Kidney Cancer Journal 83
from this study showed that over 80% did have a prior
nephrectomy. We do not know how that ultimately plays
into things. In terms of the population, if you look at the
the combination, the benefit was seen in all subgroups.
The majority of subjects, over 60%, were intermediate
risk. If you have patients who need a robust and relatively
rapid response—the median time to response was
2.5 months—it represents a great option. With the
Checkmate 214 data for ipi/nivo (ipilimumab/nivolumab)
demonstrating a benefit in intermediate and poor
risk patients, our standard for favorable risk patients remained
sunitinib. Now, with the combination data for
avelumab/axitinib we have benefit in favorable risk patients
as well. This approach now represents a standard
of care in the IMDC favorable risk group as well as in
patients with intermediate and poor risk disease.
Dr Figlin: Do you use existing risk stratification systems
(ie: IMDC, MSKCC), others) in making this assessment?
Dr Milowsky: We use the IMDC groups in the clinic for
prognostication. With newer therapies, this is likely to
change with the potential for additional variables to include
within these models. In the context of IO therapies,
the future is likely to include new predictive and
prognostic models.
Dr Figlin: Is PD-L1 scoring useful in deciding how best to
use this regimen?
Dr Milowsky: Initially the JAVELIN study was designed differently
based on a phase 1b study that showed there was
a higher percentage of patients with high PD-L1 expression
benefiting from avelumab and axitinib. The primary
endpoint of the JAVELIN Renal 101 Study was subsequently
changed to look specifically in patients with
high PD-L1 status. There was a benefit in the high PDL1
group but there was also a benefit in the overall population.
Based on JAVELIN 101, PD-L1 status should not
be used to guide treatment decisions unless we see additional
information such as more mature survival data
that could change this interpretation. Dr. Choueiri et al
presented an important biomarker analysis from JAVELIN
101 at the ASCO Annual Meeting 2019 looking at
PD-L1 expression, tumor mutational burden, T-cell subsets,
and immune gene expression signatures. This type
of work will help guide us in the future.
Dr Figlin: Are there specific sites of metastasis (ie, brain,
bone, other) that would make you less likely to use this
regimen?
Dr Milowsky: Within the context of this study, there was
no clear information to suggest that site of disease should
guide therapy with the combination. Over 50% of patients
had at least two sites of disease. The study excluded
patients with active CNS metastases. We would use the
combination in patients with treated CNS metastases.
The study excluded active autoimmune disease and we
need to be cautious in patients with autoimmune
disease. The study does not speak to a particular patient
population that should or shouldn’t be treated. The real
question is: are there patients that benefit more from IOIO
therapy vs IO-TKI?
Dr Figlin: Are there specific co-morbidities that would
make you less likely to use this regimen?
Dr Milowsky: In general, it is a regimen that is very usable.
The study, however, excluded active autoimmune disease
and again we need to be cautious about the use of IO in
patients with active autoimmune disease or in the case
of VEGFR TKI therapy, in patients with difficult to control
hypertension as one example. Overall, the toxicity
is manageable.
COMBINING PEMBROLIZUMAB AND AXITINIB
Dr Figlin: In the ever changing landscape for the management
of advanced RCCA, please summarize the key takeaways
from the recent Keynote-426 data on pem-
bro/axitinib in the front line setting?
Dr Powles: The key messages are that this randomized,
frontline, phase 3 trial, which enrolled all comers, was
the first trial to show a response rate of progression-free
survival and overall survival advantage. And it was associated
with a 47% reduction in the risk of death and a
PFS of just over 15 months. Putting that together is an
exceptionally good result. The drugs seem to work in
good, intermediate and poor-risk patients, in all risk
groups.
Dr Figlin: What populations of patients are best suited for
this approach in your practice?
Dr Powles: The regimen is suited for all risk groups or PDL1
status. It is an all comers-type approach.
Dr Figlin: Do you use existing risk stratification systems
(ie: IMDC, MSKCC, others) in making this assessment?
Dr Powles: We do not need to do that. It’s useful from a
patient perspective to know which group they are in. Essentially,
what we see from this trial is that the drugs
(pembrolizumab and axitinib) seem to work whether
across the board and seem to work particularly well in
poor-risk patients.
Dr Figlin: Is PD-L1 scoring useful in deciding how best to
use this regimen?
Dr Powles: No, not really. In the competitive arm it suggests
that ipi/nivo is more suited to the intermediate and
poor-risk patients and as a biomarker it may be important.
Dr Figlin: Are there specific sites of metastasis (ie: brain,
bone, other) that would make you less likely to use this
regimen?
Dr Powles: There do not appear to be subgroups in which
it is ineffective.
Dr Figlin: Are there specific co morbidities that would