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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 5 of 12

As a whole, the results of the Keynote-426 trial support the combination of Pembrolizumab + Axitinib as
another standard of care for mRCC patients, irrespective of IMDC risk groups (although with a limited
added benefit for good risk patients).

Nivolumab + Cabozantinib (Checkmate 9ER)
In this study, 651 previously untreated mRCC patients were randomized to either the combination of the
anti-PD1 monoclonal antibody Nivolumab with the multikinase inhibitor Cabozantinib, or Sunitinib
monotherapy .
[3]
The doses of the three agents were the following: 240 mg i.v. every 2 weeks for Nivolumab, 40 mg o.d. per os
(i.e., one dose level less than the starting monotherapy dose) for Cabozantinib, and 50 mg o.d. per os, 4
weeks on, two weeks off, for Sunitinib. Dose reductions were not allowed for Nivolumab, but permitted for
the two oral agents.

Treatment continued until disease progression or unacceptable toxicity occurred, with a maximum 2-year
duration for Nivolumab.

The primary end point was PFS among the intention-to-treat population, while secondary end points were
OS, ORR, time to and duration of response, as well as safety.

At a median follow-up of 18.1 months, median PFS was 16.6 months (95%CI: 12.5-24.9) with the immune-
based combination, and 8.3 months (95%CI: 7.0-9.7) with Sunitinib, a difference that was statistically
significant, yielding a reduction in the risk of progression or death of 49% (HR = 0.51; 95%CI: 0.41-0.64; P <
0.001). Furthermore, Nivolumab + Cabozantinib also yielded a significant OS benefit over Sunitinib, the 12-
month OS probability being 85.7% (95%CI: 81.3-89.1) with the combination, and 75.6% (95%CI: 70.5-80.0)
with the monotherapy. Overall, the reduction in the risk of death was 40% (HR = 0.60; 98.89%CI: 0.40-0.89;
P = 0.001), though at the time of publication median OS was not reached in either group.

ORR was 55.7% (95%CI: 50.1-61.2) with Nivolumab + Cabozantinib, and 27.1% (95%CI: 22.4-32.3) with
Sunitinib (P < 0.001), while complete response rate was 8.0% for the immune-based combination and 4.6%
for the monotherapy .
[3]

PFS benefit of the combination over Sunitinib was consistent across the three IMDC risk groups: HR = 0.62
(95%CI: 0.38-1.01), HR = 0.54 (95%CI: 0.40-0.72), and HR = 0.37 (95%CI: 0.23-0.58) for good, intermediate,
and poor-risk patients, respectively. The same did not occur when OS was taken into consideration: HR =
0.84 (95%CI: 0.35-1.97), HR = 0.70 (95%CI: 0.46-1.07) and HR = 0.37 (95%CI: 0.21-0.66) for each of the
three groups.

TRAEs of any grade and TRAEs grade 3 or higher were reported in 96.6% and 60.6% of the patients treated
with Nivolumab + Cabozantinib (vs. 93.1% and 50.9% in those treated with Sunitinib), respectively. The
percentage of adverse events of any cause leading to the discontinuation of a trial drug were 19.7% with the
combination (6.6% discontinued Nivolumab only, 7.5% Cabozantinib only, and 5.6% both agents), and
16.9% with Sunitinib. Finally, patients reported better health-related quality of life with Nivolumab +
Cabozantinib than with Sunitinib.