Safety and Efficacy of Tucatinib–Trastuzumab-Capecitabine Regimen for Treatment of Leptomeningeal Metastasis in HER2+ Breast Cancer: Results from TBCRC049, A Phase 2 Non-Randomized Study

Author(s):

Dr. Tripathy reviews the safety and efficacy data from a phase 2 non-randomized study of tucatinib-trastuzumab-capecitabine regimen in patients with leptomeningeal metastasis.

Treatment options for patients with leptomeningeal metastasis (LM) are limited, and the prognosis is poor (median overall survival ≈ 4-5 months)
- Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine in patients with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen in the metastatic setting, including patients with brain metastases.
- TBCRC049 (NCT03501979) is an investigator-initiated, phase 2, single-arm study evaluating the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ breast cancer with newly diagnosed LM.
Methods
- Eligible pts were adults with HER2+ metastatic breast cancer, Karnofsky performance status (KPS) > 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms).
  - Pts with treated or concurrent/new brain metastases were allowed.
  - Pts received tucatinib 300 mg orally twice daily starting with cycle 1, day 1 (C1D1); capecitabine 1000 mg/m2 orally twice daily on days 1-14 of a 21-day cycle, starting on C1D1; and trastuzumab loading dose of 8 mg/kg IV on C1D1, and then 6 mg/kg IV once every 21 days, starting with C2D1.
  - The primary endpoint was OS. Planned enrollment was 30 pts; however, due to lack of accrual since the FDA approval of tucatinib (4/2020), the study was closed after 17 patients were enrolled.
Results
- All pts had MRI evidence of LM in the brain, and 14/17 (82%) had brain metastases, of which 11 (65%) had received prior treatment for brain metastases.
  - Median age at study treatment initiation was 53 years.
  - Median number of treatment cycles received was 5 (range: 2-27).
  - Median OS time was 11.9 months (95% CI: 4.1, NR).
  - At data cutoff (6/22/21), 7/17 pts (41%) remained alive and median followup was 17 months (8-26).
  - Median time to CNS progression was 6.9 months (95% CI: 2.8, 13.8).
  - Safety:
    - Mostly grade 1-2 adverse events: Diarrhea, fatigue, nausea, vomiting, HFS, and liver dysfunction
    - Grade 3 events: nausea/vomiting (1 patient), HFS (1 patient), LFT elevation (3 patients)
    - Grade 4 events: 1 patient with ALT elevation after 1 cycle that led to treatment discontinuation and resolved after 1 month
Conclusions
- In patients with LM disease from HER2+ metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine, the median overall survival time was 10 months.
- This is the first prospective evidence of clinical benefit with a systemic regimen for HER2+ LM.
- Safety data in this LM population was consistent with prior studies of tucatinib in combination with trastuzumab and capecitabine.
- Further studies evaluating brain-penetrant oral drugs in this rare patient population are needed.