Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer
Por:
Jhaveri KL, Accordino MK, Bedard PL, Cervantes A, Gambardella V, Hamilton E, Italiano A, Kalinsky K, Krop IE, Oliveira M, Schmid P, Saura C, Turner NC, Varga A, Cheeti S, Hilz S, Hutchinson KE, Jin Y, Royer-Joo S, Peters U, Shankar N, Schutzman JL, Juric D
Publicada:
20 nov 2024
Ahead of Print:
5 sep 2024
Resumen:
PURPOSETo investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110 alpha that promotes the degradation of mutated p110 alpha, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172).METHODSWomen >= 18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.RESULTSFifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade >= 3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.CONCLUSIONInavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.
Filiaciones:
Jhaveri KL:
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY
Accordino MK:
Columbia University Irving Medical Center, New York, NY
Bedard PL:
Princess Margaret Cancer Centre-University Health Network, University of Toronto, Toronto, ON, Canada
Cervantes A:
Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
Gambardella V:
Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
Hamilton E:
Sarah Cannon Research Institute, Nashville, TN
Italiano A:
Faculty of Medicine, University of Bordeaux, Bordeaux, France
Kalinsky K:
Winship Cancer Institute at Emory University, Atlanta, GA
Krop IE:
Yale Cancer Center, New Haven, CT
Oliveira M:
Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Schmid P:
Barts Cancer Institute, Queen Mary University, London, United Kingdom
Saura C:
Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Turner NC:
Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom
Varga A:
Gustave Roussy Cancer Campus, Villejuif, France
Cheeti S:
Genentech, Inc, South San Francisco, CA
Hilz S:
Genentech, Inc, South San Francisco, CA
Hutchinson KE:
Genentech, Inc, South San Francisco, CA
Jin Y:
F. Hoffmann-La Roche Ltd, Mississauga, ON, Canada
Royer-Joo S:
Genentech, Inc, South San Francisco, CA
Peters U:
Genentech, Inc, South San Francisco, CA
Shankar N:
Genentech, Inc, South San Francisco, CA
Schutzman JL:
Genentech, Inc, South San Francisco, CA
Juric D:
Massachusetts General Hospital, Boston, MA
Green Submitted
|