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Porta et al. J Cancer Metastasis Treat 2021;7:49 https://dx.doi.org/10.20517/2394-4722.2021.86 Page 11 of 12

most frequent toxicity) should be used to create a new algorithm able to identify those patients
unquestionably unsuitable for each therapy, across different treatment lines.

Although a useful practical suggestion, this approach is now flawed by the fact that the safety profiles of
combinations of an ICI plus a VEGFR-TKI are extremely similar, not to take into account that the trade-off
between efficacy and safety a first line patient is willing to accept is usually unbalanced in favor of efficacy.

Furthermore, beyond the number and severity of TRAE, we should also consider their relative duration.
Indeed, multiple, long-lasting, low-grade, adverse events usually negatively impact on patients’ quality of life
more than single, high-grade, toxicities, especially if rapidly resolving; not to take into account that, for
patients treated with the Ipilimumab + Nivolumab immune combination, severe adverse events are mainly
limited to the induction phase, when both ICIs are simultaneously given, while they tend to be less
troublesome during the Nivolumab-alone maintenance phase of the treatment.

In conclusion, waiting for more mature trial data, as well as for real-world experiences, in the absence of
validated biomarkers, our first line treatment choice cannot but rely on methodologically incorrect
treatment comparisons, personal preferences, and experience.

DECLARATIONS
Authors’ contributions
Made equal contribution in the collection and critical interpretation of the data summarized in this
manuscript: Porta C, Rizzo M

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
Porta C acted as a Consultant and/or Speaker for Angelini, Astra Zeneca, BMS, Eisai, EUSA, General
Electric, Ipsen, Janssen, Merck, MSD, Novartis and Pfizer; as an Expert Testimony for EUSA and Pfizer; and
as a Protocol Steering Committee Member for BMS, Eisai and EUSA; finally, he received travel support
from Roche. Rizzo M acted as a Consultant and/or Speaker for Novartis, Pfizer, and MSD.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.

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