Clinical data from patients with non-clear cell renal cell carcinoma (nccRCC) receiving targeted therapy are limited, and many clinical trials have excluded these patients from study entry. We sought to investigate the outcomes of patients with nccRCC treated in clinical trials in the modern era compared with the outcomes of patients with clear cell RCC (ccRCC).

We conducted a retrospective study of patients with metastatic RCC who had received targeted therapy in Pfizer-sponsored phase II and III clinical trials from 2003 to 2013. Associations between the histologic type and treatment outcome (overall survival [OS] and progression-free survival [PFS]) were assessed using the log-rank test on univariate analysis or the Wald χ test from Cox regression on multivariable analysis, adjusted for baseline characteristics, including age, sex, Eastern Cooperative Oncology Group performance status, body mass index, International Metastatic RCC Database Consortium risk factors, previous nephrectomy, previous therapy, metastatic sites, angiotensin system inhibitor use, and statin use.

We identified 4527 patients with metastatic RCC: 4235 with ccRCC and 337 with nccRCC. Overall, the median OS was shorter for those with nccRCC than for those with ccRCC (15.7 vs. 20.2 months; hazard ratio [HR], 1.41; 95% confidence interval 1.22-1.63; P < .001). When stratified by the International Metastatic RCC Database Consortium risk group, the median OS was inferior for the intermediate- and poor-risk patients with nccRCC than for those with ccRCC. However, no differences were found in the favorable risk group for nccRCC versus ccRCC. The patients with nccRCC who had received vascular endothelial growth factor-targeted therapy had shorter PFS compared with that of ccRCC patients (median, 6.1 vs. 8.5 months; HR, 1.49; P < .001) but similar PFS when treated with mammalian target of rapamycin inhibitors (median, 4.3 vs. 4.4 months; HR, 0.92; P = .63).

Our findings have confirmed that patients with nccRCC are underrepresented in clinical trials and highlight the need for further prospective studies exploring current and novel agents for this patient population.