COMMENTARY

Setbacks and Advances in Renal Cell Carcinoma Treatment

Evan T. Hall, MD, MPhil

Disclosures

August 13, 2019

Given the variability in disease aggressiveness and the lack of highly predictive biomarkers in renal cell carcinoma (RCC), nothing resembling a "one size fits all" treatment approach has emerged for this disease. Instead, research has sought to uncover optimal strategies for the various subsets of RCC, with careful consideration of each patient's unique profile.

Front-line Immunotherapy Regimens in Sarcomatoid RCC

Several recent regulatory approvals have transformed the treatment of first-line metastatic RCC. Data had been lacking, however, on first-line therapy in sarcomatoid variants of RCC, a relatively rare, often more aggressive, and clinically challenging subset of this disease.

Subset analyses of patients with sarcomatoid RCC from three recent high-profile front-line metastatic trials were presented at this year's American Society of Clinical Oncology (ASCO) meeting, each of which showed significantly prolonged progression-free survival when compared with sunitinib. The trials compared sunitinib with three separate immunotherapy-containing regimens: axitinib plus pembrolizumab,[1] atezolizumab plus bevacizumab,[2] and ipilimumab plus nivolumab.[3]

These results suggest that checkpoint inhibitor–containing regimens, either together or in combination with a tyrosine kinase inhibitor (TKI), are the preferred first-line option for patients with sarcomatoid variants of RCC.

Another Strike Against TKIs in the Adjuvant Setting

A number of recent studies have examined vascular endothelial growth factor TKIs in the adjuvant or "no evidence of disease" setting, including the ASSURE,[4] S-TRAC,[5] and PROTECT[6] trials. The lone positive study among these was S-TRAC, which showed that a year of adjuvant sunitinib prolonged disease-free survival by approximately 1 year, although it did not affect overall survival. This trial led the US Food and Drug Administration to approve sunitinib for completely resected RCC at high risk for recurrence.

At this year's ASCO meeting, investigators presented the results of a randomized trial comparing 1 year of treatment with the TKI pazopanib or placebo in patients with no evidence of disease after metastasectomy for metastatic RCC.[7] Unfortunately, this trial joins others in supporting the notion that such TKIs lack compelling activity in this setting. Patients receiving pazopanib not only failed to experience significantly prolonged progression-free survival, but they also appeared to have worsened overall survival.

Given the significant side-effect and toxicity profiles of these agents, as well as the fairly consistent picture of minimal to zero clinical benefit, this is further evidence against their routine use to prevent relapse after complete surgical resection.

Nonetheless, we eagerly await the results of the many adjuvant checkpoint inhibitor trials that are currently underway (eg, KEYNOTE-564, CHECKMATE-914, PROSPER, IMmotion-010) to see if they show more efficacy in this setting.

Active Surveillance for Select Patients?

In another important study, researchers assessed the safety and outcomes of active surveillance in a large observational Canadian cohort of more than 1800 patients with metastatic RCC.[8] Nearly half (47%) of patients were treated with an initial strategy of surveillance rather than systemic treatment.

While survival outcomes for this group appeared very favorable (70% of patients on active surveillance were alive at 5 years), patients in this cohort probably had more favorable tumor biology as well as lower volume of disease and symptom burden.

These real-world data further support recently published prospective data[9] suggesting that active surveillance is a reasonable initial treatment option in selected patients.

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