Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast
Elena Shagisultanova1,2, William Gradishar3, Ursa Brown-Glaberman4
1Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, Colorado.
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.
Insights
The TLP combination of tucatinib, letrozole, and palbociclib is a safe and effective oral regimen for HR+/HER2+ metastatic breast cancer (MBC). This chemotherapy-free approach demonstrated promising efficacy, including a median progression-free survival of 8.4 months.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Hormone receptor-positive (HR+), HER2-positive (HER2+) metastatic breast cancer (MBC) often develops resistance to standard therapies.
- The cyclin D1-CDK4/6 complex is implicated in resistance to antihormonal and HER2-targeted agents.
- Novel therapeutic strategies are needed to overcome treatment resistance in HR+/HER2+ MBC.
Purpose of the Study:
- To evaluate the safety and efficacy of an oral combination therapy (TLP) for patients with HR+/HER2+ MBC.
- The TLP combination includes the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib.
- To assess the TLP regimen in patients previously treated with multiple HER2-targeted agents.
Main Methods:
- Phase Ib/II clinical trial (NCT03054363) enrolled 42 women with HR+/HER2+ MBC.
- Patients received tucatinib, letrozole, and palbociclib (TLP combination).
- Primary endpoints included safety (NCI CTCAE v4.3) and efficacy (median progression-free survival - mPFS).
Main Results:
- The TLP combination was generally safe and tolerable, with manageable adverse events like neutropenia and diarrhea.
- Tucatinib increased palbociclib exposure, necessitating dose reduction.
- In 40 response-evaluable patients, mPFS was 8.4 months, with an overall response rate of 44.5% and clinical benefit rate of 70.4%.
Conclusions:
- The TLP combination is a safe and tolerable all-oral, chemotherapy-free regimen for HR+/HER2+ MBC.
- The study demonstrated excellent efficacy, supporting further investigation of the TLP combination.
- TLP offers a promising new treatment option for patients with advanced HR+/HER2+ breast cancer.
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