulvestrant in Patients with HR+/HER2- Metastatic Breast Cancer Previously Treated with CDK4/6 Inhibitor: A Single-Arm Phase I Trial.
| Τίτλος: | Avutometinib, Abemaciclib, and Fulvestrant in Patients with HR+/HER2- Metastatic Breast Cancer Previously Treated with CDK4/6 Inhibitor: A Single-Arm Phase I Trial. |
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| Συγγραφείς: | Waks AG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Segui E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain., Li T; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Lipsyc-Sharf M; UCLA David Geffen School of Medicine, Los Angeles, California., Kallfelz E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., DiLullo M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Patel A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Rahman T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Junkins K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Rahee H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Frey AM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Kelly E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Stalteri M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Wrabel E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Williams A; Biovica International, Uppsala, Sweden., Parsons HA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Poorvu PD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Partridge AH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Abravanel DL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Poorvu N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., LeStage B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Sicinski P; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Tolaney SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Wagle N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Tayob N; Harvard Medical School, Boston, Massachusetts.; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain., Shapiro GI; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts. |
| Πηγή: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2026 Oct 01; Vol. 32 (19), pp. 4250-4260. |
| Τύπος έκδοσης: | Journal Article; Clinical Trial, Phase I |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for Cancer Research 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 |
| Imprint Name(s): | Original Publication: Denville, NJ : American Association for Cancer Research, c1995- |
| Ιατρικοί όροι (MeSH): | Breast Neoplasms*/drug therapy , Breast Neoplasms*/pathology , Breast Neoplasms*/metabolism , Breast Neoplasms*/mortality , Antineoplastic Combined Chemotherapy Protocols*/therapeutic use , Antineoplastic Combined Chemotherapy Protocols*/adverse effects , Antineoplastic Combined Chemotherapy Protocols*/administration & dosage, Benzimidazoles/administration & dosage ; Benzimidazoles/adverse effects ; Aminopyridines/administration & dosage ; Aminopyridines/adverse effects ; Fulvestrant/administration & dosage ; Erb-b2 Receptor Tyrosine Kinases/metabolism ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Receptors, Progesterone/metabolism ; Receptors, Estrogen/metabolism ; Protein Kinase Inhibitors/administration & dosage ; Humans ; Female ; Middle Aged ; Aged ; Adult ; Maximum Tolerated Dose |
| Περίληψη: | Purpose: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative metastatic breast cancer is limited by resistance mechanisms, including mitogen-activated protein kinase (MAPK) pathway activation. We performed a phase I trial evaluating avutometinib, a dual rapidly accelerated fibrosarcoma/MAPK kinase (RAF/MEK) inhibitor, combined with abemaciclib and fulvestrant. Patients and Methods: Eligible patients had prior progression on CDK4/6i; prior fulvestrant was allowed. The primary endpoint was the maximum tolerated dose (MTD). Planned dose levels were abemaciclib 50, 100, or 150 mg orally twice daily, with avutometinib 2.4, 3.2, or 4 mg orally twice weekly (3 weeks on/1 week off) plus fulvestrant 500 mg intramuscularly every 28 days. Secondary endpoints included safety, pharmacokinetics (PK), overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS). Results: Sixteen patients were treated (median age 61; 88% visceral disease; 63% prior selective estrogen receptor degrader). The MTD and recommended phase II dose (RP2D) were abemaciclib 100 mg twice daily, avutometinib 3.2 mg twice weekly, and fulvestrant 500 mg intramuscularly every 28 days. Common treatment-related adverse events (TRAE) were creatine phosphokinase elevation (50%), neutropenia (50%), diarrhea (44%), and skin rash (44%). No grade 4 to 5 TRAEs occurred. ORR was 13% (2/15 patients with measurable disease), 24-week CBR 40% (6/15 patients with measurable disease), and median PFS 3.6 months (95% confidence interval, 2.1-not reached). PK was consistent with prior reports. Conclusions: The regimen was well tolerated at the RP2D, with no new safety signals, and showed preliminary clinical activity. A phase II trial is ongoing. (©2026 The Authors; Published by the American Association for Cancer Research.) |
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| Grant Information: | P50 CA168504 National Institutes of Health (NIH); R35 CA305086 National Institutes of Health (NIH); Verastem Oncology (Verastem Inc.); Sociedad Española de Oncología Médica (SEOM); P50 CA168504 United States CA NCI NIH HHS; Eli Lilly and Company (Lilly); CRIS Cancer Foundation (CRIS Foundation); R35 CA305086 United States CA NCI NIH HHS; P01 CA250959 United States CA NCI NIH HHS; P01 CA250959 National Institutes of Health (NIH) |
| Substance Nomenclature: | 60UAB198HK (abemaciclib) 0 (Benzimidazoles) 0 (Aminopyridines) 22X328QOC4 (Fulvestrant) EC 2.7.10.1 (Erb-b2 Receptor Tyrosine Kinases) EC 2.7.11.22 (Cyclin-Dependent Kinase 6) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) 0 (Receptors, Progesterone) 0 (Receptors, Estrogen) 0 (Protein Kinase Inhibitors) EC 2.7.10.1 (ERBB2 protein, human) EC 2.7.11.22 (CDK4 protein, human) EC 2.7.11.22 (CDK6 protein, human) |
| Entry Date(s): | Date Created: 20260713 Date Completed: 20261001 Latest Revision: 20261006 |
| Update Code: | 20261006 |
| PubMed Central ID: | PMC13628087 |
| DOI: | 10.1158/1078-0432.CCR-26-0721 |
| PMID: | 42440363 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-26-0721 |