Page 49 - Read Online

Sawhney et al. J Cancer Metastasis Treat 2021;7:48 https://dx.doi.org/10.20517/2394-4722.2021.64 Page 5 of 9

The ASSURE trial, which was the first VEGFR inhibitor trial to report, evaluated sunitinib and sorafenib in
the setting of high-grade, T1b or greater, completely resected non-mRCC. The study randomized 1943
patients to sunitinib, sorafenib, or placebo. There was no survival benefit seen with either agent, but a
[17]
significant treatment discontinuation rate occurred despite dose reductions as a result of toxicity . Median
DFS was 5.8 years for sunitinib with a HR of 1.02 (97.5%CI: 0.85-1.23, P = 0.8038) and 6.6 years for placebo.
Sorafenib also failed to show benefit with a median DFS of 6.1 years (HR = 0.97, 97.5%CI: 0.80-1.17, P =
0.7184). The treatment discontinuation rate due to AEs was 44% for patients who received sunitinib, and
this was a common theme across all VEGFR TKI adjuvant trials, which had higher rates of treatment
discontinuation due to treatment-related AEs, in terms of both frequency and severity, than when the same
drugs were investigated in the metastatic setting [13-16] .

The S-TRAC randomized phase 3 trial evaluated sunitinib in the setting of locoregional, high-risk ccRCC
after nephrectomy. It enrolled 615 patients who were randomized to receive either sunitinib or placebo.
Median DFS was 6.8 years (95%CI: 5.8 to not reached) in the sunitinib cohort vs. 5.6 years (95%CI: 3.8-6.6)
in the placebo cohort (HR = 0.76, 95%CI: 0.59-0.98, P = 0.03), demonstrating DFS benefit. However, it is
notable that the DFS benefit came at the expense of toxicity with 34.5% of patients in the sunitinib group
requiring dose reductions due to AEs vs. 2% of patients receiving placebo. Similarly, dose reductions
occurred more frequently in the sunitinib group at 34.3% vs. 2%, as did treatment stoppage at 28.1% vs.
5.6%, respectively. The sunitinib group also had a higher frequency of Grade 3 or 4 AEs at 48.4% for Grade 3
[18]
and 12.1% for Grade 4 vs. 15.8% and 3.6% in the placebo cohort, respectively . Although the trial failed to
demonstrate an OS benefit, based on the DFS data, sunitinib was FDA approved in November 2017 for
adjuvant treatment in high-risk adult patients.

The PROTECT randomized phase 3 trial evaluated pazopanib in the setting of high-risk, locally advanced
RCC after nephrectomy. It enrolled 1538 patients who were randomized to receive pazopanib or placebo for
one year. The initial starting dose of 800 mg pazopanib had to be reduced to 600 mg because of a high
treatment discontinuation rate, echoing the problems encountered in the ASSURE trial. Once again, in a
TKI trial, DFS analysis showed no benefit of pazopanib over placebo. Treatment discontinuations as a result
of AEs were 35% and 39% in the pazopanib 600 and 800 mg groups in comparison with 5% and 6% for the
placebo 600 and 800 mg groups, respectively .
[19]

The ATLAS randomized phase 3 trial evaluated axitinib in the setting of locoregional RCC at risk of
recurrence after nephrectomy. The study enrolled 724 patients who were randomized to receive axitinib or
placebo. The trial did not meet its primary endpoint of DFS, and there were more Grade 3 or 4 AEs in the
axitinib group vs. placebo, 61% vs. 30%, respectively. With axitinib vs. placebo, the AEs led to dose
reductions in 56% vs. 8% of patients, dose interruptions in 51% vs. 22%, and permanent treatment
discontinuation in 23% vs. 11%, respectively. However, in the highest-risk sub-group, a 36% reduction in
risk of DFS events was observed per investigator (HR = 0.641, 95%CI: 0.468-0.879, P = 0.0051), once again
highlighting the importance of patient stratification .
[20]
The SORCE phase 3 trial enrolled 1711 post-nephrectomy RCC patients with intermediate to high risk of
recurrence who were randomly assigned to receive three years of placebo, one year of sorafenib followed by
two years of placebo, or three years of sorafenib. No differences in DFS in all groups or subgroups were
found. Moreover, despite treatment adaptations, over half the patients stopped their treatment by 12
months, with 24% of patients who received sorafenib reporting Grade 3 hand-foot skin reactions. In
addition, the restricted mean survival time was 6.81 years for three years of sorafenib vs. 6.82 years for
placebo (95%CI: 0.49-0.48 years, P = 0.99) . As the latest of all the VEGFR TKI trials to report, SORCE
[21]