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sunitinib as the primary endpoint, the study indeed confirmed that patients treated with either lenvatinib
combination (pembrolizumab or everolimus) achieved significantly prolonged PFS compared to sunitinib
alone (HR = 0.39 for pembrolizumab combination and HR = 0.65 for everolimus combination, respectively,
see also Table 1). In addition, patients treated with lenvatinib/pembrolizumab demonstrated superior OS
compared to sunitinib (HR = 0.66), with a high overall response rate (71%), notable CR rate (16.1%), and
low rate of primary PD (5.4%). The OS for patients treated with lenvatinib/everolimus was not found to be
superior to sunitinib (HR = 1.15). Subgroup analyses support that the OS benefit seen for combination
lenvatinib and pembrolizumab over sunitinib likely extends to those patients with PD-L1 negative tumors,
but this could not be confirmed in patients with favorable risk disease.

In all ICI/TKI trials, safety and tolerance observed for these above regimens listed here were largely in
keeping with the adverse event profiles typically seen with each of the individual agents without the sense
that an amplified toxicity signal emerged as being dose-limiting. Individual regimens varied in the reported
incidence of hepatic and GI toxicity, which may be related to mechanisms of action, drug interaction,
differences in the starting dose, or all the above.

All combinations described above have expanded the number of combination options available to patients
with advanced disease and increased the complexity of individualizing care. The choice between an ICI
doublet (ipilimumab/nivolumab) and one of the various TKI/ICI combinations may be driven by: (1)
IMDC risk status (as ipilimumab/nivolumab being solely approved in intermediate/poor risk patients); (2) a
notably lower upfront failure rate for all TKI/ICI combinations (explained by dual mechanism of action and
relevant in patients with rapidly progressive, symptomatic disease who may not reach second-line therapy
for which the risk remains higher with ipilimumab/nivolumab) ; (3) the above mentioned PFS “tail of the
[29]
curve” for ipilimumab/nivolumab (which should motivate consideration of this regimen in patients with
no/little concern for rapid progression and deterioration, until TKI/IO datasets are more mature and can
speak to the presence of absence of a tail of the curve for those regimens); and (4) co-morbidities
(uncontrolled cardiovascular disease arguing against TKI-containing regimen; conditions limiting
tolerability of high-dose corticosteroids causing concern for use of the ICI doublet, which comes with a
notably higher risk of requiring steroids for high-risk immune related toxicity). Once the determination is
made to proceed with TKI/ICI, treating physicians are left with several regimens that have met all primary
endpoints during the registration process. Study populations for KeyNote-426, CheckMate 9ER and CLEAR
varied notably, and a clear “winner” cannot be chosen while follow-up is comparatively short for all of
these, and the “tail-of-the-curve” question is left unanswered still. Instead, the decision will be driven by
physician experience with and their preference for individual agents, reported starting doses (e.g.,
cabozantinib is started at an attenuated dose with nivolumab; axitinib is started at a standard dose with
pembrolizumab; lenvatinib is started at a higher dose with pembrolizumab compared to the previously
approved combination with everolimus) and the individual nuances of toxicity that may be particularly
enticing with each (e.g., low rate of hepatic events with lenvatinib and pembrolizumab or low rate of dose
reductions needed for cabozantinib with nivolumab).

OPTIMIZING ICI THERAPY - CAN WE ACHIEVE MORE WITH LESS?
Deep responses and durable anticancer effects have been observed in those patients receiving ICI
[30]
monotherapy - albeit in a lesser proportion of patients . Results from KeyNote-427 Cohort A, a phase II
study of pembrolizumab monotherapy in systemically untreated ccRCC patients, demonstrated an ORR of
36.4%, of which 3% of patients also achieved a complete response and 15% of patients achieved a high depth
of response with > 80% tumor reduction . Such ICI monotherapy comes at a notably lower risk for high-
[30]
grade toxicity than ICI-containing combination therapy. Several groups have investigated adaptive designed