genes with higher risk of disease recurrence, with the
strongest effects observed in the placebo arm.15
PROTECT: Evidence Suggestive of a Relationship
Between Outcomes and Dose Intensity
One of the unresolved issues from the ASSURE and STRAC
trials remains the importance of dose intensity and
whether maintaining it can result in an improvement in
DFS. The PROTECT study pursued this avenue as it provided
more data on the relationship between dose and
benefit and whether adjustments in exposure to pazopanib
could have a significant impact. The PROTECT
study evaluated the efficacy of pazopanib as an adjuvant
therapy for patients with locally advanced RCC at a high
risk of relapse after surgery. The primary objective of the
study had to be amended to examine DFS in a cohort that
received a reduced dose of pazopanib (600 mg daily instead
of the initial 800 mg) due to toxicity.16 In the 600
mg cohort, a DFS benefit for pazopanib over placebo was
not observed. Although a DFS benefit was observed in the
sustained 800 mg cohort, it was not considered tolerable.
Sun et al introduce the intriguing concept of whether the
potential benefit of adjuvant therapy is not completely
driven by the starting dose of the drug but rather by
blood concentration levels.
This was the focus of another recent report by Sternberg
et al17 who evaluated the relationship between pazopanib
exposure (Ctrough) and efficacy and safety. One of
the issues elucidated in this report is whether higher pazopanib
exposure as indicated by Ctrough values could improve
DFS without increasing treatment discontinuations
of grade 3 and 4 AEs. Sternberg et al found that higher
pazopanib exposure was associated with an improved DFS
without an increase in the AEs. The analysis also reviewed
pharmacokinetic simulations showing overlapping pazopanib
exposure with 600 and 800 mg doses. Therefore,
some patients achieve higher pazopanib exposure—associated
with improved DFS—regardless of whether the
starting dose is 600 or 800 mg. Clearly, further study is
needed to delineate to what extent the potential benefit
of adjuvant therapy is driven by a pharmacokinetic benefit
rather than by dose. An additional issue up for debate
is whether the results from this study could be extrapolated
to sunitinib and other VEGFR receptor TKIs. If the
controversy over adjuvant therapy needed yet another
focus to stimulate debate, then the challenge has been issued.
Pooled Analysis, a Fourth Trial of Targeted
Therapy and Future Directions
Skeptics of S-TRAC can also point to another report by
Sun et al16 who took a different approach to examining
the data with a pooled analysis from ASSURE, S-TRAC and
PROTECT. This analysis, based on eight articles and five
studies of the three trials, revealed:
• No statistically significant effect between adjuvant
VEGFR-targeted therapy and improved DFS or OS in patients
92 Kidney Cancer Journal
with intermediate/high risk local or regional fully
resected RCC.
• No evidence that dose intensity could significantly improve
DFS. Any effect on DFS, they suggest, could be
too costly in terms of the toxicity experienced by a majority
of patients.
In April of 2018, Pfizer announced by press release that
the independent data monitoring committee for the
Phase III ATLAS trial (randomized to adjuvant axitinib for
up to 3 years vs placebo, NCT01599754) recommended
stopping the trial at a planned interim analysis due to futility.
18 This represented the fourth trial of adjuvant therapy
with a targeted therapy agent and the third to suggest
no benefit. However, the full results have not been presented
at a scientific congress, nor have they been published;
they are eagerly awaited. Three other ongoing
randomized clinical trials are evaluating the clinical benefit
of adjuvant targeted therapies, including SORCE (adjuvant
sorafenib vs placebo, NCT00492258), EVEREST
(adjuvant everolimus vs placebo, NCT01120249), and
E2810 (adjuvant pazopanib vs placebo in patients with
no evidence of disease following metastasectomy,
NCT01575548) (10).
Currently, there are several trials evaluating anti-PD-1
or anti-PD-L1 antibodies in the adjuvant setting: Check-
Mate 914 (combination of nivolumab and ipilimumab vs
placebo), PROSPER (nivolumab neoadjuvantly for 2 doses
then adjuvantly vs immediate nephrectomy then observation),
IMmotion 010 (atezolizumab vs placebo), and
KeyNote 564 (pembrolizumab vs placebo) (ClinicalTrials.
gov: NCT03138512, NCT03024996, NCT03142334,
NCT03055013). However, there are no combination adjuvant
studies of VEGF/VEGFR inhibition with PD-1 or
PD-L1 inhibition. The available data would support such
an approach in the adjuvant setting.
Conclusion
The landscape of adjuvant therapy remains unsettled and
many issues need to be resolved before a consensus can be
reached. Four pivotal trials, ASSURE, S-TRAC, PROTECT
and ATLAS, have provided discordant results as to
whether antiangiogenic therapy in the setting of locoregional
RCC can meet the endpoint of DFS. The question
of OS is also unresolved. The focus of the initial debate,
in large part related to selection of the high risk cohort,
dose intensity, independent radiographic review for the
DFS endpoint, histology, and independent pathologic review
of histology, has shifted as new reports highlight the
potential importance of biomarkers and pharmacokinetic
factors in determining the optimal approach. Maintaining
high-dose intensity has been the tenet of the pivotal
trials but it may no longer be the most important question
to be addressed. Ongoing trials, including the examination
of immune checkpoint inhibitor immunotherapies,
will need to address many of these concerns as
a consensus remains elusive.