Tesetaxel: Activity of an oral taxane as first-line treatment in metastatic breast cancer.

1016 Background: Tesetaxel, unlike standard taxanes (docetaxel, paclitaxel), is not a substrate for Pgp, a major cause of taxane resistance in tumor models. In a DU4475 breast cancer xenograft that overexpresses Pgp, tesetaxel induced a 94% reduction in tumor size, markedly exceeding the activity of docetaxel (46%) and paclitaxel (26%). Tesetaxel is associated with substantially less neuropathy preclinically than equi-myelotoxic doses of docetaxel. In clinical studies to date, tesetaxel is not associated with hypersensitivity reactions (0% incidence in > 450 patients [pts]), thus eliminating the need for premedication and extended observation. In a prior study, tesetaxel (27-35 mg/m 2 Q3 wks) achieved a 38% partial response (PR) rate as 2 nd -line therapy in pts with metastatic breast cancer (MBC) who had progressed after multidrug anthracycline-containing regimens. To extend these data, we initiated a phase 2 study of tesetaxel as 1 st -line therapy in women with MBC. Methods: Eligibility included MBC; HER2-; ECOG PS 0-1; and adequate organ function. Adjuvant chemotherapy (including taxanes) was allowed. Tesetaxel was administered orally without anti-allergic premedication at a starting dose of 27 mg/m 2 once every 3 wks. Overall response rate (ORR; RECIST) was the primary endpoint. Results: All 45 pts have been accrued. Median age is 58 y (range 36-80); median time from diagnosis, 4.0 y (range 0-21); triple negative status, 8 pts at diagnosis, 14 at time of metastasis. Metastatic sites are lung (22 pts), lymph nodes (22), liver (24), and bone (21). Prior treatment includes anti-estrogen therapy (32 pts), adjuvant chemotherapy (31), prior taxane (25), and radiotherapy (28). ORR in 24 pts evaluable for response is 50% (1 CR [4%], 11 PR [46%]); 5 responding pts had prior taxane therapy. Neutropenia is the most common ≥ Grade 3 adverse event with 50% of cases observed after dose escalation to 35 mg/m 2 ; febrile neutropenia and Grade 3 peripheral neuropathy occurred in 2 pts each. There were no hypersensitivity reactions. Conclusions: Tesetaxel is highly active in 1st-line MBC and overcomes multiple limitations of standard taxanes. Updated ORR and PFS for all pts will be presented. Weekly dosing will be evaluated in a new cohort of pts.