Figure 1. Potential Mechanism for Tumor Flare Associated With Immunotherapy.
may be longer than what is typically seen for response
times when targeted therapies are used in RCC.2
Revisiting the RECIST Criteria
The standard for evaluating response has been the RECIST
criteria. In early 2017, the RECIST working group
developed a guideline of a modified RECIST 1.1 for immune
based therapeutics.7 Patterns of response based on
RECIST criteria include complete response (total remission
of all target and non-target lesions, including the
lack of appearance of new lesions; to be confirmed no
less than 4 weeks after the first assessment); partial response
(a decrease of at least 30% in the total tumor burden
compared to baseline; to be confirmed after at least
4 weeks); stable disease (the change of the total tumor
burden is reduced of less than 30% when compared with
baseline or increased less than 20% compared to baseline
or nadir); unconfirmed progressive disease (increase in
the total tumor burden of at least 20% compared to
nadir/ baseline; further confirmation at imaging is needed
to rule out PP); progressive disease (increase in the
total tumor burden of at least 20% when compared to
nadir confirmed by a further progression after 4–8 weeks
or appearance of new lesion).8
As new reports present emerging data on TBP, the RECIST
criteria have become the center of controversy as
to whether they should be followed for treatment guidelines.
When treatment response to immunotherapy is assessed
by these criteria, tumor flare occurring with an
agent like nivolumab will be viewed as disease progression.
When it is considered as progression, discontinuation
of treatment before the potential clinical benefit of
a check point inhibition is realized will yield diminishing
results. Thus, it is important to determine whether patients
receiving immunotherapy may still realize benefit
if treated beyond RECIST-defined progression.
Evidence for the appearance of pseudoprogression has
been documented in immunotherapy studies in which
treatment is associated with an initial tumor flare but reduced
tumor burden and shrinkage have been reported
later. When nivolumab therapy was used in melanoma
and non-small-lung cancer trials a subgroup of patients
70 Kidney Cancer Journal
treated beyond first progression
showed an uncommon
pattern of benefit relative to
another group not treated beyond
first progression.9-11
Pivotal Trials Verifying TBP
Several analyses, including results
from Phase 2 and 3 trials
and subgroup data, are providing
a more accurate picture of
clinical benefit derived from
TBP. In a study by George et
al,12 the authors presented a
subgroup analysis of a blinded,
randomized, multicenter, phase
2 trial to further delineate the
potential for reduction in tumor
burden after RECIST-defined
first progression (Figure
2). This subgroup analysis continued the line of investigation
in the initial assessment when some patients had
sustained reductions or stabilization in the size of their
target lesions.13 The analysis is important for several reasons:
1) it further elucidates the hypothesis that immunologic
treatment may induce infiltration of immune
cells and inflammation of the tumor, thereby increasing
tumor size as measured objectively by imaging; (2) the
transient growth of tumor during this time may result in
a decrease in RECIST-defined PFS but not necessarily OS;
and (3) it calls attention to the hypothesis that RECISTdefined
progression may not necessarily be a marker for
biologic disease progression, at least during this initial
phase. This leads to proposed immune-related response
criteria (irRC) that could be used to better characterize
patterns of response observed with immunotherapies.6
In the subgroup analysis by George et al, 154 of 168
patients were randomized to nivolumab in the Checkmate
010 trial; 36 were treated beyond progression, 26
were treated beyond first progression for 6 weeks or less,
and 92 were not treated beyond first progression.12
Of the 36 treated beyond first progression, 25 demonstrated
reductions in tumor burden or stabilization in the
size of target lesions after first progression. Thus, the
analysis offers compelling evidence that sustained reductions
in tumor burden or stabilization in the size of target
lesions can be achieved if nivolumab treatment is continued
after initial disease progression in mRCC is
observed.
CheckMate 025 Confirms Value of TBP
If one were looking for Phase 3 results to further delineate
the value of TBP then CheckMate 025 provides significant
data from a large pivotal study. From this
landmark study by Escudier et al,14 a subgroup analysis
addressed similar questions on treatment in 406
nivolumab-treated patients, 316 of whom had progressed
by RECIST criteria. Treatment beyond progression was
defined as treatment for at least 4 weeks after first progression
The key “take-away” messages from CheckMate
025 are:
• Patient TBP with nivolumab had additional clinical