First-line immune checkpoint inhibitors in advanced or metastatic renal cell carcinoma with sarcomatoid features

Advanced or metastasized renal cell carcinoma (mRCC) can present with sarcomatoid features, which is considered a poor prognosis marker and a treatment challenge. Several trials in first line mRCC have included immune checkpoint inhibitors (ICI) in combination either with other ICI or tyrosine kinase inhibitors (TKI), that have led to the approval of some of these treatment strategies and their recommendation in international guidelines. The authors review all randomized phase III trials in first-line treatment with ICI for advanced or mRCC and selected prospective phase I-IV trials, that included patients with tumors with sarcomatoid features. All these trials, in first-line treatment with ICI immunotherapy in combination with another ICI or TKI, included patients with mRCC with sarcomatoid features, corresponding from 5 to 15% of the study population. The efficacy and survival end points were superior in the sarcomatoid features subgroup with ICI in combination vs TKI in monotherapy, achieving overall response rates of 50-60%. A new benchmark has been established by trials reporting over 20 months in median overall survival. Even when considering ICI in monotherapy, the efficacy has been remarkable in patients with sarcomatoid features, demonstrating a striking consistency in these groundbreaking results. No biomarkers predictive of response to ICI were identified. The toxicity profile seems similar to the general study population. Despite the limitations of the clinical trials design to infer definitive conclusions in the sarcomatoid features patients, the data overwhelmingly support that ICI-based therapy should be the preferred strategy.