Nanochemo-immunotherapy of ER-positive metastatic breast cancer (MBC) with PEG-liposomal doxorubicin (PLD) and pembrolizumab (PEM).

1060 Background: PLD is a nanomedicine containing doxorubicin, a potent immunogenic cell death inducer. Based on the pharmacological profile of PLD, we hypothesized that PLD-based chemotherapy should allow for improved immune recognition of tumor cells and activation of T cells by PD1 blockade. We report here the results of a phase 1B study with a combination of PLD and PEM in ER+/Her2 negative MBC. Methods: Patients with MBC, whose disease progressed on hormonal, CDK 4/6 inhibitors and up to 3 lines of chemotherapy, were eligible for enrollment. Primary objectives were evaluation of safety and tumor response, and secondary objectives were overall survival and pharmacokinetic analysis of PLD and PEM. In a first cohort of 15 patients, PLD 30 mg/m 2 was infused along with PEM 200 mg on day 1 every 3 weeks. In a second cohort of 20 patients, PLD 40 mg/m 2 was infused on day 1 every 4 weeks without change of PEM dose-schedule. Responding and stable patients continued treatment until disease progression or treatment intolerance. All patients were followed up on for survival. Results: 35 patients were enrolled. A total of 201 PLD and 257 PEM treatments were administered until data lock. Treatment was well tolerated with no grade 3-4 neutropenia, no cardiac events, and no grade 2 hair loss. In one patient, a severe infusion reaction to PLD was observed forcing discontinuation of PLD in the 2 nd cycle. There were 2 cases of grade 4 hepatitis, 1 case of grade 4 hemolytic anemia, and 5 cases of grades 1-2 hypothyroidism, possibly or probably related to PEM. PLD-related skin toxicity (palmar-plantar erythema, grades 1-2) was observed after 3 or more cycles, forcing treatment delays. Among evaluable patients receiving ≥3 cycles of PEM (n=30), we observed 8 partial and 2 complete responses with a long median duration of response (11 mo) and survival (28 mo). In 5 patients, near complete responses of large liver metastases were observed. Median survival was 25 mo for all patients and 26 mo for evaluable patients. Eight patients, including 1 patient still under treatment, remain alive at data lock with survival in the range of 10+ to 51+ mo. The plasma clearance of PLD was mono-exponential with high Cmax, long T½ (~3 days), slow clearance, and small Vcc. There was a significant increase of ~20% in the average AUC of PLD between the 1 st and 3 rd cycle indicating delayed clearance upon PLD retreatment. Analysis of PEM plasma levels revealed a mean T½ of ~11 days with high trough concentration by end of the cycle implying saturation of all accessible PD1 receptors. Conclusions: The combination of both dose levels of PLD with PEM is well tolerated, active, and feasible for extended treatment with durable responses. The favorable response and survival data in this heavily pretreated patient group suggest that PEM has significant contribution to the anti-tumor effect. A randomized study in ER+ MBC patients based on this regimen is warranted. Clinical trial information: NCT03591276 .