In a phase 1b/2 trial, tucatinib in combination with letrozole and palbociclib was well-tolerated and active for HR+/HER2+ metastatic breast cancer, according to interim safety and efficacy analyses presented at the virtual SABCS Annual Meeting.

“In hormone receptor-positive / HER2-positive (HR+/HER2+) breast cancer, the HER2 and estrogen receptor (ER) signals merge on the cyclin D1-CDK4/6-RB1 pathway,” wrote Elena Shagisultanova, University of Colorado Denver, Aurora, and colleagues, on the background of targeting HER2, ER, and CDK4/6 with a combination of tucatinib, letrozole and palbociclib in this phase 1b/2 trial.

Previously treated patients with HR+/HER2+ metastatic breast cancer and at least 2 HER2-targeted therapies were eligible to enroll, as well as patients with untreated asymptomatic or stable brain metastases.

“Treatment consisted of tucatinib 300mg PO BID and letrozole 2.5mg PO daily continuously, and palbociclib 125mg PO daily 21 days on, 7 days off,” Dr Shagisultanova explained, noting drug-drug interaction, “…dose of sensitive CYP3A4 substrate palbociclib was reduced to 75mg for all study participants, as it became evident that tucatinib is a strong CYP3A4 inhibitor.”

The primary endpoints were safety and progression-free survival. Secondary endpoints included pharmacokinetic evaluation and objective response rate.

A total of 40 patients enrolled in the study between November 2017 and April 2020 were evaluated.

Median progression-free survival is 8.7 months (10.1 for patients without brain metastases; 6.0 months for patients with brain metastases). Researchers found the combination was well-tolerated with expected adverse events.

Neutropenia (n = 25), leukopenia (n = 10), diarrhea (n = 8), and fatigue(n = 6) were the most common grade ≥3 AEs.

“The combination of tucatinib with letrozole and palbociclib showed a tolerable and manageable safety profile and evidence of considerable anti-tumor activity that warrant further clinical investigation in pts with HR+/HER2+ MBC,” Dr Shagisultanova et al concluded.—Kaitlyn Manasterski

Shagisultanova E, Gradishar W, Brown-Glaberman U, et al. Interim safety and efficacy analysis of phase IB / II clinical trial of tucatinib, palbociclib and letrozole in patients with hormone receptor and HER2- positive metastatic breast cancer. Presented at: the San Antonio Breast Cancer Symposium; December 8-11; virtual. Abstract PS10-03