In vivo synergy between trastuzumab (herceptin ® ) and larotaxel (RPR 109881A), a new taxoid.
Authors: Patricia Vrignaud, Marielle Chiron, Murray Stackhouse, Claudia Zuany-Amorim, Helene Goulaouic, Marie-Christine Bissery
Journal: Cancer Research (2007)

1432  Larotaxel (RPR 109881A/XRP9881) is a taxoid, that is currently in development for breast cancer and other tumor types. Like docetaxel, it stabilizes microtubules, and has a broad spectrum of antitumor activity in taxane-sensitive tumors. In addition, it is active in vitro and in vivo against taxane-resistant tumors. In tumor-bearing mice, it was found to be active by the intravenous (iv) and oral route, and to cross the blood-brain barrier with activity against intracranial tumors (Proc AACR, 2004). The in vivo combinations of larotaxel with doxorubicin, cisplatin or vinorelbine were previously found synergistic (Proc AACR, 2005). We report here the preclinical in vitro and in vivo combination data of larotaxel with trastuzumab (herceptin®), using mammary UISO BCA-1, a human tumor model expressing Her2 and refractory in vivo to docetaxel.  Larotaxel was first evaluated in vitro on human mammary UISO BCA-1 cell line, after a 96-hour incubation, using 14C-thymidine incorporation read-out. The IC50 of larotaxel (~ 3nM) was not significantly modified when combined to trastuzumab.  Thereafter, in nude mice bearing UISO BCA-1, a 3 arm dose-response study was performed comparing the antitumor efficacy single agents and their combination. Mice bearing measurable (125 mg) tumors were treated iv with larotaxel (12.4, 20, 32.3 and 52.1 mg/kg/day, on days 17, 21, 25 post tumor implantation), or sc with trastuzumab (2.5, 10, 25 and 40 mg/kg/day, on days 17, 21, 25, 29). In the combination, each dose of larotaxel was combined with the dose-response of trastuzumab using the same schedule of administration as the single agents alone. Therapeutic synergism was declared when superior activity by at least 1 log cell kill (log CK = tumor growth delay / 3.32 x tumor doubling time) was observed with the combination in comparison with either of the single agents. At the Highest nonToxic Dose (HNTD) of 32.3 mg/kg/day (total dose 96.9 mg/kg), larotaxel, as a single agent, induced a 5% body weight loss (bwl) and was found active with a 1.3 log CK. Trastuzumab alone, at the highest dose tested, 40 mg/kg/day (total dose 160 mg/kg), was found inactive, although UISO BCA-1 xenografts overexpressed Her2. The HNTD of the combination (larotaxel at 32.3 mg/kg/day, with herceptin at 2.5 mg/kg/day), induced a 4 % bwl and exhibited a greater antitumor activity with 2.6 log CK, 6/8 complete regressions (regression below the limit of palpation) and 2/8 tumor free survivors on day 121. A good antitumor activity was maintained at the 5 combined dosages below the HNTD. In order to further explore this synergy between both agents, mechanistic studies are ongoing. In conclusion, the larotaxel- trastuzumab combination was found synergistic in mice bearing a human breast tumor refractory to docetaxel, as well as anthracycline and other agents. These data provide a good rationale for further clinical evaluation of this combination in breast cancer with Her2 overexpression.