Liposomal Irinotecan Shows Promising Phase 1 Results in Heavily Treated Breast Cancer Patients

Treatment with a liposomal formulation of irinotecan — meaning the chemotherapy is wrapped up in tiny fatty spheres —was well-tolerated and partially reduced the tumor burden in 35% of heavily pretreated breast cancer patients in a Phase 1 clinical trial, including those with brain metastasis.

Results were presented in the poster, “Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC),” at the recent American Association for Cancer Research Annual Meeting 2019 in Atlanta.

Irinotecan is an anti-cancer treatment that induces cancer cell death by causing breaks in DNA strands. The treatment is used primarily for colorectal and lung cancers, but has shown limited therapeutic activity in preclinical models of breast cancer.

Irinotecan liposome injection (Nal-IRI) is a new formulation of irinotecan where the therapy is contained inside fatty spheres called liposomes. This formulation — sold as Onivyde by Ipsen for pancreatic cancer — shields irinotecan from rapid clearance and metabolism and improves the delivery of the active metabolite into the tumor.

In preclinical breast cancer studies, liposomal ironotecan showed anti-tumor activity at much lower doses than free irinotecan. As a result, Ipsen designed a Phase 1 trial (NCT01770353) to determine the safety and efficacy of this treatment in heavily treated breast cancer patients.

The study enrolled 30 patients with metastatic breast cancer who had received one to five prior lines of therapy (a median of three). Patients were included in one of three groups: hormone receptor (HR)-positive, HER2-positive breast cancer (Cohort 1); triple-negative breast cancer (Cohort 2); and breast cancer with active brain metastasis (Cohort 3), with 10 patients in each group.

The trial’s main objective was to assess the levels of irinotecan and its active metabolite SN-38 within the tumor. This was measured using an imaging technique called ferumoxytol magnetic resonance imaging (FMX-MRI).

Additional goals included safety and measures of efficacy, including tumor response rate, duration of response, and time to disease worsening or death.

Patients received an Nal-IRI infusion every two weeks until progressive disease or signs of toxicity. On average, patients received the treatment for 12.3 weeks — 6.1 weeks in Cohort 1,  12.3 weeks in Cohort 2, and 13.9 weeks in Cohort 3.

Of the 29 patients who received at least one Nal-IRI infusion, 10 (35%) achieved a partial response. Responses were particularly higher for those with HR-positive breast cancers (40%), but were also seen in 33% of those with triple-negative breast cancer, and 30% of those with brain metastasis.

In addition, eight additional patients achieved stable disease, including three with triple-negative breast cancer, two in extracranial lesions of those with brain metastasis, and three in the intracranial lesions of these patients.

The median duration of response in Cohort 1 was 7.5 months and 5.6 months for Cohort 2. In Cohort 3, the median duration of response was 4.1 months for extracranial lesions and 1.8 months for intracranial ones.

The most common severe treatment-related adverse events were gastrointestinal disorders — mainly diarrhea (28%) and nausea (17%) — fatigue (14%), low potassium levels (10%), and physical weakness (10%). No life-threatening adverse events were reported.

These results show that treatment with Nal-IRI was well-tolerated and reduced tumor burden in one-third of breast cancer patients, including those with active brain metastasis, the researchers said.