Brain metastases are common in patients with lung and breast cancer and associated with poor outcomes. While there is some intracranial activity with systemic therapies, most chemotherapies are minimally effective. Etirinotecan pegol (EP), a PEGylated chemotherapy with favorable pharmacokinetics over irinotecan, was administered at a dose of 145 mg/m2 IV every 3 weeks to patients with previously treated metastatic non-small cell lung cancer (NSCLC, n=12), small cell lung cancer (SCLC, N=3) and breast cancer (MBC, n=12), having progressive brain metastases after brain-directed radiotherapy or refusal. The primary endpoint was a 25% or greater disease control rate, defined as CR, PR + SD, in the central nervous system (CNS) at 12 weeks; secondary endpoints included toxicity and systemic disease control. Prior whole brain radiotherapy had been administered to 3 patients with NSCLC and 8 patients with MBC. The CNS control rate at 12 weeks in NSCLC and MBC was 17% (2 patients in each cohort) and 0% in SCLC. The median overall progression free survival for NSCLC was 2.7 months (95% CI: 1.3, 6.7) and MBC was 1.4 months (95% CI: 1.3, 6.9). The most common adverse events were diarrhea (48%), nausea (48%) and fatigue (26%). Six patient deaths occurred on this study. Dehydration/diarrhea (1) and neutropenic sepsis (3) from study treatment was at least possibly related to these deaths. This study demonstrates that EP did not meet the threshold of clinical efficacy in patients with refractory CNS metastasis from lung or breast cancer.