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Page 10 of 12 Porta et al. J Cancer Metastasis Treat 2021;7:49 https://dx.doi.org/10.20517/2394-4722.2021.86

Figure 1. Comparison between the heads of the PFS curves from Checkmate 214, Keynote 426, Checkmate 9ER, and CLEAR. Possible
[1-4]
interpretation is reported within the text (modified from ).
After these initial months, separation of the curves, and consequently, a positive impact on median survival
occurs; thus, there is no surprise in the observation that four out of five of the considered combinations
were able to improve OS over the same control treatment (i.e., Sunitinib).

The lack of OS impact of the Avelumab-based combination might be related to a lower activity/efficacy of
anti-PD-L1 agents, as compared to anti-PD1 (at least in mRCC), as also suggested by the results of the
[17]
[9]
IMmotion 151 trial of Atezolizumab + Bevacizumab . Indeed, it is clear that not all ICIs are born equal ,
although these differences may also be dependent on specific tumor types.
Finally, with immunotherapy, a survival plateau is often observed after few years, suggesting the presence of
a certain number of long-survivors (“cured”) patients. For sure, this tail looks striking in Checkmate
214 [1,11-13] , although follow-up periods across the different studies are too different to draw definitive
conclusions. Furthermore, it is definitely too early to confirm the presence of cured patients by any of the
tested immune-based combos.

As a whole, the only possible, though highly empiric, present driver of our therapeutical choice could be the
biological aggressiveness of the tumor. Indeed, in the case of a very aggressive disease, the use of an ICI plus
a VEGFR-TKI seems a very reasonable choice, in order to try to control early disease growth, while waiting
for the “tail” effect of immunotherapy.

Otherwise, one could head for the long-term benefit of the immune combination, trying to spare the
additional toxicities deriving from the continuous use of the VEGFR-TKI.

In conclusion, with the present lack of biomarkers predictive of response from (or, on the contrary, of
[18]
inefficacy of) the different available treatments , we should still rely just on clinical parameters (like those
included in the IMDC risk classification system), personal judgement, and experience.

As far as safety, it is usually considered another key element for choosing the best treatment for each given
patient. In the recent past, Bracarda et al. proposed that the polarizing toxicity of each treatment (i.e., the
[19]