Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor.
This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer.
Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27710, USA. black034@mc.duke.edu.
Kimberly
K
Blackwell
Sarah Cannon Research Institute, Nashville, TN, USA.
Howard
H
Burris
Vall d'Hebron, Barcelona, Spain.
Patricia
P
Gomez
University of Michigan Medical School, Ann Arbor, MI, USA.
N
N
Lynn Henry
Massachusetts General Hospital, Boston, MA, USA.
Steven
S
Isakoff
Sanofi, Cambridge, MA, USA.
Frank
F
Campana
Sanofi, Cambridge, MA, USA.
Lei
L
Gao
Sanofi, Bridgewater, NJ, USA.
Jason
J
Jiang
Sanofi, Vitry sur Seine, France.
Sandrine
S
Macé
Dana-Farber Cancer Institute, Boston, MA, USA.
Sara M
SM
Tolaney
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077289:Letrozole; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D019233:Retreatment; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
D047072:Aromatase Inhibitors; D000077289:Letrozole; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013449:Sulfonamides; D014230:Triazoles; C576808:XL765
HER2-negative; Hormone-receptor-positive metastatic breast cancer; PI3K; Pilaralisib; Voxtalisib