Xentuzumab and Abemaciclib plus Endocrine Therapy in Locally Advanced/Metastatic Breast Cancer

Conference Correspondent  - SABCS 2017 - Breast Cancer

Resistance to endocrine therapy remains an important clinical problem in hormone receptor (HR)-positive, HER2-negative breast cancer, necessitating alternative treatment options.1 The insulin-like growth factor (IGF) axis and CDK4/6-retinoblastoma pathway have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including breast cancer.2 Binding of IGF-I and -II to the IGF receptor results in upregulation of cyclin D1 and subsequent progression through the cell cycle, thus providing rationale for the simultaneous inhibition of IGF-I and -II and CDK4/6.

At SABCS 2017, the trial design of an ongoing phase 1b trial was presented to assess the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, tolerability, and preliminary efficacy of the IGF ligand-neutralizing antibody, xentuzumab, in combination with abemaciclib, a selective, small-molecule inhibitor of CDK4/6, in patients with solid tumors. The trial includes 4 dose-finding cohorts followed by 2 expansion cohorts. Only results from those cohorts that will include patients with postmenopausal HR-positive/HER2-negative breast cancer were presented.3

Eligible patients include postmenopausal women aged ≥18 years (≥20 years for Japan) with measurable or evaluable disease, adequate organ function, Eastern Cooperative Oncology Group performance status ≥1, and locally advanced or metastatic HR-positive/HER2-negative breast cancer (cohorts B-D, F). CDK4/6 inhibitor–naïve patients (cohorts B-D) and patients who received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (cohort F) are included. The MTD/RP2D of xentuzumab plus abemaciclib to be used in cohorts B-D will be established in patients with solid tumors (cohort A), who will receive xentuzumab (starting dose, 1000 mg weekly intravenously) plus abemaciclib (starting dose, 150 mg every 12 hours). CDK4/6 inhibitor–naïve patients with breast cancer will receive xentuzumab plus abemaciclib at the RP2D determined in cohort A in combination with letrozole (2.5 mg daily; cohort B), anastrozole (1 mg daily; cohort C), or fulvestrant (500 mg monthly; cohort D). Patients with advanced breast cancer who were pretreated with a CDK4/6 inhibitor (cohort F) will receive xentuzumab plus abemaciclib and fulvestrant at the RP2D determined in cohort D.

Primary end points in the breast cancer cohorts are the MTD and/or RP2D of xentuzumab plus abemaciclib in combination with endocrine therapies, and the objective response (OR) in patients with advanced breast cancer who were pretreated with a CDK4/6 inhibitor (cohort F); disease control (DC), duration of DC, time to OR, duration of OR, and progression-free survival in cohort F are secondary end points. In addition, pharmacokinetic outcomes, safety, and tolerability will be assessed in all cohorts. Patient screening started in May 2017. Recruitment is ongoing in Japan, the US, France, and Spain. Target enrollment is approximately 88 patients, including approximately 56 patients with advanced HR-positive/HER2-negative breast cancer, of whom approximately 20 had previously been treated with CDK4/6 inhibitors. Results of this study will be available in late 2018/early 2019.

References

  1. Cortés J, et al. Cancer Treat Rev. 2017;61:53-60.
  2. Motallebnezhad M, et al. Tumour Biol. 2016;37:11711-11721.
  3. Yee D, et al. SABCS 2017. Abstract OT3-06-02.
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Last modified: December 10, 2017