Combine targeting of RET and MEK or ERK is more effective at inhibiting tumor growth than single agents. Mice bearing SR-Sarc-0001pdx or HMSC-RET xenograft tumors were treated with vehicle, selpercatinib (Selpercat), ulixertinib (Ulix), trametinib (Tram), or the indicated combinations. A, Volume of SR-Sarc-0001pdx tumors. Treatment began 13 days after implantation (day 0 on graph). B, AUC analysis of data up to day 28 of treatment (last day that all animals were alive). The mean tumor volume of each treatment group was significantly different from the vehicle group (P < 0.0001). C, AUC analysis of data up to day 42 of treatment (last measurement). D, Percent change in volume of individual tumors on day 28. The mean ± SEM values are shown above the bars. All data represent the mean tumor volume ± SEM of five tumors. E, Animal weight. No treatment caused a statistically significant change in animal weight or other aspects of health. F, Volume of HMSC-RET xenograft tumors. Treatment began nine days after implantation (day 0 on graph). G, AUC analysis of data up to day 11 of treatment (last day that all animals were alive). Tumor volume of all treatment groups was significantly different from the vehicle group (P < 0.0001). H, AUC analysis of data up to day 31 of treatment (last day all animals were alive in the three groups). I, Percent change in volume of individual tumors on day 11. The mean ± SEM values are shown above the bars. All data represent the mean tumor volume ± SEM of five tumors. J, Animal weight. No treatment caused a statistically significant change in animal weight or other aspects of health. BID, twice daily; QD, once daily.