Xentuzumab Combination Shows Promise in Advanced Breast Cancer

Xentuzumab in combination with Verzenio (abemaciclib), with or without endocrine therapy, appeared to be safe and effective in treating patients with solid tumors and breast cancer, according to an interim analysis of phase 1b study findings presented at the 37^th Annual Miami Breast Cancer Conference^®.

“The (insulin-like growth factor) and CDK 4/6—Rb pathways are implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including HR-positive, HER2-negative breast cancer,” the researchers explained, adding that dual inhibition of insulin-like growth factor and CDK 4/6 could decrease cell proliferation through the disruption of cell-cycle progression.

Xentuzumab is a humanized IgG1 insulin-like growth factor monoclonal antibody that targets IGF ligands 1 and 2 in cancer cells. The drug works by binding to both ligands, inhibiting the binding of these ligands to their receptor, IGF-1R, and blocking the insulin growth factor signaling pathway.

In cancer, the insulin growth factor signaling pathway is upregulated and plays a role in proliferation of the disease and its resistance to chemotherapy. Xentuzumab also prevents the binding of IGF-2 to insulin receptor variant A, which prevents its activation. Unlike IGF-1R antibodies, xentuzumab does not elevate growth hormones or induce hyperglycemia, the researchers noted.

The prospective, open-label, non-randomized, multiple dose-finding phase 1b study aimed to determine the maximum tolerated dose of xentuzumab in combination with Verzenio, with or without endocrine therapy (Femara [letrozole], Arimidex [anastrozole] or Faslodex [fulvestrant]). The Food and Drug Administration approved Verzenio, a CDK4/6 inhibitor, in combination with an aromatase inhibitor to treat HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy; in combination with Faslodex (fulvestrant) for progression following endocrine therapy; and as monotherapy for progression following endocrine therapy and prior chemotherapy in the metastatic setting.

In part one of the study, patients with advanced/metastatic, measurable or evaluable non-resectable solid tumors (cohort A; six patients) received a starting dose of 150 mg of Verzenio and 1,000 mg of xentuzumab. In part two, postmenopausal women with HR-positive, HER2-negative breast cancer not amenable to curative resection, or metastatic disease, were separated into three cohorts:

• Verzenio plus 2.5 mg/day of xentuzumab plus Femara (cohort B; seven patients)
• Verzenio plus 1 mg/day of xentuzumab plus Arimidex (cohort C; seven patients)
• Verzenio plus 500 mg of xentuzumab plus Faslodex (cohort D; eight patients)

The primary endpoint of the study was maximum tolerated dose for each cohort, and the number of patients with dose limiting toxicities during the maximum tolerated dose evaluation period (first 28-day cycle). In addition, tumor response and progression-free survival (the time from treatment to disease worsening or progression) were also assessed in the study.

At the time of data analysis, 40% of patients were still receiving treatment.

During cycle one, one patient in cohort A and one patient in cohort B experienced grade 3 neutrophil count decrease, one patient in cohort C had grade 4 thrombocytopenia and one patient in cohort D experienced grade 3 neutropenia.

No patients experienced a serious side effect in cohort A; however, 11 patients in the other cohorts experienced at least one serious side effect.

Most drug-related side effects were reversible, with the most common including decreased appetite and diarrhea for cohort A and diarrhea for cohorts B, C and D.

Two patients in cohort B discontinued xentuzumab due to side effects. No deaths were reported in any cohort.

In cohort A, one patient had a partial response to treatment, and one had stable disease. In cohorts B, C and D, four patients had partial responses to treatment and 11 patients had stable disease, which lasted 24 weeks or longer in four individuals. Median progression-free survival was 1.7 months in cohort A and 9.1 months in Cohorts B, C and D, in which 81.8% of patients had visceral metastasis and more than 50% had received chemotherapy for advanced disease.

“Expansion cohorts to evaluate the efficacy of xentuzumab plus abemaciclib and fulvestrant in HR-positive, HER2-negative breast cancer are ongoing,” the researchers noted.