A phase 1b study of chemo-immunotherapy with pegylated liposomal doxorubicin and Pembrolizumab in estrogen receptor positive metastatic breast cancer

PURPOSE: Pegylated liposomal doxorubicin (PLD) is a potent immunogenic cell death inducer, allowing for improved tumor immune recognition and T cell activation. We report a phase 1B study of combined PLD and pembrolizumab in ER-positive/HER2-negative, metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with MBC, who progressed on hormonal, biological and cytotoxic chemotherapy were eligible. Study objectives were safety, response, survival, and pharmacokinetics (PK). The study consisted of 2 cohorts: PLD 30 mg/m2 Q3W and PLD 40 mg/m2 Q4W, with pembrolizumab 200 mg Q3W in both cohorts. Responding and stable patients continued treatment until disease progression or intolerance. RESULTS: 35 patients were enrolled and received a total of 201 PLD and 257 pembrolizumab treatments. Treatment was well tolerated with no significant neutropenia, no cardiac events, and minimal hair loss. Treatment-related serious adverse events were observed in 3 patients. In patients receiving >3 cycles, cutaneous toxicity often forced treatment delays. Disease control rate was 67%, including 10 responses with median duration of 11 months. Responses of large liver metastases were observed. Median overall survival was 25 months. PLD PK was mono-exponential with high Cmax, long half-life (~3 days), slow clearance, and small Vcc. Pembrolizumab plasma levels indicated mean half-life of ~11 days with high trough concentrations. Gene expression tumor profiling identified 16 genes upregulated in responders versus nonresponders including interferon-stimulated genes. CONCLUSIONS: The combination of PLD with pembrolizumab is well tolerated, active, and feasible for extended treatment with durable responses. The results suggest possible contribution of pembrolizumab to the anti-tumor effect.