Abstract
Simple SummaryFirst-line treatment options for metastatic clear cell renal cell carcinoma have significantly increased. The current recommended therapeutic strategy is based on a combination, but monotherapy remains an alternative. However, the choice of the type of combination, i.e., dual immunotherapy or immunotherapy combined with an antiangiogenic drug, has not been clearly standardized. A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. This review summarizes all recent data from the main combinations evaluated in first-line treatment and discusses the choice of drugs according to the patient’s profile and the benefit/risk balances of each combination.The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient’s profile, and consideration of second-line and subsequent treatments.
Highlights
Clear cell renal cell carcinoma used to be associated with a very poor prognosis when diagnosed at an advanced stage
According to the post-hoc analysis of the CheckMate 214 study performed according to the number of International Metastatic Database Consortium (IMDC) risk factors, a benefit of treatment with NIVO + IPI on SUN was found for all patients at intermediate risk, including those with one or two risk factors (ORR (40–44% vs. 16–38%), Overall survival (OS) (HR 0.50–0.72), and progression-free survival (PFS) (HR 0.44–0.86)) [23]
Based on a meta-analysis that included four trials (CheckMate-214, Keynote-426, IMmotion-151 and JAVELIN Renal 101), immune checkpoint inhibitors (ICI)-based combinations were associated with a higher risk of all-grade pruritus (HR 3.11) and all-grade rash (HR 1.44) compared to patients treated with SUN
Summary
Clear cell renal cell carcinoma (ccRCC) used to be associated with a very poor prognosis when diagnosed at an advanced stage. Combining therapies to further improve survival and response rates has been tested in large phase III randomized trials, in particular CheckMate-214 (nivolumab (PD-1) + ipilimumab (CTLA-4) vs sunitinib (TKI)), JAVELIN Renal 101 (axitinib (TKI) + avelumab (PD-L1), vs sunitinib), KEYNOTE-426 (axitinib + pembrolizumab (PD-1) vs sunitinib), CheckMate 9ER (nivolumab + ipilimumab vs sunitinib) and CLEAR (lenvatinib (TKI) + pembrolizumab) [5,6,7,8,9,10,11,12]. Our approach integrates data available in routine clinical practice, such as effectiveness data, IMDC groups, PD-L1 status, tolerability of treatments and perspectives of treatment sequence
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