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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 3 of 12

conventional dose of 50 mg once daily (o.d.), on a 4 weeks-on, 2 weeks-off, schedule.

Notably enough, the dose of the two ICIs were the opposite of those used in melanoma (i.e., Ipilimumab
3 mg/kg and Nivolumab 1 mg/kg).

Co-primary, but hierarchical, endpoints were overall survival, followed by objective response rate (ORR),
and finally by progression-free survival, among patients with International Metastatic RCC Database
[10]
Consortium (IMDC) intermediate and poor risk features. However, good risk patients were also enrolled,
representing an exploratory endpoint population.

[1]
In this first study with a median follow-up of 25.2 months, in the target population of intermediate and
poor risk patients, the 18-month OS rate was 75% [95% confidence interval (CI): 70%-78%] with the
immune combination and 60% (95%CI: 55%-65%) with Sunitinib; however, the median OS was not reached
with the immune combination vs. 26.0 months with Sunitinib [hazard ratio (HR) = 0.63; P < 0.001]. The
ORR was 42% with immune combination vs. 27% with Sunitinib (P < 0.001), with a huge percentage of
patients from the combination arm achieving a complete response, 9% (vs. 1% for Sunitinib-treated
patients). Finally, median PFS was 11.6 months and 8.4 months for immune combination and Sunitinib,
respectively (HR = 0.82; P = 0.03), a difference that was not statistically significant per the prespecified 0.009
threshold.

As far as safety, treatment-related adverse events (TRAEs) occurred in 93% of the subjects randomized to
receive Ipilimumab + Nivolumab, and in 97% of Sunitinib-treated patients, with grade 3 or 4 events
occurring in 46% and 63% of the patients, respectively. Finally, TRAEs leading to treatment discontinuation
occurred in 22% and 12% of the patients, respectively.

Subsequent analyses, conducted at different follow-up times, confirmed the above results [11-13] ; indeed, at the
[13]
latest study update , after 4 years minimum follow-up, the immune combination yielded better results in
intermediate and poor risk patients, both in terms of OS (median, 48.1 months vs. 26.6 months; HR = 0.65;
95%CI: 0.54-0.78) and of ORR (39.1% vs. 32.4%) while, as often happens with ICIs, PFS benefit proved to be
limited, realistically due to their latency of action, time being needed for the activation, and expansion and
trafficking of the effector immune cells.

On the contrary, in favorable risk patients, the difference in OS was not statistically significant (HR = 0.93;
95%CI: 0.62-1.4), median OS having not been reached in either arm, and OS probabilities at 4 years being
[13]
similar between the two treatment arms, 65.1% for the immune combination vs. 68.9% for Sunitinib .

Pembrolizumab + Axitinib (Keynote-426)
In this study, 1062 previously untreated mRCC patients were randomized to either the combination of the
anti-PD1 monoclonal antibody Pembrolizumab with the highly selective VEGFRs inhibitor Axitinib, or
[2]
Sunitinib monotherapy .
Pembrolizumab was administered i.v. at a dose of 200 mg every 3 weeks for a maximum of 35
administrations, while Axitinib was administered orally at a dose of 5 mg twice daily (t.i.d.) until disease
progression or intolerance; Axitinib dose could be increased till a maximum of 10 mg t.i.d., in case of
adequate tolerance, or reduced till 2 mg t.i.d. in case of safety concerns. Sunitinib was administered orally at
a dose of 50 mg o.d., on the classical 4:2 schedule, but starting from the second cycle dose reductions till a
minimum of 25 mg o.d. were allowed in case of toxicity. Finally, in the case of confirmed complete