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Page 2 of 12 Porta et al. J Cancer Metastasis Treat 2021;7:49 https://dx.doi.org/10.20517/2394-4722.2021.86

INTRODUCTION
In the past couple of years, we have witnessed a “third” revolution in the medical treatment of metastatic
renal cell carcinoma (mRCC). After the development of targeted therapies and subsequently of single-agent
immunotherapy, the outcome of our patients, affected by this once-orphan disease, has been further
improved by the use of immune-based combinations, including either two different immune checkpoint
inhibitors, or one vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) and
one immune checkpoint inhibitor (ICI).

To date, five of these combinations have been tested within phase III trials; four of them yielded a
significant overall survival (OS) benefit (Ipilimumab + Nivolumab, Pembrolizumab + Axitinib, Nivolumab
[1-4]
+ Cabozantinib, and Pembrolizumab + Lenvatinib) . While the combination of Avelumab + Axitinib
reached the study primary endpoint, it only demonstrated a significant progression-free survival (PFS)
[5]
benefit . All these combinations were ultimately approved by different regulatory authorities, and are
indeed included in the most important international guidelines .
[6-8]
Another combination, Atezolizumab + Bevacizumab, although yielding formally positive results within
[9]
another phase III study , has not been registered, and its development in mRCC has been stopped due to
conflicting results.

Here, we are going to review the results achieved by means of these novel combinations (with the exception
of the Atezolizumab + Bevacizumab combination), and discuss how to practically select the best treatment
choice for any new given patient entering our hospitals.

METHODS
We have extensively reviewed the literature regarding the use of immune-based combinations for the first-
line treatment of mRCC, not only considering the primary publications of each trial, but also all available
updates, either published in extenso or just presented at conferences.

RESULTS
As stated above, five immune-based combinations have been registered - by different regulatory authorities
- for the upfront treatment of mRCC patients, thus yielding the status of novel standards of treatment in
this specific setting. Four of the five combinations were able to significantly prolong OS, while the latter was
able to improve PFS (but not OS).

Here, we summarize the results of the randomized, controlled, phase III trials of each of these five
combinations, starting with those which achieved an OS benefit.

Ipilimumab + Nivolumab (Checkmate-214)
The very first randomized controlled phase III trial addressing the frontline role of an immune-based
combination in mRCC patients was the Checkmate-214 study, which compared Ipilimumab + Nivolumab
[1]
with Sunitinib for the first-line treatment of mRCC patients .

In this study, 1096 patients were randomized to either the combination of the two ICIs, or Sunitinib
monotherapy. Ipilimumab was administered intravenously (i.v.) at the dose of 1 mg/kg every 3 weeks for a
total of four doses, while nivolumab was given at the dose of 3 mg/kg every 3 weeks, and continued also
after the withdrawal of Ipilimumab. On the other hand, Sunitinib was administered, per os, at the