Mini Review
New Perspectives in the Treatment of Advanced Kidney Cancer
Calvani N*, Orlando L, Fedele P, Lutrino SE and Cinieri S
Medical Oncology Division and Breast Unit, A. Perrino Hospital, Brindisi, Italy
*Corresponding author: Calvani Nicola, Medical Oncology Division and Breast Unit, A. Perrino Hospital, Brindisi, Italy
Published: 03 Aug, 2016
Cite this article as: Calvani N, Orlando L, Fedele P, Lutrino
SE, Cinieri S. New Perspectives in the
Treatment of Advanced Kidney Cancer.
Clin Oncol. 2016; 1: 1031.
Abstract
Treatment scenario of advanced renal cell carcinoma (RCC) has been characterized in the last
decade by the approval of a number of new drugs. Choice of first line treatment falls essentially
on sunitinib or pazopanib, two tyrosine kinase inhibitors (TKI), both exerting anti-tumor
activity through inhibition of neoangiogenesis. In the second line setting, nivolumab, an immune
checkpoint inhibitor antibody, has been shown to prolong overall survival (OS) vs. the mTOR
inhibitor everolimus by restoring the adaptive anti-cancer immune response. Cabozantinib, a multi
target TKI, may also get use in second line based on OS advantage vs. everolimus although toxicity
appears substantial. The TKI axitinib remains still a viable option. Finally, combination therapy
seems a very promising area and is under frenetic investigation in those patients progressing or
refractory to angiogenesis inhibition as well as in first line setting.
Keywords: Renal cell carcinoma; Nivolumab; Anti-PD-1 antibody; Cabozantinib; Tyrosine
kinase inhibitor
Introduction
Worldwide incidence of renal cell carcinoma (RCC) is 338,000 of new cases per year with 30% of
patients presenting with metastatic disease at diagnosis [1,2]. After almost 25 years of silence since
the first use of cytokines in early 1980’s, treatment scenario of advanced RCC has been characterized
in the last decade by the frenetic approval of a number of new drugs. Choice of first line treatment
falls essentially on sunitinib or pazopanib. Both are tyrosine kinase inhibitors (TKI) of vascular
endothelial growth factor receptor (VEGFR) pathway and exert anti-tumor activity through
suppression of neoangiogenesis. Sunitinib is the standard whereas pazopanib seems to be not
inferior in terms of efficacy and apparently less toxic as shown by the head-to-head COMPARZ trial
[3]. However, several methodological aspects have raised doubts about the reliability of this study.
The indication of anti-VEGF bevacizumab plus interferon alpha has been actually overcome by
clinical practice [4]. Same thing happened to the mTOR inhibitor temsirolimus in poor prognosis
patients whereas tumors with non clear cell histology are a separate category and require further
investigations [5].
What happens to those patients progressing or refractory to VEGFR inhibition? At least half
of them starts a second line treatment and even 15% a third line. Among TKIs, axitinib is better
than sorafenib after first line sunitinib whereas the mTOR inhibitor everolimus exerts its activity
after one as well as after two TKIs [6,7]. Toxicities to first line TKI and disease burden may drive
the choice. Everolimus has a toxicity profile quite different from TKIs but you won’t give it to your
patient if you need significant tumor shrinkage to control symptoms. Finally, there is an unmet
need for treatment of RCC patients who progress after treatment with VEGF targeted therapies and
mTOR inhibitors.
In daily practice we learned how to sequence all available drugs pursuing the slogan “use them
all but use them well” to optimize treatment and provide to our patients longer progression-free
survival (PFS) intervals along with a better quality of life. However, none of the above mentioned
agents taken individually has been shown to significantly increase the overall survival (OS) of RCC
patients. This was the story, at least until late 2015 when data on nivolumab and cabozantinib
started to be released.
Programmed death-1 (PD-1) inhibition to restore the adaptive immune response
against RCC
Immune-oncology is one of the most exciting areas in cancer research today. This is especially
true in kidney cancer traditionally linked to immunotherapy studies,
which led in 1992 to the approval of high dose IL2 due its ability to
induce durable responses in a small percentage of patients [8]. The
immune system is capable of recognize and eliminating tumor cells
through a complementary network of self-defense. The innate immune
response is the first line of defense; it identifies and attacks tumor cells
without antigen specificity. Natural Killer cells are the main effector
cells of innate immunity. However, a durable response that attacks
tumor antigens is induced by the adaptive immune response. Once
activated, it can be sustained through a memory response. Cytotoxic
T cells are the main effectors cells of adaptive immunity. Tumor cells
can use various mechanisms to escape detection and enable growth.
Pathways that can be modulated to restore the adaptive immune
response are currently under frenetic investigation in RCC.
Nivolumab is a fully human IgG4 PD-1 immune checkpoint
inhibitor antibody that selectively blocks the interaction between
PD-1, which is expressed on activated T cells, and PD-1 ligand 1
(PD-L1) and 2 (PD-L2), which are expressed on immune cells and
tumor cells. Interaction between PD-1 and PD-L1 or PD-L2 normally
results in inhibition of the cellular adaptive immune response. It has
been postulated that disruption of PD-1/PD-L1 signaling mediated
by nivolumab leads to restored antitumor immunity [9]. Checkmate
025 is the nivolumab pivotal study in RCC [10]. This study is an openlabel
phase III trial in which 821 advanced or metastatic patients
progressing to one or two regimens of antiangiogenic therapy were
randomly assigned (1:1 ratio) to receive 3 mg of nivolumab per Kg of
body weight intravenously every 2 weeks or a 10-mg everolimus tablet
orally once daily. Seventy-two percent of patients received only 1
prior antiangiogenic drug before the study entry in both arms, mostly
sunitinib. Primary endpoint was OS. Patients treated with nivolumab
had a 27% reduction in the risk of death as compared to those treated
with everolimus. Median OS was 25 months with nivolumab and
19.6 months with everolimus. Survival benefit with nivolumab was
observed regardless of number of prior antiangiogenic treatments
and PDL-1 expression but not in the subgroup of patients aged ≥75
years (about 10% of study population). Objective response rate (ORR)
was higher with nivolumab than with everolimus, namely 25% vs. 5%.
Median time to response was 3.5 months among patients responding
to nivolumab vs. 3.7 months in the everolimus responding group
of patients. Median PFS was almost the same, namely 4.6 months
in the nivolumab group and 4.4 months in the everolimus group.
However, the late separation of PFS curves suggests a potential
delayed benefit in PFS with nivolumab, which probably contributes
to the OS benefit. Patients receiving subsequent treatments were
lesser in the nivolumab group as compared to the everolimus group,
namely 55% vs. 63%. Anti–PD-1 therapy was given as subsequent
therapy to only 7 patients in the everolimus group thus reducing the
potential confounding bias of crossover. Moreover, treatment with
nivolumab beyond progression can be associated with late tumor
shrinkage after first progression especially in those patients with
good performance status and less bulky tumor burden [11]. This is
not unexpected since immunotherapy response patterns differ from
traditional therapies, and patients may benefit from treatment after
initial RECIST progression. Finally, long-term OS results from phase
I and II nivolumab studies have been recently reported with about
one-third of patients treated with nivolumab alive at 5 years in the
phase I study and 3 years in the phase II study [12].
Nivolumab has proven to be a very well tolerated treatment
in RCC patients with specific adverse events mostly reflecting
its immune stimulating activity. In the Checkmate 025 trial the
most common treatment-related adverse events among patients
treated with nivolumab were fatigue, nausea, and pruritus. Grade
3 or 4 treatment-related adverse events occurred in 19% of patients
treated with nivolumab and in 37% of patients treated with
everolimus. Treatment-related adverse events leading to treatment
discontinuation occurred in 8% of patients treated with nivolumab
and in 13% of patients treated with everolimus.
Targeting multiple tyrosine kinases involved in RCC
pathogenesis to overcame resistance
Mechanisms of resistance to first line TKI are various. In
particular, increased expression of the oncogenes MET and AXL
has been implicated in the development of resistance to VEGFR
inhibitors in preclinical models of several cancers including RCC
[13] and drugs targeting these multiple pathways are now under
investigation. The most promising of these drugs is cabozantinib, an
oral small-molecule inhibitor of tyrosine kinases, including MET,
VEGFR and AXL.
METEOR is a randomized, open-label, phase III clinical trial
comparing cabozantinib to everolimus in patients with advanced RCC
that had progressed after VEGFR/TKI therapy [14]. A total of 658
patients were randomly assigned (1:1 ratio) to receive cabozantinib
60 mg orally once daily or everolimus 10 mg orally once daily. About
70% of patients received only 1 prior antiangiogenic drug before the
study entry in both arms, mostly sunitinib. Primary endpoint was PFS.
The rate of progression was 42% lower with cabozantinib than with
everolimus with a median PFS of 7.4 and 3.8 months, respectively.
The ORR was 21% with cabozantinib and 5% with everolimus.
The secondary endpoint of improved OS for cabozantinib-treated
patients was met as recently reported [15]. The median OS was
21.4 months for cabozantinib vs. 16.5 months for everolimus, with
a 33% reduction in the rate of death. OS benefit with cabozantinib
was observed regardless of number of prior antiangiogenic and anti-
PD-1/PD-L1 treatments, as well as tumor MET expression level. In
summary, cabozantinib is the only agent to demonstrate a significant
benefit in OS, PFS, and ORR in a phase III trial in previously treated
patient with advanced RCC.
Toxicity is an “issue” with cabozantinib and dose reductions
occurred in 60% of patients treated with cabozantinib and 25%
treated with everolimus enrolled in the METEOR trial. The most
common adverse events (any grade) leading to dose reductions with
cabozantinib were diarrhea, the palmar-plantar erythrodysesthesia
syndrome, and fatigue. Incidence of adverse events of grade 3 or 4
was 68% with cabozantinib and 58% with everolimus. However, rate
of treatment discontinuation due to adverse events potentially drugrelated
was similar, namely 9% in the cabozantinib group and 10% in
the everolimus group.
Table 1
Conclusion and Future Direction
Table 1 resumes the new options we have to treat metastatic RCC
patient’s refractory or progressing to first line VEGFR inhibition.
Nivolumab is likely to be the second line standard of care based on OS
advantage and tolerability. Cabozantinib may also get use in second
line although toxicity appears substantial whereas axitinib remains
still a viable option.
What’s next? Combination therapy seems a very promising area
and data on combination of everolimus with lenvatinib, a multiple
TKI against VEGFR1, VEGFR2 and VEGFR3, have been recently
reported in the second line setting [16]. OS and PFS were 25.5 and
12.8 months, respectively, with 35% ORR. However, efficacy results
were not matched by a good tolerability profile and incidence of
adverse events of grade 3 or 4 was 71%. Combinations of nivolumab
with cabozantinib in patients with genitourinary cancers, including
RCC, are currently being investigated (ClinicalTrials.gov number,
NCT02496208).
Checkmate 016 is a phase I study designed to evaluate safety,
effectiveness and best dose of nivolumab in combination with
sunitinib, pazopanib or ipilimumab in RCC patients who did not
receive any prior treatment for metastatic disease (ClinicalTrials.gov
number, NCT01472081). Checkmate 214 is a phase III, randomized,
study of nivolumab combined with ipilimumab vs. sunitinib in
previously untreated advanced RCC (ClinicalTrials.gov number,
NCT02231749). Both these studies will tell us if nivolumab may move
to the first line setting. Other combination trials focusing on first line
setting are currently enrolling. In particular, a phase I/II study aimed
to evaluate the combination of pazopanib with pembrolizumab,
another PD-1 immune checkpoint inhibitor antibody (ClinicalTrials.
gov number, NCT02014636), and JAVELIN Renal 101 a phase III
randomized study evaluating avelumab, an anti-PD-1L antibody, in
combination with axitinib vs. sunitinib (ClinicalTrials.gov number,
NCT02684006).
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