In vivo antitumor activity of RAD001 (everolimus) combined with paclitaxel/carboplatinum or pemetrexed against human NSCLC tumor xenograft models Free

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Background. RAD001 (everolimus) is an orally-active mTOR inhibitor currently in Phase II/III clinical trials. Although displaying activity as a single agent, RAD001 can also be combined with other antitumor agents. This study evaluated RAD001 in combination with carboplatinum plus paclitaxel (Taxol^®) (C+T), or with pemetrexed (P); therapeutic modalities widely used for the treatment of NSCLC. Methods. Dose response curves and checkerboard titrations each cytotoxic, alone and in combination with RAD001, using sc xenografts of NCI H-520 and NCI H-596 NSCLC tumors. Both tumors were RAD001-susceptible (administered p.o for 5 consecutive days in a 7 day cycle; NCI H-520 ED50 0.21 mg/kg/day; NCI H-596 ED50 0.91 mg/kg/day). Results (1). In no case was antagonism of antitumor effect observed. The regimen of 20 mg/kg C (i.p., once per week) and 8 mg/kg T (i.v., 3x per week) was chosen due to a slightly less than maximal antitumor activity associated with only minor body weight loss (approx. 5%). The addition of RAD001 to C+T produced clear evidence of positive combination effects in one of two experiments with NCI H-596 tumors 0, 1, 2 or 3 mg/kg RAD001 in combination with C+T produced T/C values of 54, 28, 9 and 16 %, respectively, with the second showing a narrow dose-response curve of improvement of antitumor effect (3 mg/kg RAD001, 28 % T/C, C+T alone, 59%, and 1, 2 or 3 mg/kg RAD001 in combination with C+T produced T/C values of 28, 17 and 12 % regressions, respectively). With NCI H-520 tumors, there was no statistically significant positive interaction of combining RAD001 and C+T. However, the shape of the dose-response curves suggested that a positive interaction occurred, but the dose range was narrow and quickly saturated by RAD001. There was no pronounced exacerbation of toxicity by the combination. Results (2). For the pemetrexed study, various doses of RAD001, administered p.o. daily, were titrated onto a fixed dose of 150 mg/kg pemetrexed, administered i.p. 3x week. For NCI H-596 tumors, RAD001 interacted with pemetrexed (T/C 54%) to produce an improved antitumor response, the addition of 1, 3 or 5 mg/kg RAD001 produced T/C values of and 21, 9.4, -11.1 %, respectively, and in a second experiment, 18, 10% T/C and 3% regressions, respectively, with pemetrexed alone giving a 33% T/C. The combination did produce greater body weight losses than either agent alone, but this was not strictly RAD001 dose-dependent. The combination of pemetrexed and RAD001 (0.5 or 1 mg/kg) did not improve the antitumor effect against NCI H-520 tumors, but demonstrated some enhanced tolerability problems. Conclusions. This study provides further evidence of the potential value of RAD001 in combination C+T and with pemetrexed, although with the latter caution should be taken due to apparent decreased tolerability of the combination.