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Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial.
Tian, Jun; Chen, Jonathan H; Chao, Sherry X; Pelka, Karin; Giannakis, Marios; Hess, Julian; Burke, Kelly; Jorgji, Vjola; Sindurakar, Princy; Braverman, Jonathan; Mehta, Arnav; Oka, Tomonori; Huang, Mei; Lieb, David; Spurrell, Maxwell; Allen, Jill N; Abrams, Thomas A; Clark, Jeffrey W; Enzinger, Andrea C; Enzinger, Peter C; Klempner, Samuel J; McCleary, Nadine J; Meyerhardt, Jeffrey A; Ryan, David P; Yurgelun, Matthew B; Kanter, Katie; Van Seventer, Emily E; Baiev, Islam; Chi, Gary; Jarnagin, Joy; Bradford, William B; Wong, Edmond; Michel, Alexa G; Fetter, Isobel J; Siravegna, Giulia; Gemma, Angelo J; Sharpe, Arlene; Demehri, Shadmehr; Leary, Rebecca; Campbell, Catarina D; Yilmaz, Omer; Getz, Gad A; Parikh, Aparna R; Hacohen, Nir; Corcoran, Ryan B.
Afiliação
  • Tian J; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Chen JH; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Chao SX; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Pelka K; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Giannakis M; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Hess J; Gladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes Department of Microbiology and Immunology, UCSF, San Francisco, CA, USA.
  • Burke K; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Jorgji V; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Sindurakar P; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Braverman J; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Mehta A; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Oka T; The Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Huang M; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Lieb D; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Spurrell M; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Allen JN; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Abrams TA; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Clark JW; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Enzinger AC; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Enzinger PC; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Klempner SJ; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • McCleary NJ; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Meyerhardt JA; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Ryan DP; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Yurgelun MB; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Kanter K; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Van Seventer EE; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Baiev I; Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Chi G; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Jarnagin J; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Bradford WB; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Wong E; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Michel AG; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Fetter IJ; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Siravegna G; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Gemma AJ; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Sharpe A; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Demehri S; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Leary R; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Campbell CD; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Yilmaz O; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
  • Getz GA; Novartis Institute for Biomedical Research, Cambridge, MA, USA.
  • Parikh AR; Novartis Institute for Biomedical Research, Cambridge, MA, USA.
  • Hacohen N; The Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Corcoran RB; The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Nat Med ; 29(2): 458-466, 2023 02.
Article em En | MEDLINE | ID: mdl-36702949
ABSTRACT
While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration NCT03668431.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Melanoma Tipo de estudo: Clinical_trials Limite: Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Melanoma Tipo de estudo: Clinical_trials Limite: Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos