Liposomal irinotecan in patients with HER2-negative breast cancer and brain metastases: The PHENOMENAL phase 2 study

Patients with breast cancer (BC) and brain metastases (BMs) have a poor prognosis, particularly those with human epidermal growth factor 2-negative (HER2[-]) BC, including hormone receptor-positive (HR[+]) and triple-negative breast cancer (TNBC). Liposomal irinotecan (nal-IRI) crosses the blood-brain barrier and enhances antitumor activity.

PHENOMENAL (NCT03328884) was a single-arm, open-label, multicenter phase 2a study in Spain. Eligible patients had HER2[-] BC with active or stable BMs and prior chemotherapy regimen for metastatic disease (≥1 taxane line required). Nal-IRI was administered intravenously at 60 mg/m² (salt-base) or 50 mg/m² (free-base) every 14 days until progression and/or unacceptable toxicity. The primary endpoint was intracranial objective response rate (IC-ORR) in patients with progressive BMs. Key secondary endpoints included ORR, clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety.

Fifty-six women (median age 52 years; range, 32-83) were enrolled across 16 sites. Of these, 51.8 % had TNBC, and 91.1 % had progressive BMs at baseline. Median follow-up was 5.7 months (range, 0.4-56.5). The trial achieved its primary endpoint, with IC-ORR of 22.0 % (95 % CI, 11.5-36.0; p < 0.001) among patients with progressive BMs. Median PFS was 1.5 months (95 % CI, 1.4-2.9), while median OS reached 6.4 months (95 % CI, 4.9-10.8). Treatment-emergent adverse events (TEAEs) occurred in 96.4 % of patients; 57.1 % were considered treatment-related and 14.3 % experienced grade ≥ 3 treatment-related events. Only one patient had a serious treatment-related event, and no treatment-related deaths occurred.

nal-IRI demonstrated IC activity in HER2[-] BC with BMs. While overall efficacy was limited and long-term outcomes remain poor, these results highlight the unmet need in this challenging population and support the importance of developing more treatment strategies.