Abstract PS10-03: 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
Authors: Shagisultanova Elena , Gradishar William , Brown-Glaberman Ursa , Chalasani Pavani , Brenner Andrew J. , Stopeck Alison , Mayordomo Jose , Diamond Jennifer R. , Kabos Peter , Borges Virginia F. 
Published: February 2021

Abstract
Background: 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. Thus, a combined pharmacological intervention with individual drugs targeting HER2, ER and CDK4/6 is warranted. Here, we present the safety and efficacy results of the combination of tucatinib with letrozole and palbociclib in patients (pts) with HR+/HER2+ metastatic breast cancer (MBC) (NCT03054363).
Methods: Pts with HR+/HER2+ MBC previously treated with at least 2 HER2-targeted agents were enrolled in this phase IB/II clinical trial. Pts with untreated asymptomatic or stable treated brain metastasis (BM) were included. Pts with treated progressing BM were enrolled after local treatment and classified as treated stable. 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. Due to drug-drug interaction issues found in the middle of the trial and not related to this study, the 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 end-points were assessment of safety using CTCAE v.4.03 criteria, and progression free survival (PFS). Secondary end-points included pharmacokinetic evaluation (PKs) and objective response rate by RECIST 1.1. BM response was evaluated using RANO-BM criteria. All pts who received at least one cycle of therapy were assessed for safety.
Results: Between 11.21.2017 and 04.20.2020, we enrolled 42 pts of whom 40 were evaluable. Median age was 52.5 years (range, 22 to 82) and the median number of prior lines of therapy for MBC was 2 (range, 0 to 7); 23 pts (58%) had visceral disease and 15 (38%) had BM. All pts had prior therapy with trastuzumab and pertuzumab and 18 pt (45%) had prior T-DM1. As of 06.15.2020 data cut off, 14 patients were on active therapy while 26 were off study (22 due to progressive disease [PD], 1 due to toxicity and 3 for other reasons). Median follow up time was 6 months. The combination was well tolerated with manageable and expected adverse events (AEs). The most common grade ≥3 AEs were neutropenia (25 pts, 60%), leukopenia (10 pts, 24%), diarrhea (8 pts, 19%), fatigue (6 pts, 14%), and infections (6 pts, 14%). One pt came off study due to asymptomatic grade 4 elevated LFTs that resolved without sequelae. There were no deaths due to AEs. Among 26 pts with measurable disease at the time of data cut-off, 8 pts (31%) had partial response, 16 pts (62%) had stable disease (SD) (7 pts [27%] had SD for ≥ 6 months and 6 pts [23%] have not yet reached 6 months of follow up) and 2 pts (8%) had PD. Among 14 patients with BM and evaluable disease by RANO-BM, 1 pt had complete response in the brain, 6 pts had SD in the brain for ≥6 months, and 7 pts had SD for 2-6 months (4 pts on active therapy have not yet reached 6 months of follow up). Median PFS is 8.7 months (10.1 months for pts without BM and 6.0 months for those with BM). Updated analysis including PKs, tumor response, and PFS will be presented.
Conclusion: 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.
Citation Format: Elena Shagisultanova, William Gradishar, Ursa Brown-Glaberman, Pavani Chalasani, Andrew J. Brenner, Alison Stopeck, Jose Mayordomo, Jennifer R. Diamond, Peter Kabos, Virginia F. Borges. 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 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-03.