With the goal of finding more effective and tolerable chemotherapy-free combination regimens for HER2-positive breast cancer, the ongoing randomized, open-label, phase 1b/2 UCLA B-13 trial is evaluating the safety and efficacy of the HER2-targeted tyrosine kinase inhibitor tucatinib plus the cyclin-dependent kinase 4/6 inhibitor ribociclib and the HER2/neu receptor inhibitor trastuzumab in the neoadjuvant setting in patients with HER2-positive breast cancer.
The phase 1b/2 trial will be conducted in 2 parts, consisting of a phase 1b dose-escalation study 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 breast cancer (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, and tucatinib with or without fulvestrant versus docetaxel, carboplatin, trastuzumab, and pertuzumab in patients with hormone receptor (HR)-positive or HR-negative, HER2-positive breast cancer (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 adverse events. The primary study objectives are the assessment of dose-limiting adverse events to establish the maximum tolerated dose and the recommended phase 2 dose (once 6 patients have received treatment at the highest dose level), and safety assessment. At the data cutoff, 2 patients have completed dose level 1, and no adverse events were observed.
In the phase 2, neoadjuvant segment of the trial, enrollment will be stratified by hormone receptor status. Eligible patients will be randomly assigned 1:1 to receive 6 cycles of one of these combination regimens: ribociclib, trastuzumab, and tucatinib (28-day cycles); ribociclib, trastuzumab, tucatinib, and fulvestrant (28-day cycles); or docetaxel, carboplatin, trastuzumab, and pertuzumab (standard of care; 21-day cycles) preceded by 1 run-in cycle of trastuzumab plus pertuzumab. The primary study 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 the objective response rate, safety, changes in molecular biomarkers after treatment 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, open-label, 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.