Renal cell carcinoma (RCC) is a rare malignancy accounts for 2%-3% of all adult malignancies (1) with a reported incidence of 2.95-16.67 in the European region (2). Surgery has been the mainstay treatment for localised disease and no adjuvant treatment has shown to benefit in terms of oncological outcomes. In metastatic setting, historically, RCC is among one of the very few malignancies shown to benefit from immunotherapies. Since the introduction of VEGF targeted monoclonal antibodies or tyrosine kinase inhibitors (TKI), immunotherapies lost their attraction owing to easier administration, manageable toxicities and clinical efficacy of these novel classes of agents.
With increasing understanding of molecular interplays between tumor and the immune system, recently, efforts at bench turn into a major breakthrough at bedside in treatment of certain malignancies. PD-1 blockade via nivolumab is stunning in this regard. After having heard the melanoma and lung cancer trial results, November 5 issue of the New England Journal of Medicine published the results of a randomised, open-label, phase 3 study compared nivolumab (3 mg/kg, i.v., q2w) with everolimus (10 mg, p.o., once daily) in patients with previously treated RCC (3). Treatments were continued until progressive disease, unacceptable toxicity or patients’ withdrawal of consent. The primary end point was overall survival, and secondary end points were the objective response rate and safety. To note patients with CNS metastasis, previously treated with an mTOR inhibitor, or with a condition requiring glucocorticoid treatment (equivalent to >10 mg of prednisone daily) excluded.
Everolimus is an mTOR inhibitor, currently accepted as one of the standard of care drugs, and has shown clinical activity in previously treated mRCC patients (4). Nivolumab is a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor that selectively blocks the interaction between PD-1 and PD-1 ligand 1 & 2. Interaction between PD-1 and PD-L1 or PD-L2 normally results in inhibition of the cellular immune response (3). Thus PD-1 blockade is thought to overcome this inhibition. A phase II study of nivolumab with varying doses (5) conducted in previously treated mRCC demonstrated ≈ 20% response rate and 18-25 months of overall survival.
In CheckMate 025, 821 patients with clear cell mRCC were randomized to treatment arms (1:1). Median OS was 25 months for the nivolumab and 19.6 months for the everolimus arm (HR of death 0.73 [CI: 98.5% CI, 0.57 to 0.93; P=0.002). The objective response rate (ORR) was 25% vs 5% for nivolumab and everolimus, respectively (p<0.001). Median progression-free survival (PFS) was 4.6 vs. 4.4 months for nivolumab and everolimus, respectively (HR 0.88; 95% CI, 0.75 to 1.03; p=0.11). The OS benefit with nivolumab was observed across prespecified subgroups; subgroups defined according to region, MSKCC prognostic score, and number of previous regimens of antiangiogenic therapy. Ninety-two percent of overall population was evaluable for PD-L1 expression. Survival benefit was observed with nivolumab irrespective of PD-L1 expression levels (≥1% vs <1% and ≥5% vs <5%) (3).
Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (2%), and the most common event with everolimus was anemia (8%). Treatment-related AEs leading to treatment discontinuation occurred in 8% treated with nivolumab and 13% treated with everolimus. No deaths from nivolumab were reported whereas two deaths were reported in the everolimus arm.
The message of this study is pretty straightforward, and findings added the nivolumab into the therapeutic armamentarium of previously treated mRCC.
- With the introduction of nivolumab, which parameters may have importance in decision making in second / third line therapy of mRCC patients?
- How will health care systems cope with huge financial burden caused by novel immunotherapies?
- Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009; 373: 1119–1132.
- Motzer RJ, Escudier B, McDermott DF, et al. CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015; 373(19): 1803-13.
- Motzer RJ, Escudier B, Oudard S, et al. RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet. 2008; 372(9637):449-56.
- Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 2015; 33: 1430-7.
Dr. Mehmet Akif Öztürk declares no conflict of interests.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.