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Page 10 of 19 Serzan et al. J Cancer Metastasis Treat 2021;7:39 https://dx.doi.org/10.20517/2394-4722.2021.76

In contrast, two unique combinations of axitinib with either pembrolizumab or avelumab (anti-PD-L1)
have demonstrated PFS benefits relative to sunitinib. The Keynote 426 phase 3 trial for first line ccRCC
randomized patients to axitinib/pembrolizumab or sunitinib with co-primary endpoints of OS and PFS in
[59]
the intention-to-treat population . At first interim analysis at a median follow up 12.8 months, the
combination demonstrated improvements in risk of death (HR OS = 0.53; 0.38-0.74; P < 0.0001), risk of
progression (HR PFS = 0.69; 0.57-0.84; P < 0.001), and ORR (59.3% vs. 35.7%; P < 0.001) relative to sunitinib
[Table 1]. The PFS and OS benefits were observed across all IMDC risk groups and PD-L1 expression
categories. In a subsequent analysis at median follow up 27 months, the PFS benefit was maintained (HR =
0.71), but the OS benefit was reduced (HR OS = 0.68; 055-0.85; P < 0.001) and was no longer apparent for
[60]
the favorable risk population (HR OS = 1.06; 0.60-1.86) . Axitinib/pembrolizumab had similar rates of
grade 3-4 treatment-related adverse events compared to sunitinib at 67% and 62%; however, the
combination had higher rates of grade 3-4 liver enzyme elevation 7%-12% vs. 2%-3%, respectively [Table 2].
These results led to FDA approval of axitinib plus pembrolizumab for all-risk patients with advanced RCC
in April 2019.

Axitinib combined with avelumab was compared to sunitinib in the Javelin Renal 101 phase 3 trial for first
line ccRCC with independent primary endpoints of OS and PFS in patients with PD-L1 positive tumors .
[61]
In the PD-L1 positive group, axitinib and avelumab demonstrated improvements in PFS (HR = 0.62; 0.49-
0.78; P < 0.001) and ORR 55.9% vs. 27.2% relative to sunitinib [Table 1]. These benefits of the combination
were also demonstrated in the overall study population PFS (HR = 0.69; 0.56-0.84; P < 0.001) and ORR
52.5% vs. 27.3% . Axitinib and avelumab was well tolerated compared to sunitinib with similar rates of
[62]
grade 3-4 treatment-emergent adverse events (71.2% vs. 71.5%) with 11% of combination therapy patients
requiring corticosteroids for IRAE [Table 2]. These results led to FDA approval of axitinib plus avelumab
for all-risk patients with advanced RCC in May 2019.

Two additional trials utilizing combinations of antiangiogenics with anti-PD-1 agents have resulted within
the past year. In the Checkmate9ER phase 3 trial patients with treatment naïve ccRCC were randomized to
cabozantinib/nivolumab or sunitinib with the primary endpoint of PFS by blinded independent central
review . At first interim analysis of median follow up 18.1 months, the combination demonstrated
[63]
improvements in PFS (HR = 0.51; 0.40-0.64; P < 0.0001) and OS (HR = 0.60; 0.40-0.89; P < 0.001) relative to
sunitinib [Table 1]. The PFS and OS benefits were observed across all IMDC risk groups and PD-L1
expression categories leading to FDA approval in January 2021. Cabozantinib/nivolumab had similar rates
of grade 3-4 treatment-related adverse effects compared to sunitinib at 61% and 51% with 16% of patients on
the combination requiring corticosteroids for IRAE [Table 2]. The CLEAR phase 3 trial for first line ccRCC
randomized patients to sunitinib, lenvatinib/everolimus, or lenvatinib/pembrolizumab with primary
endpoint PFS by IRC per RECIST1.1 . At first interim analysis at a median follow up of 27 months,
[29]
lenvatinib/pembrolizumab was superior to sunitinib in PFS (HR = 0.39; 0.32-0.49; P < 0.001) and OS (HR =
0.60; 0.40-0.89; P = 0.001). Lenvatinib/pembrolizumab also had high rates of grade 3-4 treatment-related
adverse events (82%) necessitating dose reduction of lenvatinib in 68% and discontinuation of the
combination in 13% of patients. Both cabozantinib/nivolumab and lenvatinib/pembrolizumab achieved
high response rates as well as significant PFS and overall survival benefits for the intent to treat population.
However, the contribution of cabozantinib and lenvatinib as more efficacious TKIs relative to sunitinib may
confound these early results. Furthermore, the ability of these regimens to produce long-term plateauing of
the PFS curve as well as their impact on OS over time will be of particular interest given the more limited
effective treatment options following disease progression on regimens involving the use of more potent
TKIs in the front-line setting.