Abstract P5-18-13: Inhibiting telomerase to reverse trastuzumab (T) resistance in HER2+ breast cancer

Abstract

Background: Preclinical studies have shown the combination of imetelstat (GRN163L), an inhibitor of telomerase, and T results in synergistic growth inhibition and restoration of T sensitivity in T-resistant cells (Clin Can Res 12(10):3184–92, 2006). Here we translate those findings to the clinic with the first-in-man phase I trial of imetelstat+ T in patients (pts) with T-refractory HER2+ metastatic disease. Methods: T (6 mg/kg q3 wk) was administered with increasing doses of imetelstat (240/300/375 mg/m2 q3 wk) using a standard 3+3 dose escalation design. Maximum Tolerated Dose (MTD) was based on toxicity observed during cycle 1. Responding or stable pts continued treatment until progression. Tumor biopsy and bone marrow aspirate for biologic correlates were obtained at baseline and prior to cycle 2. Limited pharmacokinetics (PK) for T and imetelstat were included. Results: Ten pts were enrolled; median age was 54 (28–64). Patients were extensively pre-treated with the number of prior regimens ranging from 3 to >12. Prior cytotoxic therapies included anthracyclines (n = 9), taxanes (n = 9), vinorelbine (n = 8), capecitabine (n = 8), gemcitabine (n = 6), ixabepilone (n = 4), and eribulin (n = 4). Prior anti-HER2 targeted therapies included trastuzumab (n = 10), capecitabine (n = 8), T-DM1 (n = 6), and pertuzumab (n = 1). Therapy was well tolerated; no treatment related grade 4 toxicities were observed. Myelosuppression was limited to one pt with Grade 2 anemia and one each with Grade 2/3 thrombocytopenia. MTD was not reached. There were no objective responses; 2 pts. in cohort 3 had SD. Serial tumor biopsies and bone marrow aspirates have been analyzed for 7 pts (cohort 1: 001–004; cohort 2: 005–007; cohort 3: analysis ongoing). Tumor hTERT (p = ns) and phosphorylated HER2 (p = 0.03) decreased after treatment in nearly all pts. Bone marrow S-phase did not change consistently with treatment. Conclusion: The combination of trastuzumab + imetelstat is well tolerated and results in decreases in HER2 phosphorylation similar to that seen in preclinical models. Additional biologic correlates and PK analyses are ongoing. Further study of this combination in less heavily pre-treated patients is planned. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-13.

Human Epidermal Growth Factor Receptor Family-Targeted Therapies in the Treatment of HER2-Overexpressing Breast Cancer

“…Telomerase inhibitors have shown synergy with trastuzumab in inhibiting HER2-positive cancer cell growth and restoring trastuzumab sensitivity in trastuzumab-resistant cell lines [100]. Preliminary results with imetelstat (GRN163L; Geron Corporation, Menlo Park, CA, http://www.geron.com) and trastuzumab in women with trastuzumab-resistant breast cancer showed no significant toxicity, although no responses were seen [101].…”

Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

“…A phase 1 study of imetelstat in patients with trastuzumab-resistant breast cancer has been completed, and, in an initial report of 10 patients with trastuzumab-refractory HER2 + metastatic breast cancer enrolled in the study, no objective responses were reported; however, two patients achieved stable disease (ClinicalTrials.gov identifier NCT01265927). 95 VEGF inhibitors. HER2 induction of VEGF expression is believed to play a role in the pathogenesis of HER2amplified breast cancer.…”