Sunitinib-associated hypertension may be a strong predictive marker for treatment efficacy in metastatic RCC.

ObjectivesTo evaluate the clinical significance of hypertension (HTN), neutropaenia and thrombocytopaenia as possible new biomarkers of sunitinib efficacy in non-trial patients with metastatic renal cell carcinoma (mRCC). Patients and MethodsIn all, 181 consecutive patients with mRCC were treated with sunitinib; 39 (22%) received sunitinib 50 mg/day 4 weeks on/2 weeks off, 80 (44%) received 37.5 mg/day continuously and 62 (34%) received 25 mg/day continuously as their starting dose. Treatment-induced adverse events (AEs) and their impact on outcome were analysed on multiple sunitinib doses. ResultsDuring sunitinib treatment 60 patients (33%) developed ≥grade 2 HTN, 88 (49%) ≥grade 2 neutropaenia and 135 (75%) ≥grade 1 thrombocytopaenia. These AEs were associated significantly with longer progression-free survival (PFS; 15.7 vs 6.7; 14.6 vs 6.9; 10.4 vs 4.2 months, respectively; P < 0.001) and overall survival (OS; 37.5 vs 16.2; 33.7 vs 13.2; 22.3 vs 13.2 months, respectively, P ≤ 0.008). Although only neutropaenia was associated with a significantly improved PFS and OS in all sunitinib doses, a similar trend was also seen with HTN and thrombocytopaenia in all sunitinib doses. In multivariate analysis, HTN and neutropaenia were significantly associated with PFS and OS and thrombocytopaenia was significantly associated with PFS. In a 12-week landmark analysis, HTN and thrombocytopaenia were significantly associated with PFS and OS. Patients who developed all three AEs (a favourable biomarker profile) had significantly better outcome than patients without these AEs (a poor biomarker profile); response rate 47% vs 4%, median PFS 27.1 vs 3.5 months and OS not reached vs 5.3 months (all P < 0.001). ConclusionHTN, neutropaenia and thrombocytopaenia were all biomarkers of sunitinib efficacy in patients with mRCC. Our results may help to individualise sunitinib dosing during therapy based on these common sunitinib-related AEs.

High c-Met expression was associated with poor survival in patients with mRCC treated with sunitinib. Interestingly, the prognostic role may vary based on the location of metastases.

The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to anti-angiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.