The treatment of metastatic renal cell carcinoma (mRCC) has undergone several major changes, with the first approval of targeted therapy in 2005 and the first approval of an immune checkpoint inhibitor in 2015. The success of targeted therapy is limited by the inevitability of acquired resistance, and, similarly, the success of immunotherapy has been limited by the number of patients who respond. Cases of durable complete responses (CRs) with combination therapy that include immunotherapy and, in some cases, targeted therapy, raise the question of whether cure is possible.1

Prior to the era of targeted therapy, the 5-year survival of patients with advanced RCC was just 7.3%; this has since risen to 11.6%.2 Though this is an improvement, this low number highlights the need for treatment options leading to durable responses among a larger number of patients.

Outcomes With Monotherapy

Currently, the only curative therapy for mRCC is high-dose interleukin (IL)-2, which leads to a cure for 5% to 7% of patients.1 Its use is limited, however, by multiorgan toxicity and the unpredictability of which patients will respond.

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Compared with chemotherapy, molecularly targeted therapies shift the survival curve to the right, with rapid responses that typically do not last more than a year.1 The overall response rate (ORR) of first-line VEGF or VEGF receptor-targeted agents, such as bevacizumab, sunitinib, and pazopanib, range from 30% to 39%, leading to a median progression-free survival (PFS) of 9.2 to 11 months.3 The ORR of the mTOR inhibitor, temsirolimus, is 8.6%, leading to a median PFS of 5.5 months in the first line. The second-line efficacy of these agents is broader, with ORR rates of 1.8% to 57% and a median PFS of 4.9 to 14.6 months.

Immune checkpoint inhibitors shift the survival curve upward, generally resulting in less rapid but more durable responses than targeted therapies.1 Nivolumab, the first and only immune checkpoint inhibitor approved for mRCC, resulted in an ORR of 25%, a median PFS of 4.6 months, and a median overall survival (OS) of 25 months in the second line.3 A small subset of patients may, however, have long-term responses with immune checkpoint inhibition.

“What is notable about immunotherapy is that although most patients are not cured and most of them go on to other treatments, the survival is just so long,” Elizabeth R. Plimack, MD, MS, chief of the division of genitourinary medical oncology and director of genitourinary clinical research at Fox Chase Cancer Center in Philadelphia, Pennsylvania, told Cancer Therapy Advisor.

“What we haven’t measured very well is the outcomes of patients who stop treatment, and we will. We will know more in the coming years. In a lot of trials ongoing now, immunotherapy is discontinued at 2 years and then patients are monitored to see if their cancer comes back.”