Immunotherapy in Advanced Renal Cancer — Is Cure Possible?
Mené sur 1 096 patients atteints d'un carcinome rénal à cellules claires de stade avancé, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, du taux de réponse objective et de la survie sans progression, et la toxicité d'un traitement combinant nivolumab et ipilimumab par rapport à un traitement à base de sunitinib (durée médiane de suivi : 25,2 mois) en traitement de première ligne
Treatment for advanced renal-cell carcinoma has traced a remarkable arc during the past 25 years. In the 1990s, options included interferon, interleukin-2, megestrol, and 5-fluorouracil chemotherapy.1 Although a small proportion of patients had durable regression of renal-cell carcinoma with interleukin-2,2 no randomized, controlled clinical trials showed a survival benefit with any therapy in that era. Knowledge about von Hippel–Lindau gene mutations in renal-cell carcinoma and the downstream up-regulation of hypoxia-inducible factors led to insights about how these pathways influence angiogenesis. This led to the development of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors of multiple receptors related to angiogenesis and cell growth, including vascular endothelial growth factor, fibroblast growth factor, stem-cell factor, and platelet-derived growth factor. There are currently nine Food and Drug Administration (FDA)–approved TKIs or mTOR inhibitors, most of which are oral agents. These agents have by consensus become first-line therapies and have transformed the treatment of metastatic as well as high-risk renal-cell carcinoma after nephrectomy.
Although TKIs are associated with a substantial probability of objective response, improved disease-free and overall survival, and manageable toxic effects, they induce complete remission in approximately 1% of patients with advanced renal-cell carcinoma.3 Solid tumors that have metastasized to visceral organs or bone are infrequently cured; however, it has been observed in the past that interleukin-2 immunotherapy could induce complete remissions lasting years, albeit in only 5 to 7% of patients with advanced renal-cell carcinoma.2 This observation provided encouragement to develop new immunotherapies for cancer treatment, but it has taken more than two decades for agents to emerge that have broad antitumor activity and a higher probability of objective response and that can be safely administered outside centers specializing in the administration of high-dose cytokines. The key insight was the development of antagonistic antibodies to T-cell checkpoints, including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1, and programmed death ligand 1.4 Since 2011, six T-cell checkpoint antibodies have been approved by the FDA to treat at least nine different cancers. The first checkpoint antibody approved to treat advanced renal-cell carcinoma was nivolumab in 2016, on the basis of a higher objective response rate than with everolimus (25% vs. 5%) and longer overall survival (25.0 months vs. 19.6 months) among patients with renal-cell carcinoma who had disease progression after using a TKI.5 Among patients treated with nivolumab, 24% had a partial response and 1% had a complete response.(...)
New England Journal of Medicine , éditorial en libre accès, 2017