vival seen with either sunitinib or sorafenib as compared
to placebo from the double-blind randomized ECOG
2805 study that evaluated a subgroup of non-clear cell
patients (550 of 1943) with localized RCC post nephrectomy.
30 In high-risk patients with medullary, or collecting
duct carcinoma, adjuvant platinum-based chemotherapy
should be considered.31
For patients with advanced recurrent or metastatic disease,
the treatment of choice is systemic therapy. Although
there have been significant advances in the
treatment of metastatic RCC in the post-cytokine era, the
majority of studies to date have mostly involved clearcell
RCC with a subset of patients with non-clear cell histology.
It is noteworthy to mention that the efficacy of
the same agents in non-clear cell RCC is reduced with decreased
response rates and shorter durations of response.30
Given the fatal disease and the lack of randomized clinical
trials as well as no specific FDA approvals, the general
approach to management of non-clear cell metastatic
RCC is similar to that of clear cell; however subtype specific
clinical trials are evolving (Table 4).
Papillary
The phase II ASPEN trial is one of the largest trials that
support the use of VEGF inhibitors in papillary cancer
(Table 2). In this study 108 previously untreated nonclear
cell RCC patients (68 with papillary, 16 with chromophobe,
and 22 with unclassified) were randomized to
either sunitinib or everolimus. Median PFS, which was
the primary endpoint, was longer in patients assigned to
the sunitinib arm. Compared with everolimus, sunitinib
showed a longer PFS (8.3 vs 5.6 months), and higher objective
response (18% versus 9%). Interestingly, subgroup
analysis for the good and intermediate-risk group had
longer PFS (14 months versus 5.7 months for good risk
and 6.5 versus 4.9 months for intermediate-risk), compared
to the poor-risk group that had shorter PFS with
sunitinib compared with everolimus (4.0 versus 6.1
months).32
The ESPN trial is a phase two study that randomly assigned
treatment with everolimus or sunitinib to 73 patients
with metastatic non-clear cell RCC (27 papillary,
12 chromophobe, 7 translocation, 10 unclassified, and 12
sarcomatoid) with crossover to the other arm at disease
progression. The study concluded that everolimus was
not superior to sunitinib as both PFS and overall survival
did not show any statistical difference between the two
groups (16.2 versus 14.9 months) for the initial treatment
with sunitinib and everolimus respectively.33
RECORD-3 trial is a phase two study that compared
the sequence of sunitinib followed by everolimus versus
everolimus followed by sunitinib in first-line metastatic
RCC (including both clear cell and non-clear cell type. A
total of 66 non-clear cell RCC patients were included in
the analysis and there was a trend toward a longer PFS
with sunitinib as the initial treatment as compared with
everolimus (7.2 versus 5.1 months).34
A phase II PANORAMA trial of pazopanib in non-clear
22 Kidney Cancer Journal
cell RCC reported an 81% disease control rate and partial
responses in 27% of patients (10 of 37). Median PFS was
15.9 and OS were 17.2 months.35
In 2015, the SUPAP phase two study enrolled 61 patients
with metastatic papillary RCC (15 with type 1 and
46 with type 2) who were treated with sunitinib with results
showing overall survival of 17.8 and 12.4 months
and PFS of 6.6 and 5.5 months, in type 1 and 2 papillary
RCC, respectively.36 Subsequently, the phase 2 RAPTOR
trial in 2016 enrolled 92 patients with papillary RCC
treated with everolimus demonstrating an overall survival
of 21 months, and PFS of 3.9 months.37
A phase II trial that was presented in 2014 European
Organisation for Research and Treatment of Cancer-National
Cancer Institute-American Association for Cancer
Research (EORTC-NCI-AACR) included 41 patients with
papillary RCC who were treated with bevacizumab in
combination with erlotinib (an epidermal growth factor
receptor). This combination demonstrated a 30% objective
response rate both groups that had sporadic disease
and hereditary leiomyomatosis and renal cell cancer. The
median PFS was 24 months for those with hereditary
leiomyomatosis compared to only seven months with
sporadic papillary RCC.38
As discussed previously met oncogene plays a significant
role in papillary cancer. With that knowledge, several
clinical trials with MET directed-therapies have shown activity
in papillary RCC.
In a recent EORTC 90101 CREATE phase II trial, the
ALK-inhibitor crizotinib, which appears to have affinity
for MET kinase, has shown activity among MET-positive
papillary RCC type 1. Schöffski and colleagues treated 23
eligible patients out of 41. The response rate was 50% for
patients that were MET-positive (2 out of 4 patients) with
a mean treatment duration noted to be longer in the MET
altered cohort (11.9 versus 5.3 months).39
Additionally, a randomized phase II SWOG 1500 PAPMET
clinical trial will evaluate a total of 180 patients with
metastatic type 1 and type 2 papillary RCC to receive either
sunitinib, crizotinib, cabozantinib (a dual VEGFR2/
MET inhibitor), or savolitinib (a distinct and more specific
MET inhibitor). This study is currently ongoing and
recruiting patients.40
Foretinib is a multi-targeted TKI that targets MET and
VEGF receptors that has demonstrated some benefit in
papillary RCC based on a phase II trial that included 74
patients. The ORR was 13.5% and the median PFS was 9.3
months. However, the RR was 50% in patients with
germline MET mutation. The OS was 70% at one year.41
In a similar phase II trial that evaluated another MET
inhibitor, Savolitinib, for 109 patients with papillary RCC,
there was an ORR of 7% and tumor shrinkage in 20%.
For the 40% of patients with MET-driven disease, the ORR
was noted to be 18% (8 out of 44 patients) and tumor
shrinkage in 61%. The median PFS was 6.2 months compared
to 1.4 months with MET-negative papillary RCC
which was statistically significant with a hazard ratio of
0.33 in favor of MET-driven papillary RCC as compared to