Rationale: Treatment of brain metastasis (BM) remains an unmet medical need due to the inability of most anti-cancer agents to effectively cross the blood-brain barrier (BBB). GRN1005 is a peptide-drug conjugate (PDC) consisting of 3 molecules of paclitaxel conjugated to a 19-amino acid peptide, Angiopep-2. GRN1005 effectively penetrates the BBB by targeting the low-density lipoprotein receptor-related protein 1 (LRP1), which is expressed on the surface of the BBB and on certain neoplastic cells. In a phase 1 study, GRN1005 demonstrated encouraging anti-tumor activity in breast cancer (BC) patients with BM.

Methods: Up to 157 patients (pts) with measurable BM from BC, with or without extra-cranial disease, are currently being enrolled in an ongoing open label study. Prior cranial irradiation is allowed but lesions previously treated with stereotactic radiosurgery (SRS) are excluded from the efficacy analysis. All currently enrolled pts received GRN1005 at a starting dose of either 650 or 550 mg/m2 IV every three weeks, until intra-cranial disease progression (iPD), unacceptable toxicity, or initiation of non-protocol systemic therapy. HER2 positive pts received concomitant trastuzumab. The primary endpoint is intra-cranial objective response rate (iORR), as assessed by independent review using CNS RECIST 1.1. Additional endpoints include safety, duration of intra-cranial response, 3-month intra-cranial progression free survival (iPFS3), extra-cranial ORR, and neurocognitive function.

Results: As of 4 June 2012, 24 pts (13 at 650 mg/m2 and 11 at 550 mg/m2) have been treated with a median of 2 cycles of GRN1005 (range 1–5). Median age was 51.5 years (34–68) and 14 (58%) pts have HER2-positive disease. Pts received a median of 6 (3–14) prior systemic regimens; 19 had received prior whole brain radiation therapy (WBRT) ± SRS and 2 had received prior SRS only (data pending on 3 pts). Six (25%) pts have discontinued treatment with GRN1005, including 2 due to iPD and 2 due to adverse events (AE). One additional pt had clinical progression and discontinued GRN1005.

The AEs observed at 650 mg/m2 are qualitatively consistent with conventional paclitaxel but are more frequent and more severe than observed with q3 week paclitaxel which led to a protocol amendment and dose reduction to 550 mg/m2 for all subsequent pts. Among all treated pts, the most frequent AEs were neutropenia (75%), fatigue (50%), mucositis (33%), neuropathy (29%), and diarrhea (25%). Notable Grade 3–4 AEs were neutropenia in 12 pts (including 1 case of febrile), and arthralgia, fatigue, and rash in 3 pts each. Preliminary anti-tumor activity has been observed in both intra-cranial and extra-cranial lesions.

Conclusions: GRN1005 is a promising treatment for BM associated with breast cancer and demonstrates a safety profile qualitatively similar to paclitaxel dosed every 3 weeks. Due to tolerability concerns at the 650 mg/m2 dose, the 550 mg/m2 dose is currently being evaluated in these heavily pretreated BC pts. Updated efficacy and safety data will be presented at the meeting.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-04.