Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma

We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy.Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4).Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients.During the last years potent therapeutic options evolved for patients with mRCC [1-4]. The introduction of targeted agents has significantly improved the treatment perspectives and prognosis of these patients. The majority of patients with good and intermediate prognosis according to the MSKCC criteria are treated with rTKI, particularly sunitinib, based on the results of two meta-analyses [5,6]. In spite of this progress in treatment options, a relevant subset of patients remains refractory to first rTKI therapy. On a molecular level, rTKIs target the vascular endothelial growth factor (VEGF) pathway to induce hypoxia, thereby inhibiting tumor growth. However, recent reports suggest that hypoxia may also select for a more malignant RCC phenotype, which may aggregate metastatic development and prone cells to insensitivity for antiangiogen