Renal cell cancer (RCC) is responsible for 3.7 % of all cancers diagnosed yearly and is ranked as the third most common urological cancer in the US population. The average age at diagnosis is 64 years old and one third of patients present with metastatic disease. It is a disease that is usually resistant to conventional chemotherapy and radiotherapy, and the current standard of treatment is based on tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors. These agents are associated with an improvement in PFS and OS but at the expense of a significant rate of AEs that are poorly tolerated by patients. This problem is more significant in older adults who often have a decreased performance status and may suffer from multiple comorbidities.
Efficacy of immune mediated therapies in the treatment of RCC was established in the early 1990s with the approval of high-dose interleukin-2 (IL2). In 1995, Fyfe et al. Reported positive outcomes with the use of high-dose IL2 in patients with metastatic RCC. A response rate of 14 % was achieved although this was at the expense of a high rate of treatmentrelated toxicity. Checkmate-025 explored the role of nivolumab in the second line treatment of patients with metastatic RCC who progressed on previous antiangiogenic therapy. Patients were randomized to 3 mg/kg of nivolumab intravenously every 2 weeks or everolimus tablet 10 mg orally daily. Nivolumab demonstrated superiority to everolimus with a median OS of 25.0 months (95 % CI, 21.8- not reached) compared to 19.6 months, HR for death in the general study population of 0.73 (98.5 % CI, 0.57–0.93), and an overall response rate of 25 versus 5 % with everolimus. Nivolumab was also associated with lower rates of grade 3– 4 AEs (19 vs 37 %). There was no difference in survival benefit or response rates based on the degree of PD-L1 expression. Efficacy analysis based on age showed a HR of 0.64 (95 % CI, 0.45–0.91) in patients aged 65 to 75 years compared to 1.23 (95 % CI, 0.66–2.31) in those older than 75. However, no real conclusions can be drawn from these numbers. Out of the 821 patients enrolled in this trial, 39 % were older than 65 years but only 9 % were older than 75 years. Dual check point inhibition with nivolumab and ipilimumab is being compared to sunitinib monotherapy. This trial expects to randomize about 1070 treatment-naïve patients stratified by International mRCC Database Consortium prognostic score and by region. The primary endpoints will be PFS and OS, secondary endpoints include ORR and safety. Currently, nivolumab in metastatic RCC is the only approved indication for a checkpoint inhibitor in genitourinary malignancies.
Reference:
Rawad Elias & Joshua Morales & Yasser Rehman & Humera Khurshid. Curr Oncol Rep (2016) 18: 47