Page 69 - Read Online

Page 4 of 19 Serzan et al. J Cancer Metastasis Treat 2021;7:39 https://dx.doi.org/10.20517/2394-4722.2021.76

MET and AXL expression has been associated with aggressive disease and may mediate resistance to
[27]
VEGFR TKI therapy . The randomized phase 2 CABOSUN trial compared cabozantinib, an oral multi
kinase inhibitor to VEFGR, MET, and AXL to sunitinib for treatment-naïve patients with intermediate/poor
[13]
risk disease . The trial met its primary endpoint of investigator assessed PFS (HR = 0.66; 95%CI: 0.46-0.95;
P = 0.012) which was confirmed by independent radiology committee (IRC) with extended follow up (HR =
0.48; 95%CI: 0.31-0.74, P = 0.0008) . Further analysis demonstrated PFS benefit of cabozantinib over
[28]
sunitinib across both IMDC risk groups, and regardless of tumor burden, metastatic site and MET
expression status. Although there was a trend towards longer overall survival with cabozantinib 26.6 months
vs. sunitinib 21.2 months (HR = 0.80; 95%CI: 0.53-1.21), this study was underpowered to assess OS
differences. Cabozantinib tolerance was similar to sunitinib with comparable rates of dose reduction (46%
vs. 35%) and discontinuation (21% vs. 22%). Also, common grade 3-4 adverse events were similar between
cabozantinib and sunitinib with hypertension (28% vs. 21%), fatigue (6% vs. 17%), diarrhea (10% vs. 11%),
and thrombocytopenia (1% vs. 11%). Based on the PFS benefit, cabozantinib was approved by the FDA in
December 2017 for patients with intermediate/poor risk treatment naïve ccRCC.

Most recently, the phase 3 CLEAR study for patients with all-risk ccRCC compared first line sunitinib to
lenvatinib/everolimus or lenvatinib/pembrolizumab . The study met its primary endpoint of PFS by IRC
[29]
for lenvatinib/everolimus compared to sunitinib (HR = 0.65; 95%CI: 0.53-0.80). Despite this PFS benefit
with higher ORR (54% vs 36%) and CR rates (10% vs 4%), there was no difference in overall survival (HR =
1.15; 95%CI: 0.88-1.50). These results suggest that either the FGFR inhibition from lenvatinib or the
addition of mTOR inhibition with everolimus may lead to enhanced initial antitumor response; however,
this benefit may compromise the efficacy of subsequent therapy, thereby limiting the impact of this regimen
on OS.

Despite the PFS benefits of sunitinib, pazopanib, cabozantinib, and lenvatinib/everolimus in the first line,
these therapies were associated with frequent dose reductions (35%-51%) and rates of discontinuation due
to adverse effects (20%-24%), many of which were postulated to be mediated by off-target inhibition of the
PDGFR, KIT, and FLT-3 pathways. First line trials utilizing the more potent and selective second generation
VEGFR TKIs axitinib and tivozanib compared to sorafenib were hypothesized to improve efficacy and
reduce adverse effects. A phase 3 trial of first line axitinib compared to sorafenib showed numerical
differences in PFS; however, it did not establish a statistically significant difference between the two
treatments 10.1 months vs. 6.5 months (HR = 0.77; 0.56-1.05) . In addition, while axitinib showed
[30]
significantly higher ORR 32% vs. 15% (1 sided P = 0.0006), no difference in median OS 21.7 months vs. 23.3
months (HR = 0.95; 0.73-1.36) compared to sorafenib was observed. One key limitation of this study was
relatively small sample size (N = 288) to detect anything but a large magnitude of difference between
therapies. The TIVO-1 study of first line tivozanib, a potent and selective TKI to VEGFR, c-Kit, and PDGFR
compared to sorafenib met its primary endpoint of improved median PFS 11.9 months vs. 9.1 months (HR
[31]
= 0.79; 0.63-0.99; P = 0.042) . However, OS analysis showed a trend toward longer survival on the sorafenib
arm than on the tivozanib arm - median 29.3 months vs. 28.8 months (HR = 1.245; 0.95-1.62; P = 0.105).
These discordant PFS and OS results were hypothesized to be related to a greater proportion of patients in
the sorafenib arm receiving next-line VEGFR TKI treatment (63% vs. 13% in the tivozanib arm) particularly
with tivozanib (as part of the study). Although neither axitinib nor tivozanib were approved by the FDA for
the first line setting, both of these agents have improved PFS compared to sorafenib in the second or later
lines of therapy (leading to their FDA approval) and because of their improved therapeutic index related to
their more selective targeting of the VEGF axis, they might offer advantages as backbones for combination
regimens [32,33] .