In 22 patients, PD during first rTKI therapy was determined by the occurrence of a new metastatic lesion. Of these, 16 patients received sequential treatment. 12 patients remained refractory to subsequent therapy AGI-6780? while four patients had disease stabilization. 13 patients had PD by continuous growth of the initial metastatic lesions. Of these, 9 patients received sequential treatment, Inhibitors,Modulators,Libraries and 6 patients achieved disease stabilization. Disease control by any of the sequential therapy lines was achieved in 15 patients. Only 14 and 7 patients received a third and fourth line of tar geted treatment with a median estimated PFS of 1. 9 and 2. 6 months, respectively. Overall, only one patient accomplished a partial response on sequential treatment with temsiroli mus. The median OS from the first rTKI therapy was 14.

9 months. Patients with new meta static lesions on first rTKI therapy had a shorter, how ever statistically not significant, median OS of 10. 7 months than patients with growth of the initial lesions achieving a median OS of 19. 1 months. Discussion In this study we report on 35 patients with intrinsic resistant Inhibitors,Modulators,Libraries mRCC to rTKI treatment. This subset of patients seems to be characterized by a low likelihood of response to any form of available targeted therapy, with mTOR inhibitors being equally inefficacious as switching to another TKI. The median OS from initia tion of first rTKI therapy was only 14. 9 months and the median PFS upon second line targeted therapy was limited to 3. 5 months with a disease control rate of roughly 40% in the sequence setting.

The primary development of a new metastatic lesion during first rTKI treatment may indicate Inhibitors,Modulators,Libraries a particularly unfavour able prognosis. In spite of recent substantial advances in treatment options the salvage strategy for patients with intrinsic resistance to rTKI treatment is not well defined. According to our data this subgroup of patients may have a low chance of overcoming rTKI resistance or responding to the available sequential treatment options. The rationale for sequential therapy with mTOR inhibi tors in rTKI refractory patients lies in the expectation that resistance of the tumor to rTKI treatment may be reversed by targeting a different signaling pathway. In the placebo controlled phase 3 RECORD 1 trial everolimus turned out to be an efficacious treat ment option following failure of rTKI therapy.

How ever, disease control can be achieved by rTKI treatment in the majority of treatment Inhibitors,Modulators,Libraries na ve mRCC patients, sug gesting underlying sensitivity to VEGFR targeted agents. Whether mTOR inhibitors exert Inhibitors,Modulators,Libraries superior clinical activity in intrinsic resistant disease remains unknown. Nonetheless, prospective data on the best sequential Ixazomib order therapy among the available sequence options in mRCC are still lacking. In their retrospective study Vickers et al.