Medical treatment of renal cancer: new horizons.

Renal cell carcinoma (RCC) makes up 2-3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer

Kidney- and Site-Selective Delivery of 5-Fluorouracil Utilizing the Absorption on the Kidney Surface in Rats

The present study was undertaken to elucidate the kidney- and site-selective delivery of 5-fluorouracil (5-FU) utilizing the absorption on the kidney surface in rats. An experimental system utilizing a cylindrical diffusion cell attached to the right kidney surface was established. After intravenous administration of 5-FU, the concentration of 5-FU in the right and left kidneys was almost the same and was rapidly eliminated. After right kidney surface application of 5-FU, however, the concentration of 5-FU in the right kidney was significantly higher than in the left kidney and other tissues. The 5-FU concentration in four sites of the right kidney after intravenous administration was almost the same. In contrast, 5-FU was site selectively delivered in the kidney after kidney surface application. The blood concentration of 5-FU was low (<1.7 μg/ml) until 120 min after kidney surface application. The maximum blood concentration of 5-FU after kidney surface application was much lower than after intravenous administration

Nivolumab + ipilimumab (NIVO + IPI) adjuvant versus placebo dans le carcinome rénal localisé à haut risque de récidive après néphrectomie : résultats de l’étude de phase 3 randomisée Checkmate 914 (CM914)

Objectifs NIVO + IPI a démontré une amélioration de la survie globale versus sunitinib dans le CCR métastatique (NEJM2018 ;378 :1277–90). CM914, est une étude de phase 3, randomisée, en double aveugle, multicentrique, évaluant NIVO + IPI versus placebo (partie-A) ou NIVO monothérapie versus NIVO + IPI versus placebo (partie-B), chez des patients atteints de CCR localisé à haut risque de récidive après néphrectomie. Nous rapportons ici la première analyse de la partie-A. Méthodes Les critères d’inclusion principaux comportent : néphrectomie radicale ou partielle avec marges chirurgicales négatives, composante à cellules claires prédominante, pT2a (G3-4) N0M0, pT2b/pT3(a,b,c)/pT4 (tout grade) N0M0, ou pT0-4 (tout G) N1M0 ; sans signe de maladie résiduelle ou métastases. Les patients étaient randomisés 1 :1 sous NIVO 240 mg/2 semaines (×12) + IPI 1 mg/kg/6 semaines (×4) ou placebo, avec stratification selon stade TNM et type de néphrectomie ; durée de traitement de 24 semaines ou jusqu’à récidive/toxicité inacceptable. Le critère d’évaluation principal était la survie sans maladie (DFS) en revue centralisée (BICR). La survie globale et la tolérance étaient des objectifs secondaires. Résultats L’inclusion des patients dans la partie-A a commencé en juillet 2017 et s’est terminée en février 2021. L’analyse finale de la DFS par le BICR et les objectifs secondaires disponibles sera présentée pour les 800 patients randomisés dans le bras NIVO + IPI ou placebo dans la partie-A de l’étude CM914. Au total, environ 227 événements de DFS parmi les patients randomisés dans la partie-A sont attendus, assurant une puissance de 90 % pour détecter un hazard ratio de 0,65 avec un risque global d’erreur de type I de 0,05 (bilatérale). Conclusion Ces résultats devraient soutenir le rôle de NIVO + IPI en tant que nouvelle option d’immunothérapie adjuvante pour les patients atteints de carcinome rénal localisé présentant un risque élevé de récidive post-néphrectomie

LBA4 Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial

Background CheckMate 914 (NCT03138512) is a phase III, randomized, double-blind, multicenter, 2-part trial evaluating NIVO+IPI vs PBO (part A) or NIVO monotherapy vs NIVO+IPI vs PBO (part B) in mutually exclusive patients (pts) with localized RCC at high risk of post-nephrectomy relapse. We report the primary analysis for part A of this trial. Methods CheckMate 914 key inclusion criteria: radical or partial nephrectomy with negative surgical margins &gt; 4 and ≤ 12 weeks before randomization; predominant clear cell histology; pathological TNM stage T2a (grade [G] 3 or 4) N0M0, T2b (any G) N0M0, T3 (any G) N0M0, T4 (any G) N0M0, or any T (any G) N1M0; and no clinical/radiological evidence of residual disease or distant metastases. Pts were randomized 1:1 to NIVO 240 mg Q2W (× 12 doses) + IPI 1 mg/kg Q6W (× 4 doses) or equivalent PBO for 24 weeks or until disease recurrence/unacceptable toxicity. Stratification factors: TNM stage and type of nephrectomy. Primary endpoint: disease-free survival (DFS) per blinded independent central review; secondary endpoints include overall survival and safety. Results 816 pts were randomized to NIVO+IPI (n = 405) vs PBO (n = 411). With 37.0 months of median follow-up (range, 15.4–58.0), the primary efficacy endpoint of DFS was not met (HR, 0.92; 95% CI, 0.71–1.19; P = 0.5347). Median DFS was not reached with NIVO+IPI and 50.7 months with PBO; DFS probabilities at 24 months were 76.4% and 74.0%, respectively. Median (Q1, Q3) treatment duration was 5.1 (2.8, 5.3) months and 5.1 (5.1, 5.3) months, respectively. Any-grade treatment-related adverse events (AEs) were reported in 88.9% vs 56.8% of pts treated with NIVO+IPI vs PBO; grade ≥ 3 treatment-related AEs were reported in 28.5% vs 2.0%, respectively. Treatment-related AEs led to discontinuation of NIVO+IPI in 29.0% of pts and of PBO in 1.0% of pts. Conclusions The CheckMate 914 trial of NIVO+IPI vs PBO in pts with localized RCC at high risk of relapse after nephrectomy did not meet the primary endpoint of DFS. Safety of NIVO+IPI was consistent with its known profile in advanced RCC, although the rate of discontinuation due to treatment-related AEs was higher with adjuvant NIVO+IPI vs PBO in this trial