RCC: Updates on Guidelines for Adjuvant Therapy and new drug combination

The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) guidelines panel has recently updated its recommendation on adjuvant therapy with sunitinib in non-metastatic RCC after surgical tumour removal (Bex et al., 2016). These clinical guidelines provide urologists with evidence-based information and recommendations for the management of RCC and the panel includes urological surgeons, oncologists, pathologists, radiologists and patient advocates. Based on the conflicting results of two available clinical studies (ASSURE and S-TRAC), the panel rated the quality of the evidence of the trials, the harm-to-benefit ratio, the patient preferences and the costs. As a result, the EAU panel, including representatives from a patient advocate group (International Kidney Cancer Coalition) voted and reached a consensus recommendation that adjuvant therapy with sunitinib for patients with high-risk RCC after nephrectomy should not be given.

The two phase III studies (ASSURE and S-TRAC) recently reported findings on whether adjuvant VEGF-targeted therapy can improve outcomes for patients with renal cell cancer that has been removed by surgery. In these two trials, already mentioned on previous blogs here and here, sunitinib, an oral tyrosine kinase inhibitor (TKI), or a placebo, was given to patients who underwent surgical kidney tumour removal and who presented a high risk for recurrence after surgery. The S-TRAC study, which included more than 670 patients, showed positive results with 1 year of sunitinib therapy resulting in a 1.2-year longer time of disease-free survival (DFS), its primary endpoint.  However, the ASSURE study did not show any benefits with no significant improvements in disease-free survival or overall survival compared to placebo in patients following surgical tumour removal. Many patients remained without recurrence. In addition, the side effects of sunitinib were significant in both studies and included hypertension, hand-foot reaction, fatigue and diarrhoea. The poor benefit-to-harm ratio and the lack of evidence of an overall survival benefit led the EAU RCC Guidelines Panel, including patient representatives, to recommend against using adjuvant sunitinib after tumour removal in these RCC patients.

Meric-Bernstam et al. (2016) presented at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, preliminary data from a phase I clinical trial .  The trial gave patients with clear cell and papillary RCC a combination therapy of everolimus and  CB-839, a highly selective inhibitor of glutaminase, which is a key enzyme in the use of glutamine by many cancer types. Ten patients received the combination treatment, which was well tolerated, and a very high percentage of the patients had their tumour controlled by the regimen. Out of eight patients with clear cell or papillary RCC the tumour shrank at least 30% in one patient (partial response) and was stable in the other seven patients (stable disease). In the two patients with non- clear cell or papillary RCC best tumour response was progressive disease– at least a 20% increase in tumour size. These results suggest that CB-839 is a very tolerable drug with significant potential in combination therapy for kidney cancer patients. This study is currently recruiting patients. Researchers who continue to enrol and treat patients in this trial plan to evaluate CB-839 in combination with everolimus in a randomised controlled trial in the future. In addition, in the current trial, the efficacy of CB-839 in kidney cancer in combination with another drug, cabozantinib, is also being assessed.

The development of new mono and combination drug treatments for different types of RCC and the assessment of the efficacy and safety of these drugs is a very active field with several clinical trials currently recruiting patients. The diversity of these studies is encouraging for patients with BHD syndrome that are predisposed to develop histologically diverse RCC.

  • Bex A, Albiges L, Ljungberg B, Bensalah K, Dabestani S, Giles RH, Hofmann F, Hora M, Kuczyk MA, Lam TB, Marconi L, Merseburger AS, Staehler M, Volpe A, & Powles T (2016). Updated European Association of Urology Guidelines Regarding Adjuvant Therapy for Renal Cell Carcinoma. European urology PMID: 27986369
  • Meric-Bernstam, F., Tannir, N., Harding, J., Voss, M., Mier, J., DeMichele, A., Munster, P., Patel, M., Iliopoulos, O., Owonikoko, T., Whiting, S., Orford, K., Bennett, M., Carvajal, R., McKay, R., Fan, A., Telli, M., & Infante, J. (2016). Phase 1 study of CB-839, a small molecule inhibitor of glutaminase, in combination with everolimus in patients (pts) with clear cell and papillary renal cell cancer (RCC) European Journal of Cancer, 69 DOI: 10.1016/S0959-8049(16)32626-0

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