Phase I study of liposomal irinotecan in patients with metastatic breast cancer: findings from the expansion phase

Abstract

Purpose: Metastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM).

Methods: Following the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m² free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs).

Results: For non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death.

Conclusions: Liposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies.

Clinical trial registration: Trial registration ID NCT01770353.

Keywords: Brain metastases; Heavily pretreated patients; Liposomal irinotecan; Metastatic breast cancer; Objective response rate; Phase I clinical trial.

Fig. 1

Study design. BM brain metastases, ER estrogen receptor, HER2 human epidermal growth factor receptor 2, mBC metastatic breast cancer, PgR progesterone receptor, TNBC triple-negative breast cancer

Fig. 2

Response to liposomal irinotecan over time until treatment discontinuation (liposomal irinotecan efficacy population, n = 29). Individual doses of liposomal irinotecan are displayed above each patient’s treatment timeline, and the values depict a 35, 43, 50, or 70 mg/m² free base intravenous infusion. One patient in cohort 2 was enrolled but discontinued before receiving treatment. Patient death is depicted by an ‘X’. AE adverse event, BM brain metastases, CLIN clinical, CNS central nervous system, DET deterioration, ER estrogen receptor, HER2 human epidermal growth factor receptor 2, INV DEC investigator decision, mBC metastatic breast cancer, PD progressive disease, PgR progesterone receptor, PR partial response, RECIST Response Evaluation Criteria in Solid Tumors, SD stable disease, TNBC triple-negative breast cancer, TOX toxicity

Fig. 3

Percentage reduction in tumor lesion size in patients with (a) non-CNS disease and (b) CNS disease^a. ^aOnly patients who had an evaluable post-baseline tumor assessment for designated target lesions are included in the waterfall plots. Horizontal dashed lines represent the range of stable disease (lower line, < 30% reduction in tumor size; upper line, < 20% increase in tumor size), as per RECIST v1.1 criteria. Patient numbers on the x axis relate to patient numbers on Fig. 2. BM brain metastases, CNS central nervous system, ER estrogen receptor, HER2 human epidermal growth factor receptor 2, mBC metastatic breast cancer, PgR progesterone receptor, RECIST Response Evaluation Criteria in Solid Tumors, TNBC triple-negative breast cancer