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Page 6 of 19 Serzan et al. J Cancer Metastasis Treat 2021;7:39 https://dx.doi.org/10.20517/2394-4722.2021.76

[Table 1]. PFS was improved; however, it did not meet pre-specified level of significance (HR = 0.82; P =
0.03). Subgroup analysis confirmed OS and ORR benefit regardless of PD-L1 tumor expression in
intermediate/poor risk patients. However, patients with tumor PD-L1 > 1% demonstrated enhanced OS
benefit from the combination immunotherapy (HR OS = 0.45; 0.29-0.71) relative to those with tumor PD-
L1 < 1% (HR OS = 0.73; 0.56-0.96). Patients with tumor PD-L1 > 1% demonstrated longer PFS with the
combination relative to sunitinib (HR PFS = 0.46; 0.31-0.67), whereas patients with tumor PD-L1 < 1% did
not (HR PFS = 1.00; 0.80-1.26).

In patients with favorable risk disease, sunitinib demonstrated significantly improved early outcomes
relative the nivolumab/ipilimumab with ORR 52% vs. 29% (P < 0.001) and PFS 25.1 months vs. 15.3 months
(HR = 2.18; 1.29-3.68; P < 0.001) that did not extend to OS (HR = 1.19; P = 0.44). Interestingly, the efficacy
of nivolumab and ipilimumab was similar in favorable risk patients compared with intermediate/poor risk
patients with ORR 39% and 42%, CR 8% and 11.3%, and landmark 42 months PFS 28% and 35% .
[43]
Furthermore, at 48 months there was a crossing of the Kaplan Meier OS curves between sunitinib and
nivo/ipi indicating the potential for a OS benefit to eventually emerge favoring the combination . Post hoc
[44]
analysis of patients with aggressive sarcomatoid features, the vast majority of whom had intermediate or
poor risk disease, showed remarkable benefits favoring nivolumab/ipilimumab to sunitinib in ORR 60.8%
vs. 23.1%, CR rate 18.9% vs. 3.1%, median PFS 26.5 months vs. 5.1 months (HR = 0.54; 0.33-0.86; P = 0.0093),
[45]
and median OS not reached vs. 14.2 months (HR = 0.45; 0.3-0.7; P = 0.0004) . Taken together,
nivolumab/ipilimumab has emerged as the standard regimen for patients with intermediate/poor risk
disease and those with sarcomatoid features. For patients with favorable risk disease, the early ORR and PFS
benefits observed on sunitinib may be attributable to the relative efficacy of anti-angiogenic therapy in
patients with less aggressive disease; however, maturing long term data of similar overall survival suggests a
potential role for nivolumab/ipilimumab in this population.

Treatment related grade 3-4 adverse events were lower on nivolumab/ipilimumab (46%) compared to
sunitinib (63%) [Table 2]. Nivolumab/ipilimumab was associated with high rate of immune related adverse
events at 80% with 29% requiring high dose steroids for treatment. The discontinuation rate from all-cause
adverse events was 22% for the combination and 13% for sunitinib. Interestingly, patients who discontinued
nivolumab/ipilimumab treatment due to toxicity, exhibited a better OS than patients who did not
experience treatment limiting toxicity. Patient reported outcomes of quality of life showed consistent mean
change from baseline favoring combination therapy relative to sunitinib (P < 0.001) which was evident
despite discontinuing QOL measurements at the time of treatment discontinuation even in patients
continuing to exhibit long-term disease control.

The unprecedented improvements in overall survival with nivolumab/ipilimumab have led to efforts to
investigate if subsets of patients could derive similar long-term benefits from single agent anti-PD-1 agents
while avoiding toxicity of combination with ipilimumab. The Keynote 427 single-arm phase 2 study
examined first line pembrolizumab monotherapy for patients with advanced RCC with the primary
endpoint of ORR by blinded independent central review. Patients with ccRCC (Cohort A) demonstrated
ORR 36.4% with CR 2.7%, median PFS 7.1 months, and median OS not reached at median follow up 18
months . ORR was numerically higher for patients with intermediate/poor risk disease 39.7% compared to
[46]
favorable risk 31.0% as well as patients with PD-L1 positive tumors 44.2% compared to 29.3% for those with
PD-L1 negative tumors. Patients with sarcomatoid differentiation had an ORR of 63.6%. Treatment related
adverse effects occurred in 73.6% of patients with grade 3-5 occurring in 18.2%. These results show clinical
activity of pembrolizumab monotherapy in the first line setting with perhaps increased benefit in
intermediate/poor risk disease and sarcomatoid differentiation groups and lower rates of severe grade 3-5