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Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.
Corcoran, Ryan B; Do, Khanh T; Kim, Jeong E; Cleary, James M; Parikh, Aparna R; Yeku, Oladapo O; Xiong, Niya; Weekes, Colin D; Veneris, Jennifer; Ahronian, Leanne G; Mauri, Gianluca; Tian, Jun; Norden, Bryanna L; Michel, Alexa G; Van Seventer, Emily E; Siravegna, Giulia; Camphausen, Kyle; Chi, Gary; Fetter, Isobel J; Brugge, Joan S; Chen, Helen; Takebe, Naoko; Penson, Richard T; Juric, Dejan; Flaherty, Keith T; Sullivan, Ryan J; Clark, Jeffrey W; Heist, Rebecca S; Matulonis, Ursula A; Liu, Joyce F; Shapiro, Geoffrey I.
Afiliação
  • 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.
  • Cleary JM; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • Parikh AR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Yeku OO; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Xiong N; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Weekes CD; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Veneris J; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Ahronian LG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Mauri G; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Tian J; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Norden BL; 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.
  • 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; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Chen H; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Takebe N; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
  • Penson RT; National Institute of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Bethesda, Maryland.
  • Juric D; National Institute of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Bethesda, Maryland.
  • 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; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Liu JF; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Shapiro GI; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res ; 30(9): 1739-1749, 2024 May 01.
Article em En | MEDLINE | ID: mdl-38456660
ABSTRACT

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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridonas / Pirimidinonas / Sulfonamidas / Proteínas Proto-Oncogênicas p21(ras) / Proteína bcl-X / Compostos de Anilina / Mutação / Neoplasias Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridonas / Pirimidinonas / Sulfonamidas / Proteínas Proto-Oncogênicas p21(ras) / Proteína bcl-X / Compostos de Anilina / Mutação / Neoplasias Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article