Abstract CT021: Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel (P) or eribulin (E) in patients with HER2 negative metastatic breast cancer (MBC)
Authors: Anampa Jesus D. , Xue Xiaonan , Oh Sun-young , Kornblum Noah , Sadan Sara , Oktay Maja , Condeelis John , Sparano Joseph A. 
Published: August 2018

BACKGROUND: Metastasis is the primary cause of death in breast cancer, yet no current therapies specifically inhibit metastasis. TMEM (Tumor Microenvironment of Metastasis) are the portal for tumor cell intravasation into the circulation and subsequent metastasis (Harney et al Cancer Discov 2015 [PMCID:4560669). The potent Tie2 kinase inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either P or E (Karagiannis et al STM 2017 [PMCID:5592784]; Harney et al MCT 2017 [PMCID:28838996]). We hypothesized that the addition of rebastinib to antitubulin therapy (P or E) in patients with HER2- MBC would be safe, and by inhibiting TMEM function, would also reduce CTC burden by blocking hematogenous dissemination.

METHODS: The primary objective was to determine the safety and recommended phase 2 dose (RP2D) of rebastinib (2 dose levels: 50 mg or 100 mg PO BID) in combination with P (80 mg/m2 x 12 weeks) or E (1.4 mg/m2 on day 1 & 8 q 21 days) using a standard 3+3 design (1 cycle = 21 days). Secondary objectives included evaluating the effect of the P/E + rebastinib combination on CTCs (TelomeScan). Dose limiting toxicity (DLT) was defined as grade 3-4 febrile neutropenia, thrombocytopenia, and non-hematologic toxicity during the first 6 weeks of therapy. Eligibility included HER2- MBC, ECOG PS 0-1, progression after a CDK4/6 inhibitor if ER+. Patients with ≤ 2 prior non-taxane chemotherapy regimens received P+ rebastinib, whereas those with ≥ 2 chemo regimens (including a taxane) received E+ rebastinib.

RESULTS: Of 10 treated patients, 6 received rebastinib + P and 4 received rebastinib + E (2 non-evaluable due to rapid disease progression [n=1] and non-compliance [n=1]). Among 10 patients who received 48 treatment cycles, only 1 patient (treated with eribulin) had grade 3 events (anemia and neuropathy after week 6) potentially related to treatment. When combined with P, the RP2D of rebastinib was 100 mg PO BID, with DLT occurring in 0/6 patients. When combined with E, 0/2 evaluable patients had a DLT at 50 mg BID of rebastinib (accrual ongoing). Best response included partial response/stable disease in 4(2PR/2SD) of 5 treated with P+ rebastinib (1 too early), and 2(1PR/1SD) of 4 treated with E+ rebastinib. CTCs decreased during therapy (baseline vs. day 43, median decrease 99.7 %) and 4/8 patients converted from CTC+ to CTC-.

CONCLUSIONS: When combined with P x 12 weeks, the RP2D of rebastinib is 100 mg PO BID. The P/E + rebastinib combinations are associated with antitumor activity and exhibit pharmacodynamic evidence suggesting TMEM function blockade. We plan to further evaluate the P+ rebastinib combination as neoadjuvant therapy in the I-SPY program, and continue further evaluation of P/E + rebastinib combinations in MBC.

Citation Format: Jesus D. Anampa, Xiaonan Xue, Sun-young Oh, Noah Kornblum, Sara Sadan, Maja Oktay, John Condeelis, Joseph A. Sparano. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel (P) or eribulin (E) in patients with HER2 negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT021.