KCJ MEDICAL INTELLIGENCE
FDA Approves Tivozanib as First Therapy for a Relapsed/Refractory Advanced RCC Subgroup
The first therapy for adults with relapsed or refractory advanced renal cell carcinoma who have received two or more prior systemic therapies has been granted approval by the FDA. This US FDA approval was granted based on the data from the phase 2 TIVO-3 clinical trial (NCT02627963). TIVO-3 is a controlled, multicenter, open-label, phase III trial of 350 patients with highly refractory metastatic RCC who had failed ≥2 prior regimens, including VEGF TKI treatment.
Lead investigator Dr. Brian Rini of this trial
(NCT02627963) along with other senior investigator Dr. Thomas
Hutson discussed the TIVO-3 outcomes and prospect of
tivozanib for combinatorial therapy with other IO agents (See
Page 4: Roundtable Discussion Section in this issue).
Results that the hazard ratio for overall survival (OS)
with tivozanib versus sorafenib was 0.97 (95% CI, 0.75-1.24;
P =.78). The median OS in the tivozanib arm was 16.4 months
(95% CI, 13.4-22.2) and 19.2 months in the sorafenib arm (95%
CI, 15.0-24.2). The study included a subgroup of patients who received
previous checkpoint inhibitor and VEGF inhibitor therapy,
and in this population, the HR for death was 0.55 and was 0.57
for those who received 2 prior checkpoint or VEGF inhibitors. In
terms of response, tivozanib led to an 18% (95% CI: 12%-24%)
overall response rate compared with 8% (95% CI: 4%-13%) in the
sorafenib arm. Tivozanib appeared to have a favorable safety profile
during the study. Treatment-related adverse events (TRAEs)
were observed in 84% compared with 94% of the sorafenib arm.
Serious TRAEs were observed in 11% of the patients who received
tivozanib compared with 10% of those treated with sorafenib.
Reference: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE,
Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in
patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre,
randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104.
PMID: 31810797. On January 22, 2021, the Food and Drug Administration
approved the combination of nivolumab (Opdivo, Bristol-
Myers Squibb Co.) and cabozantinib (Cabometyx, Exelixis)
as first-line treatment for patients with advanced renal cell
carcinoma (RCC). The approval of nivolumab/cabozantinib
combination regimen is based on findings from the phase 3
CheckMate-9ER trial (NCT03141177). Results indicated that
the combination reduced the risk of disease progression or death
by 49% versus sunitinib (Sutent) in treatment-naïve patients with
advanced RCC, with a median progression-free survival of 16.6
months versus 8.3 months, respectively (HR, 0.51; P <.0001). The
objective response rate (ORR) was also doubled with nivolumab/
cabozantinib in this setting compared with sunitinib, at 55.7%
versus 27.1%, respectively (P <.0001). In the combination arm,
the complete response (CR) rate was 8.0%, the partial response
(PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%.
Additionally, 5.6% of patients had progressive disease (PD) and
6.5% were not evaluable or not assessed. In the sunitinib arm, the
CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively.
Regarding safety, the incidence of the most common,
any-grade and high-grade treatment-related adverse events
(TRAEs) were similar in both arms. The overall rate of serious
AEs was similar between the 2 groups; however, liver toxicity was
more common with cabozantinib/nivolumab. Nineteen percent
of patients on the combination required corticosteroids due to
immune-related AEs, 4% of whom needed corticosteroids for at
least 30 days.
Reference: Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib
vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results
from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract
696O. Reference: Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study
of the oral HIF-2alpha inhibitor MK-6482 for Von Hippel-Lindau disease–associated
renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5003. doi:10.1200/
JCO.2020.38.15_suppl.5003. Reference: Tannir NM, Signoretti S, Choueri TK, et al. Efficacy and
safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients
with advanced sarcomatoid renal cell carcinoma. Clin Can Res. Published
Online January 2021. Accessed February 3, 2021. https://bit.ly/36W2gSr. Reference: Bi, K., et al. (2021) Tumor and immune reprogramming during immunotherapy
in advanced renal cell carcinoma. Cancer Cell. doi.org/10.1016/j.
ccell.2021.02.015.
FDA approves nivolumab/cabozantinib combo for frontline kidney
cancer
FDA Grants Belzutifan Priority Review for VHL-Associated
RCC./
The novel, selective HIF-2 alpha inhibitor belzutifan
was granted a priority review by the FDA for the treatment of
patients with VHL–associated RCC who do not require immediate
surgery. The primary end point of the study is ORR in
VHL disease–associated RCC tumors and secondary end points
include DOR, TTR, PFS, and time to surgery (TTS) in VHL disease–
associated RCC tumors as well as ORR, DOR, TTR, PFS,
and TTS in non-RCC tumors. This open-label phase 2 Study-004
trial (NCT03401788) supported the NDA, showing a significant
response rate of 36.1% (95% CI, 24.2%-49.4%) in patients with
VHL disease–associated RCC treated with belzutifan.
Treatment-related adverse events (TRAEs) were observed
in 96.7% of patients, most of which were grade 1 or 2
in severity; no grade 4 or 5 TRAEs were reported. The most
common TRAEs were anemia in 83.6%, which was considered
an on-target toxicity; fatigue in 49.2%; and dizziness in 21.3%.
Grade 3 TRAEs, primarily fatigue and anemia, were reported in
9.8% of patients. Belzutifan is also being investigated in phase 3
trials as a monotherapy and in combination regimens in patients
with RCC.
Nivolumab Plus Ipilimumab Sparks Hope for Patients With RCC
and Sarcomatoid Features.
Nivolumab plus ipilimumab combination therapy has
improved survival and response rates compared with sunitinib,
in patients with advanced renal cell carcinoma with sarcomatoid
histology, including those with intermediate and poor-risk features.
The post hoc, phase 3 CheckMate 214 clinical trial evaluated
the efficacy of nivolumab (Opdivo) plus ipilimumab (Yervoy)
versus sunitinib (Sutent) in patients with sRCC. 139 patients had
sRCC and intermediate/poor-risk disease and 6 had favorable-risk
disease from 1,096 included in the study. The study found that led
to unprecedented long-term survival, response, and complete
response when compared with sunitinib. Based on the results,
investigators support the use of nivolumab plus ipilimumab as
frontline treatment of patients with sRCC. PFS, on the other hand,
was significantly longer with nivolumab plus ipilimumab at 26.5
months (95% CI, 8.4 to NE) compared with the 5.1 months (95%
CI, 4.0-6.9) seen with sunitinib (HR, 0.54; 95% CI, 0.3-0.9; P =
.0093). The median OS however was not reached with nivolumab
plus ipilimumab (95% CI, 25.2 months–not estimable [NE]) versus
14.2 months (95% CI, 9.3-22.9) vs sunitinib (HR, 0.45; 95% CI,
0.3-0.7; P = .0004). Patients who received nivolumab with ipilimumab
also achieved a higher ORR of 60.8% (95% CI, 49%-72%)
compared with 23.1% (95% CI, 14%-35%) in the sunitinib arm (P
< .0001). The complete response rate in the combination arm was
18.9% compared with only 3.1% in the control arm. "I believe patients
with clear cell RCC, who have sarcomatoid features in the
tumor should be, in my opinion, nivolumab and ipilimumab if
you're doing that for treatment in first line setting, I think the data
we have from Checkmate-214 support this recommendation as
the preferred first-line therapy for these patients" said Nizar Tannir,
lead author of this trial.
Researchers unravel how kidney tumors' microenvironments
change in response to immunotherapy.
By using single-cell RNA sequencing, researchers from
Dana-Farber Cancer Institute and the Broad Institute of MIT and
Harvard investigated how kidney tumors' microenvironments
change in response to immunotherapy. Researchers discovered
that in advanced stage disease these CD8+ T cells were "exhausted,"
and not able to carry out their usual function. "These companion
studies shed important new light on the biology of advanced
kidney tumors and their surrounding environments. With this
increased understanding, researchers will be able to identify new
potential drug treatment targets and, overall, expand the number
of patients who can receive effective treatment." said Catherine
J. Wu, MD, professor of medicine at Harvard Medical School. “A
patient’s immune system plays a critical role in controlling both
the progression of cancer and the response to immune therapies,”
adds Toni K. Choueiri, MD, co-senior author of this paper.
In other study, researchers performed single-cell RNA and
T cell receptor sequencing on 164,722 individual cells from tumor
and adjacent non-tumor tissue. They also discovered more anti-
inflammatory or "M2-like" macrophages, a type of white blood
cell that suppresses the immune system, in advanced stage disease.
CD8+ T cells and macrophages were playing off each other and
caught in an "immune dysfunction circuit," said co-lead author
David A. Braun, MD, PhD, an oncologist at Dana-Farber. "There
may be immune evasion mechanisms outside of PD-1/PD-L1 that
play an important role in response or resistance,” said Kevin Bi,
computational biologist at Dana-Farber and co-lead author on the
paper. Study found that immune dysfunction circuit is associated
with a worse prognosis in external cohorts and identifies potentially
targetable immune inhibitory pathways in ccRCC.
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