Kidney Cancer Journal 23
the non-MET driven disease. Additionally, there were no
partial responses seen in the 46 tumors that were not
driven by MET.42 Currently, there is an ongoing phase III
SAVOIR trial, comparing savolitinib with sunitinib to determine
whether or not savolitinib has selective activity
in a MET-selected population (NCT03091192).43 There is
another randomized trial evaluating the clinical efficacy
of three distinct targeted therapies including volitinib
(MET inhibitor), cabozantinib (VEGF, MET, AXL inhibitor),
and crizotinib (ALK-1 and MET inhibitor) with
sunitinib as the comparator control arm (NCT02761057).44
If either of these studies is positive, it would herald a
change in the current standard of care for frontline treatment
in metastatic papillary RCC.
As the landscape of treatment for clear cell RCC has
shifted to immunotherapy due to the CheckMate 214
that suggested an OS advantage with the
combination of nivolumab/ipilimumab
over sunitinib in the first-line setting,
there is biological rationale to extrapolate
the activity of immunotherapy in
non-clear cell RCC. Choueiri et al. have
evaluated 101 patients with a variety of
non-clear cell subtypes and found varied
expression levels of PD-L1 in this cohort,
with 10% of papillary patients expressing
PD-L1 in tumor cells.45 Additionally,
A retrospective analysis with a PD-1 inhibitor,
nivolumab monotherapy, was
done for 41 patients with non-clear cell
histology that included 16 papillary, 14
unclassified, 5 chromophobe, 4 collecting
“In general, the current
treatment of choice for nonclear
cell RCC is a vascular
endothelial growth factor
(VEGF) receptor inhibitor
followed by a mammalian
target of rapamycin (mTOR)
inhibitor at the time of
progression. Immunotherapy
with checkpoint inhibitors
is not yet FDA approved for
non-clear cell RCC.”
duct, and 1 Xp11 translocation. There were 20% of
patients that had a PR and 29% with stable disease. Responses
were observed in unclassified, papillary, and collecting
duct subtypes which lend support to the use of
nivolumab for patients with non-clear cell RCC.59 Currently
there are studies of dual immuno- therapy that include
a non-clear cell arm that will provide additional
insight into the activity of checkpoint inhibitors in this
population. There are ongoing phase II studies with a PDL1
inhibitor, atezolizumab, in combination with a VEGF
inhibitor, bevacizumab, in patients with advanced nonclear
cell RCC (NCT02724878), thought no results have
yet been reported.46
Overall, for papillary RCC, VEGR-targeted therapies
seem to be the most effective first-line treatment for both
type 1 and type 2 papillary RCC. mTOR inhibitor, however,
has been shown to have activity in treating papillary
type RCC and can be used as a second-line therapy option.
Chromophobe
Both VEGF receptor inhibitors and mammalian target of
rapamycin (mTOR) inhibitors have been used to treat
chromophobe RCC. In the ASPEN trial, subgroup analysis
of chromophobe RCC demonstrated better clinical
outcomes with everolimus therapy.32 In 2008, a study
looked at 53 patients with non-clear cell RCC (41 with
papillary and 12 with chromophobe) treated with sunitinib
or sorafenib. The results for the 12 chromophobe
type RCC (7 treated with sunitinib and 5 with sorafenib)
showed a response rate of 25% to sunitinib or sorafenib,
PFS of 10.6 months (sorafenib treated group had a longer
median PFS of 27.5 months).47 In the ESPN trial, which
included 12 chromophobe RCC subtype, there was an objective
response rate of 2.8% and 6%, and overall survival
was 25.1 and 31.6 months for the everolimus and sunitinib
treated groups, respectively.33
Collecting Duct
Collecting duct RCC, due to its similarities with transitional
cell carcinoma, is treated with chemotherapy with
a platinum based regimen as well as with combination
chemotherapy and bevacizumab. In
2007, a phase two prospective multicenter
study evaluated 23 patients with
metastatic collecting duct carcinoma
treated with gemcitabine plus either cisplatin
or carboplatin. Results of the study
demonstrated an objective response of
26%, with a PFS of 7.1 months and an
overall survival 10.5 months.48 Another
study in 2013, enrolled 5 patients with
metastatic collecting duct RCC who were
treated with gemcitabine plus a platinum
based agent in addition to bevacizumab.
Three of the cases had partial
response, one with stable disease, and
another one with a complete remission.
Median overall survival was 27.8 months and PFS was
15.1 months.49
Medullary
Medullary RCC is typically treated with a platinum-based
chemotherapy regimen, but because it is such a rare disease,
data is still lacking to clearly support a first line regimen.
There are multiple case reports of medullary RCC
responding to combination chemotherapy with gemcitabine,
paclitaxel and a platinum agent.50-51 Treatment
with a topoisomerase II chemotherapy, such as etoposide
has shown efficacy based on a patient who achieved complete
response for 9 months after receiving a topoisomerase
II therapy.52 Another case report looked at two
patients with renal medullary carcinoma receiving combination
platinum-based therapy with bortezomib, a proteasome
inhibitor, with promising results: one patient
passing away 7 years after diagnosis, while another remains
disease free nearly 2 years from diagnosis.53 In
2004 a phase two study recruited 37 patients with
metastatic renal cell RCC (25 clear cell, 6 papillary, 1 collecting
duct, 1 medullary, and 4 unspecified) who were
treated with bortezomib.54 On a follow up report to this
study, the patient with medullary RCC received 7 months
of bortezomib, achieved a complete response, and remain
without evidence of disease after 27 months.55