Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer

Authors

Elena Shagisultanova, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, Colorado.
William Gradishar, Northwestern University, Chicago, Illinois.
Ursa Brown-Glaberman, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico.
Pavani Chalasani, George Washington University, Washington, District of Columbia.
Andrew J. Brenner, University of Texas Health San Antonio, San Antonio, Texas.
Alison Stopeck, Stony Brook University Cancer Center, Stony Brook, New York.
Hannah Parris, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, Colorado.
Dexiang Gao, Department of Bioinformatics and Biostatistics, University of Colorado Denver, Aurora, Colorado.
Tessa McSpadden, OCRST, University of Colorado Cancer Center, Aurora, Colorado.
Jose Mayordomo, Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado.
Jennifer R. Diamond, Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado.
Peter Kabos, Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado.
Virginia F. Borges, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, Colorado.

Document Type

Journal Article

Publication Date

12-15-2023

Journal

Clinical cancer research : an official journal of the American Association for Cancer Research

Volume

29

Issue

24

DOI

10.1158/1078-0432.CCR-23-0117

Abstract

PURPOSE: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC). PATIENTS AND METHODS: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS). RESULTS: Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year. CONCLUSIONS: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.

APA Citation

Shagisultanova, Elena; Gradishar, William; Brown-Glaberman, Ursa; Chalasani, Pavani; Brenner, Andrew J.; Stopeck, Alison; Parris, Hannah; Gao, Dexiang; McSpadden, Tessa; Mayordomo, Jose; Diamond, Jennifer R.; Kabos, Peter; and Borges, Virginia F., "Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer" (2023). GW Authored Works. Paper 3955.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3955

Department

Medicine