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Serzan et al. J Cancer Metastasis Treat 2021;7:39 https://dx.doi.org/10.20517/2394-4722.2021.76 Page 11 of 19

Combinations of anti-angiogenics with anti-PD-1/PD-L1 have been tolerable with common adverse effects
being fatigue, hypertension, and diarrhea similar to adverse effects observed with sunitinib alone. However,
higher rates of hypothyroidism (22%-35%) and grade 3-4 liver enzyme elevations (6%-13%) were observed
in axitinib/pembrolizumab and axitinib/avelumab than with sunitinib. These warrant close monitoring as
antiangiogenic and ICI therapies may potentiate synergistic or additive adverse effects that accumulate over
time. Current trials of combination angiogenic and ICI therapies are evaluating patient-reported outcomes
to determine in depth health-related quality of life over time while on therapy.

Novel endpoints
Over the past three years, pivotal trials of anti-PD-1 therapy combined with either anti-CTLA or various
VEGFR TKIs have led to unprecedented improvements in outcomes for patients with advanced RCC.
However, in the absence of head-to-head comparison, the optimal choice for first line therapy remains a
debated issue as these regimens have yielded important differences in some novel endpoints. Anti-PD-
1/VEGFR TKI combinations have demonstrated improvements in “early” endpoints including ORR, PFS,
and < 2-year OS rates, perhaps favoring use in patients with symptomatic disease with the goal of more
immediate disease control. Whereas, anti-PD-1/anti-CTLA therapy has led to more durable “late”
endpoints including landmark PFS/OS, > 2-year OS rates, treatment free survival (TFS), and patient-
reported quality of life, suggesting greater benefit in sustained disease control.

As data from the Checkmate-214 study continue to mature with a minimum of 4-year follow up, the
durable and late benefits have become more pronounced with PFS and OS plateaus greater than 30% and
50%, respectively. The overall survival benefits for the ITT population on nivolumab/ipilimumab relative to
sunitinib in the Checkmate 214 study have remained stable over time with initial median follow-up of 25
months (HR OS = 0.68; P < 0.001) and interval follow-up at median 43 months (HR OS = 0.72; 0.61-0.86; P
= 0.0002). Furthermore, Regan et al. [64,65] analyzed 42-month TFS, defined as time from protocol therapy
cessation to time of subsequent systemic therapy or death. In the nivolumab/ipilimumab arm, 56% of
patients were alive, 13% were on nivolumab maintenance, and 31% were surviving free of subsequent
therapy. In the sunitinib arm, 47% of patients were alive, 7% remained on sunitinib therapy, and 12% were
surviving free of subsequent treatment. The overall 42-month restricted mean TFS was 7.8 months for
nivolumab/ipilimumab and 3.3 months for sunitinib. Mean TFS for nivolumab/ipilimumab compared to
sunitinib was three times as long in favorable risk patients (11.0 months vs. 3.7 months) and over twice as
long in intermediate/poor risk patients (6.9 months vs. 3.1 months). These results highlight that patients
across all IMDC risk groups experienced benefit from ICI therapy with greater survival time treatment-free
without toxicity relative to sunitinib. Although nivolumab/ipilimumab carries a high risk of early immune
related adverse events, many of these are reversible with short-term immunosuppression without evidence
of detriment to anti-tumor immune effect. Based on its ability to produce robust and sustained anti-tumor
responses with prolonged treatment free intervals, nivolumab/ipilimumab represents an excellent treatment
choice for many patients with advanced ccRCC.

Several anti-PD-1/VEGFR TKI combinations have demonstrated substantial benefit in early endpoints of
ORR 52%-71% and median PFS 13-24 months in the ITT populations. However, the ability of these
regimens to extend early response benefits into durable long-term outcomes with PFS and OS plateaus
remains to be established. Axitinib/pembrolizumab showed remarkable early overall survival benefit in ITT
population at a median 12-month follow up (OS HR = 0.53; 0.38-0.74; P < 0.001); however, this OS benefit
appears to diminish at the median follow-up of 30 months (OS HR = 0.68; 0.55-0.85; P = 0.0003) [Table 3].
Similarly, axitinib/avelumab showed early overall survival benefit in ITT at the median follow-up of 12
months (OS HR = 0.69; 0.56-0.84; P < 0.001); however, this OS benefit appears to diminish at the median
follow-up of 19 months (OS HR = 0.80; 0.61-1.02; P = 0.03) [Table 3]. The decreasing OS benefits in these