Phase 1b/2 Trial of Ribociclib, Tucatinib, and Trastuzumab for HER2-Positive BC

With the goal of finding more effective and tolerable chemotherapy-free combination regimens for HER2-positive breast cancer (BC), the ongoing randomized, open-label, phase 1b/2 UCLA B-13 trial (NCT05319873) is evaluating the safety and efficacy of HER2 tyrosine kinase inhibitor tucatinib plus the cyclin-dependent kinase 4/6 inhibitor ribociclib and trastuzumab in the neoadjuvant setting in patients with HER2-positive BC.

The phase 1b/2 trial will be conducted in 2 parts: phase 1b dose escalation followed by the phase 2 study. The initial dose-finding phase 1b portion of the trial will evaluate the safety profile of ribociclib and tucatinib in patients with HER2-positive metastatic BC (n=18) using the 3+3 dose escalation study design. The multicenter, randomized, open-label, phase 2 neoadjuvant portion of the trial will evaluate the efficacy and safety of ribociclib, trastuzumab, tucatinib with or without fulvestrant versus docetaxel, carboplatin, trastuzumab, and pertuzumab in patients with hormone receptor (HR)-positive or HR-negative, HER2-positive BC (n=100).

In the initial dose-finding phase 1b portion of the trial, dose cohorts of 3 to 6 patients will receive increasing doses of ribociclib (200-600 mg orally once daily) with fixed doses of tucatinib (300 mg orally twice daily) and trastuzumab (standard dosing) for four 28-day cycles in the absence of disease progression or unacceptable toxicity. The primary study objectives are assessment of dose-limiting toxicity (DLT) to establish maximum tolerated dose and recommended phase 2 dose (once 6 patients have been treated at the highest dose level), and safety assessment. At data cutoff, 2 patients have completed dose level 1, and no DLTs were observed.

In the phase 2 neoadjuvant segment of the trial, enrollment will be stratified by HR status. Eligible patients will be randomly assigned 1:1 to receive 6 cycles of one of these combination regimens: ribociclib/trastuzumab/tucatinib (28-day cycles); ribociclib/trastuzumab/tucatinib plus fulvestrant (28-day cycles); or docetaxel/carboplatin/trastuzumab/pertuzumab (standard of care, 21-day cycles) preceded by 1 run-in cycle of trastuzumab/pertuzumab. The primary objective is to assess the pathologic complete response (defined as no invasive tumor in the breast or lymph nodes at the time of surgery); other objectives include objective response rate, safety, changes in molecular biomarkers after cycle 1, and health-related quality of life.

Source:

McAndrew NP, Hurvitz SA, Tetef ML, et al. UCLA B-13: a phase 1b trial evaluating the safety of ribociclib, tucatinib, and trastuzumab in patients with metastatic, HER2+ breast cancer and a multicenter, randomized, openlabel, phase 2 study of preoperative treatment with ribociclib, trastuzumab, tucatinib, with or without fulvestrant versus docetaxel, carboplatin, trastuzumab, and pertuzumab in HR+/HR-, HER2+ breast cancer. Abstract presented at: ASCO Annual Meeting, June 2-6, 2023; Chicago, IL. Abstract TPS1116.