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 HRþ/HER2þ metastatic breast cancer (MBC). Patients and Methods: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HRþ/HER2þ 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 ¼ 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.
Original language | English (US) |
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Pages (from-to) | 5021-5030 |
Number of pages | 10 |
Journal | Clinical Cancer Research |
Volume | 29 |
Issue number | 24 |
DOIs | |
State | Published - Dec 15 2023 |
Funding
This study has been funded by Pfizer ASPIRE grant to E. Shagisultanova, with additional support from Seagen for clinical trial; NIH KL2TR001080 and 1K08CA241071 career development awards to E. Shagisultanova, Robert F. and Patricia Young Connor Endowed Chair in Young Women’s Breast Cancer to V.F. Borges, University of Colorado Cancer Center support grant P3CA046934. We thank all the patients who participated in the study, as well as the medical teams of all participating centers for their dedicated effort. In addition, we thank the Academic Breast Cancer Consortium (ABRCC) for feedback on study design and support in the study conduct. We acknowledge Veronica Wessels for the manuscript proofreading, and Heather Fairchild for creating Fig. 1 signaling diagram. This study has been funded by Pfizer ASPIRE grant to E. Shagisultanova, with additional support from Seagen for clinical trial; NIH KL2TR001080 and 1K08CA241071 career development awards to E. Shagisultanova, Robert F. and Patricia Young Connor Endowed Chair in Young Women’s Breast Cancer to V.F. Borges, University of Colorado Cancer Center support grant P3CA046934. We thank all the patients who participated in the study, as well as the medical teams of all participating centers for their dedicated effort. In addition, we thank the Academic
ASJC Scopus subject areas
- General Medicine