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Page 4 of 11 Kotecha et al. J Cancer Metastasis Treat 2021;7:67 https://dx.doi.org/10.20517/2394-4722.2021.163

RCC tumors with sarcomatoid features, high response rates and survival outcomes can also be achieved
[20]
with combination ipilimumab and nivolumab . In this population, the confirmed ORR was 60.8% with
notably 18.9% of patients achieving a complete response, highlighting a significant step forward for this
patient subgroup with a historically poor prognosis.

COMBINATION ANTI-ANGIOGENESIS AND IMMUNE CHECKPOINT BLOCKADE THERAPY
The increasing number of different VEGF and ICI therapy permutations has provided valuable lessons on
careful drug selection and dosing of paired agents. Conceptually, many VEGF targeting therapies with
established roles in the monotherapy setting have favorable downstream immunomodulatory effects on the
RCC suppressive tumor microenvironment. Furthermore, with toxicity profiles that are mechanistically
non-overlapping with ICI therapy, these should, in principle, all lend themselves well to combination
strategy . However, a steadily increasing number of trials studying various TKI/ICI combinations have
[21]
revealed stark differences in efficacy and toxicity patterns, which emphasizes the importance of agent
selection. For instance, the pairing of sunitinib or pazopanib with ICI therapy was met with unacceptably
high rates of toxicity, with 39.4% and 80% of patients discontinued nivolumab plus sunitinib and
pembrolizumab plus pazopanib, respectively [22,23] . In addition, certain regimens, including axitinib with
avelumab (JAVELIN-Renal-101) and bevacizumab with atezolizumab (IMmotion-151), improved upon
radiographic responses achieved with TKI therapy alone but did not appear to carry an OS advantage [8,24] .
Amongst these reported combinations, the three that have demonstrated level 1 evidence of unequivocal
superiority over TKI monotherapy include axitinib with pembrolizumab, cabozantinib with nivolumab, and
lenvatinib with pembrolizumab.

Reported extended follow-up of KeyNote-426, the global phase III study of axitinib and pembrolizumab vs.
sunitinib, continues to confirm the significant clinical benefit for patients with systemically untreated
ccRCC with respect to dual primary endpoints PFS and OS, with HR of 0.73 and 0.68, respectively (see
Table 1) [25,26] . ORR as a key secondary endpoint also favored the combination, and patients treated with
combination axitinib and pembrolizumab achieved an ORR of 60%, of which 10% sustained a CR. The
superiority of the investigational arm was apparent early on this trial, and in the extended follow-up, 83% of
patients sustained some measure of tumor reduction, and the rate of PD as the best response was only 11%
with combination therapy. The primary analysis plan was neither specific to any IMDC risk category nor
tumor PD-L1 status, and superiority was apparent across all such groups on secondary analyses. In a recent
update, 29.9% of enrolled participants have even completed at least 2 years of systemic therapy, and of those,
[27]
14% achieved a CR . In the CheckMate 9ER study, cabozantinib combined with nivolumab was compared
to sunitinib monotherapy and demonstrated superior PFS, the primary endpoint of the trial (see Table 1).
[6]
Secondary endpoints ORR and OS were also notably improved for cabozantinib/nivolumab . At a median
follow-up of approximately 18 months, combination therapy had an ORR of 55.7%, with 8% of patients
achieving a complete response. Further, superior OS (HR = 0.6) was found regardless of PD-L1 expression
and across all IMDC risk groups, and emerging data also confirms that this clinical benefit is extended for
patients with sarcomatoid RCC . Based on the data from these pivotal studies, both
[28]
axitinib/pembrolizumab and cabozantinib/nivolumab have received FDA approval and remain standard
options in the first-line setting for all eligible advanced ccRCC patients. In contrast to
ipilimumab/nivolumab, their registration is not tied to a specific IMDC/MSKCC risk status.

The most recently reported TKI/ICI combination to gain FDA approval was gathered on the CLEAR study,
a three-arm trial which randomized patients 1:1:1 to the TKI/ICI combination of lenvatinib plus
pembrolizumab vs. the non-ICI-based combination of lenvatinib plus everolimus vs. TKI monotherapy with
standard sunitinib . In this phase III global clinical trial, which tested PFS with each combination vs.
[7]