A Phase Ib Study of Chemoimmunotherapy with Pegylated Liposomal Doxorubicin and Pembrolizumab in Estrogen Receptor-Positive Metastatic Breast Cancer.

purposePegylated liposomal doxorubicin (PLD) is a potent immunogenic cell death inducer, allowing for improved tumor-immune recognition and T-cell activation. We report a phase Ib study of combined PLD and pembrolizumab (PEM) in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC). PATIENTS AND

methodsPatients 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 two cohorts: PLD 30 mg/m2 once every 3 weeks and PLD 40 mg/m2 once every 4 weeks, with PEM 200 mg once every 3 weeks in both cohorts. Responding and stable patients continued treatment until disease progression or intolerance.

resultsThirty-five patients were enrolled and received a total of 201 PLD and 257 PEM treatments. Treatment was well tolerated with no significant neutropenia, no cardiac events, and minimal hair loss. Treatment-related serious adverse events were observed in three patients. In patients receiving >3 cycles, cutaneous toxicity often forced treatment delays. The disease control rate was 67%, including 10 responses with median duration of 11 months. Responses of large liver metastases were observed. The median overall survival was 25 months. PLD PK was monoexponential with high peak plasma concentration, long half-life (∼3 days), slow clearance, and small volume of distribution in the central compartment. PEM 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.

conclusionsThe combination of PLD with PEM is well-tolerated, active, and feasible for extended treatment with durable responses. The results suggest possible contribution of PEM to the antitumor effect. SIGNIFICANCE: The combination of PLD and PEM in ER-positive MBC resulted in durable antitumor responses and median survival exceeding 2 years in a heavily pretreated patient group. These clinical observations together with the pharmacologic rationale and gene expression data have translational relevance supporting further exploration of combinations of nanomedicines with immunotherapy in this breast cancer population.