preclude therapy. While overall, patients with favorable
risk disease did better with sunitinib in this study, the
CR rate was higher with nivo/ipi frontline. I’m not automatically
saying no to ipi/nivo in patients with favorable
risk disease. I’m looking at their presentation, at
co-morbidities, performance status. The number of patients
in the current era who would receive a single agent
TKI in the frontline space is limited. There is cabozantinib
as an option in this regard for those with bone metastases
based on the CABOSUN trial. But we need to
question the use of VEGF TKIs in the frontline space. The
current data support IO-IO combinations or IO-VEGF TKI
in the frontline.
Dr Figlin: Do you use existing risk stratification systems
(ie, IMDC, MSKCC) in making this assessment?
Dr Mckay: The MSKCC risk factors were validated in the
cytokine era. Now the IMDC system has been validated
in the TKI era. While it has not yet been validated with
use of IO therapy, it is nonetheless a critical risk stratification
to think about when you see a patient with metastatic
disease. Where I see the risk stratification system
coming in very handy is in thinking about the role of cytoreductive
nephrectomy in the context of patients with
metastatic disease. We’re being a bit more prudent in deciding
which patients derive benefit from upfront CN as
opposed to delayed CN. IMDC risk parameters really
come into play when thinking about starting a patient
on systemic therapy first or CN and system therapy later.
Overall, risk stratification systems are really helpful when
thinking about the integration of surgery with systemic
therapy for patients with advanced disease.
Dr Figlin: Is PD-L1 scoring useful in deciding how best to
use this regimen?
Dr Mckay: When reviewing the IO-IO and VEGF-IO trials,
each of these studies used a totally different assay to determine
PD-L1 expression status. The percentages of PDL1
expression based on the assays that were used varied
across the studies. For example, in CheckMate-214, PDL1
expression was seen in 24% of the total population
and in KEYNOTE-426 and JAVELIN 101 there were different
assays used, and the number was around 60% and
53%. We have a lot more to learn about the utility of PDL1.
And the other thing to consider is that the bulk of
these tests were done on archival nephrectomy specimens
as opposed to fresh biopsies at baseline. We know
that PD-L1 status is very dynamic and there are temporal
and spatial changes in this biomarker. PD-L1 is certainly
prognostic in RCC. Those who have PD-L1 expression do
worse than those without. However its role as a predictive
biomarker in RCC is still evolving.
Dr Figlin: Are there specific sites of metastasis (ie, brain,
bone, other) that would make you less likely to use this
regimen?
Dr Mckay: We know that patients with bone metastases
have historically done worse than those without bone
metastases. We have great data from the CABOSUN study
82 Kidney Cancer Journal
demonstrating efficacy of cabozantinib over sunitinib in
the frontline phase. And while that’s a phase 2 study, I
think there is rationale for using cabozantinib in the
frontline for those who have bone metastases that may
negatively impact their quality of life. Additional studies
are investigating IO combinations with cabozantinib in
the frontline. These studies will further inform management
of advanced RCC. Also, one more thing about patients
with brain metastases: we can learn from the
melanoma literature about the safety of IO therapies in
patients who have brain metastases.
Dr Figlin: Are there specific co-morbidities that would
make you less likely to use this regimen?
Dr Mckay: Patients who have underlying or concurrent
autoimmune disease—that would be a red flag. Currently,
a study is being conducted by the NCI looking at
immunotherapy in patients who have autoimmune
disease. We recently conducted a retrospective analysis
of patients with RCC who have autoimmune disease who
received IO therapy and we are reporting on their outcomes.
Management needs to be coordinated with rheumatologists
and other consultants to make sure the
risk/benefit ratio is sound.
COMBINING AVELUMAB AND AXITINIB
Dr Figlin: In the ever changing landscape for the management
of advanced RCCa, please summarize the key takeaways
from the recent data on avelumab/axitinib in
the frontline setting?
Dr Milowsky: In terms of the landscape in the frontline
setting for metastatic RCC, the benefit for avelumab/axitinib
was established in the JAVELIN Renal 101 Study.
886 patients were randomized to avelumab, a PD-L1 inhibitor
plus axitinib, a VEGF receptor TKI compared to
sunitinib, another VEGF receptor TKI. For the primary
endpoint of the study, there was a significant improvement
in progression free survival (PFS) in the PD-L1-selected
(defined as greater than or equal to 1% of the
immune cells staining positive) individuals. The PFS was
14 months for the combination vs 7 months for sunitinib
with an HR of 0.61 for progression or death. The benefit
was also seen in the overall population for ave-
lumab/axitinib over sunitinib. At this first pre-planned
interim analysis with a median followup of 11.6 months,
there was not a significant improvement in overall survival
for the combination with an HR of 0.788 (P=0.14).
Also important in this study is the response rate
which was substantially higher for patients who were
treated with the combination in both the PD-L1 selected
and overall population (55% in the PD-L1 selected avelumab/
axitinib group vs 25% for sunitinib). The tolerability
was similar to sunitinib including grade 3 adverse
events.
Dr Figlin: What populations of patients are best suited for
this approach in your practice?
Dr Milowsky: These are first-line patients, so they are previously
untreated and have advanced RCC. The data