urinary Cancer 2018 Oct 16(5) 355-359) reporting on 846
patients, showed striking differences in the survival of
intermediate-favorable patients (one risk factor =34 mos
OS),real-intermediate (2 risk factors= 20 mos OS) and
poor-intermediate (> 2 risk factors = 9 mos OS). This was
first proposed by Sella et al (CGC 2017), and thus seems
to be an important refinement of the MSKCC and IMDC
risk groups. However, the studies did use retrospective
analyses of sunitinib and pazopanib trials, not immunotherapy
trials. Thus, if the studies are imbalanced in
regards to these subgroups, differences in outcomes could
be expected.
Q: In looking at the pivotal studies presented at GU
ASCO, to what extent do various discrepancies in patient
characteristics among the trials tend to skew the results
and what’s the impact, if any?
Dr Vogelzang: When you review the results of the three
studies, we cannot really explain these differences because
the studies did not subdivide the intermediate risk groups.
All the studies were well balanced, large studies, but to
some extent it depends on where the studies obtained the
patients. In the US, patients generally present earlier than
patients in Eastern Europe and Russia and may have fewer
poor risk features. Also there is likely to be more thirdline
and fourth line treatments which may impact OS
Q.: So what was the impact of GU ASCO on your practice?
When you returned to your office and the next metastatic
RCC patient walks in the door, what’s your plan?
Dr Vogelzang: At various roundtables held outside the
symposia’s agenda for attendees, I made the point and
others tended to agree that nivo-ipi is readily available
and has a survival advantage for all three of the risk
groups—good, intermediate, and poor risk, based on
CheckMate 214. If you then look at avelumab/axitinib
which did not yet have that advantage and which is still
pending FDA approval, we all started looking at the side
effect profiles. Avelumab/axitinib, for example, had fewer
side effects than nivo-ipi which in turn appeared to have
fewer side effects than pembrolizumab/axitinib.
Q: But don’t you need to tolerate the side effects to obtain
benefit?
Dr Vogelzang: Yes, maybe, but for the good risk patients,
I’m not sure we need to have side effects because patients
do reasonably well with a TKI. Remember, sunitinib and
pazopanib are still very good drugs for good-risk patients.
Q: If a community oncologist asked you for a summary
of sorts, what take-home messages would you suggest?
And what are the key factors to be mindful of as you
define and refine your strategies?
Dr Vogelzang: For my good risk and favorable-intermediate
patients I’m probably going to use the VEGF
inhibitor axitinib upfront with either pembrolizumab or
avelumab. A lot of it depends on what drugs are covered
by what health plan. For the unfavorable-intermediate
group and for the poor risk group I’m going to use nivoipi.
So there is this refinement in my thinking going on.
If you think about the biology of this disease, perhaps the
patients with the bad genetics (BAP deletions) or more
significant mutational burdens, will probably need a
bigger immunological hit, therefore, nivo-ipi. Those patients
with small deletions in 3p, and VEGF driven, will
probably do extremely well with axitinib and a
checkpoint inhibitor.
Q: A poster at GU ASCO examined the use of nivo-ipi after
nivolumab alone. Is there likely to be an advantage in
that subset?
Dr Vogelzang: There were definite responses there, and it
suggests that the combo of nivo-ipi has some advantages
over nivo alone. I am not sure how much of an advantage
but there is some benefit there. However, toxicities are
higher with nivo-ipi. Nevertheless, the duration of response
may be better with the combination compared to
nivo alone. That comparative study should be done.
Q: Let’s return to the issue of prognostic factors and how
to more effectively drill down and integrate them into
decision making with all these combinations available.
What do you foresee happening in this regard?
Dr Vogelzang: Ultimately we will get a prognostic signature.
The prognostic signature will be, how good is good
and how poor is poor? On this spectrum from very good
to very poor we will need to position our thera-peutic
agents. I always tell my colleagues, you have no idea who
is going to walk in the door the next day. When you see
these patients, they are ‘disasters’ from a clinical perspective.
In these cases, it should probably be a de-cision
to give these patients nivo-ipi. But you may not want to
wait long enough to get the insurance approval. You may
want to start them on a TKI immediately, just to put out
the fire in these patients. This is where the cancer is just
blowing up.
Q: Which TKI?
Dr Vogelzang: Based on what I’ve seen, I usually try to get
axitinib or cabozantinib, but remember, axitinib by itself
does not have first-line indication. I’ll need to put in the
order for axitinib/avelumab or axitinib/pembrolizumab
and hopefully not wait too long to get the drugs approved.
Every insurance company makes you wait three
days for no good reason. So ultimately, the decision often
comes down to mundane, nitty gritty details, like, how
long is it going to take to get these drugs approved? What
are the underlying immunological side effects? Are you
comfortable giving nivo-ipi to someone with possibly
underlying autoimmune disease? There’s a certain granular
aspect to the process of making these choices and I
literally do not always know the obvious thing to do. For
financially challenged people, the co-pays are important.
I will write a prescription for one of the high-cost drugs
and I’ll tell the patient, “I hope you get it in two weeks.”
That may be fine for a good risk patient but in poor risk
patients I don’t want to wait two weeks where the average
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