Abstract
The last decade has brought about major advances in systemic therapy for patients with advanced clear cell renal cell carcinoma. The introduction of angiogenesis targeting agents, immune checkpoint inhibitors, and combinations thereof has resulted in a multitude of therapeutic standards for patients with newly diagnosed advanced disease. With the rapid adoption and increasing number of available options for patients, selection amongst treatment regimens has become complex. Further, a new balance is also being sought to optimize treatment outcomes and limit treatment-related toxicities. With a rising bar against which novel therapeutics are being measured, the field looks toward an evolved understanding of tumor biology to help pave new ways forward for individualized therapy. Here, we review pivotal studies that led to regulatory approvals and ongoing clinical trials conducted in patients with systemically untreated clear cell renal cell carcinoma and provide perspective on how newly emerging data can be integrated into this rapidly changing landscape.
Highlights
The introduction of contemporary immunotherapy in the form of immune checkpoint inhibitors (ICIs) initially occurred in pre-treated patients treated with progressive disease (PD)-1 directed monotherapy[3], but this quickly moved into the frontline setting where combination therapy pairing agents targeting PD-1 and CTLA-4 were shown to improve patient survival, freedom from progression and quality of life compared to the prior gold standard, single-agent tyrosine kinase inhibitors (TKIs) therapy[4]
The treatment paradigm for patients with systemically untreated clear cell renal cell carcinoma (ccRCC) has significantly evolved, and multiple ICI-based combination therapies are the new standard for all eligible patients
Current first-line combinations have entered the arena in rapid succession, and while it is increasingly difficult to select amongst these available options, certain clinical situations and the clinician’s treating experience may guide the selection of one regimen over another
Summary
Over the last two decades, the clinical management of advanced clear cell renal cell carcinoma (ccRCC) has. In the pivotal phase III PDIGREE study (NCT03793166), systemically untreated IMDC intermediate-poor risk ccRCC patients undergo treatment with induction ipilimumab and nivolumab therapy per standard schedule. Those who sustain PD are shifted towards cabozantinib monotherapy. Bempegaldesleukin was previously tested in a phase I/II study in patients with systemically treatment-naïve ccRCC and was found to have an ORR of 64% (7/11 patients) with responses seen regardless of PD-L1 expression[41] Based upon these encouraging results, a global phase III study of bempegaldesleukin in combination with nivolumab vs investigator’s choice TKI (sunitinib or cabozantinib) remains ongoing with results forthcoming (NCT03729245)[42]. As more triplicate combinations are developed, it will be helpful to discriminate these additional strategies within the known context of angiogenesis and immune activation to optimize synergism and limit overlapping toxicities
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
