Kidney Cancer Journal 81
triplet combination received nivolumab 3 mg/kg and ipilimumab
1 mg/kg every 3 weeks for four doses followed
by nivolumab 3 mg/kg every 2 weeks, with 6 patients
concurrently receiving cabozantinib 40 mg daily and 1
patient receiving cabozantinib 60 mg daily.
Grade 3 or 4 AEs were reported in 57% of all patients
receiving doublet therapy and in 72% of all patients receiving
triplet therapy. Common grade 3 or 4 treatmentrelated
AEs included diarrhea, hypertension, fatigue,
hypophosphatemia, hyponatremia, hypokalemia, lymphopenia,
neutropenia, and elevations in transaminases,
lipase, and amylase. Immune-related AEs were relatively
uncommon with either doublet or triplet therapy.
At early follow-up (median 5.2 months), objective response
was seen in 54% of patients in the RCC cohort.
All responding patients experienced a PR. The remaining
46% of patients in the RCC cohort experienced stable disease.
Patients with mRCC who experienced disease response
appeared to have a prolonged duration of
response, with median PFS estimated at 18.4 months
(95% CI 6.4-18.4). The study investigators did not present
data on RCC responses by doublet vs triplet therapy. The
ongoing phase III CheckMate 9ER trial (NCT03141177)
is comparing the combination of nivolumab plus
cabozantinib vs sunitinib in treatment-naïve patients
with advanced ccRCC. The primary endpoint is PFS of
the treatment arms.
Combination Therapy vs Monotherapy:
Is More Always Better?
The early data from combinations of immune checkpoint
inhibitors plus anti-angiogenic therapies indicate that
combination treatments may result in improved clinical
efficacy as well as the potential for enhanced toxicities.
Studies of immune checkpoint inhibitor monotherapy in
advanced RCC and other tumors have demonstrated clinical
activity in addition to a favorable toxicity profile.31-33
For example, preliminary results from the phase II
KEYNOTE-427 study of first-line pembrolizumab monotherapy
in advanced ccRCC patients have shown an ORR
of 38%, including 3% with CR and a majority of responding
patients having ongoing responses at 12
months of follow-up. Long-term follow-up results from
KEYNOTE-427 and data from the ongoing phase III combination
studies in RCC may provide additional insights
into the additive benefit anti-angiogenic agents to immune
checkpoint inhibitor monotherapy. Survival data
will be important in assessing the benefits of frontline
combination therapy relative to sequential treatment
with immune checkpoint inhibitors and VEGFR TKIs. It
is possible that some patients may respond well to singleagent
treatment and may be spared the additive toxicities
of combination therapies, while other patients may
require combination approaches to obtain clinical benefit.
Biomarker analyses such as PD-L1 expression have
been incorporated into all of the ongoing phase III studies.
Further development of candidate predictive biomarkers
such as angiogenesis- and immune-associated
gene expression profiling29 and tumor mutational burden34
may provide guidance on optimizing treatment
strategies for mRCC patients.
Conclusion
Combinations of immune checkpoint inhibitors plus
anti-angiogenic therapies are advancing rapidly through
clinical evaluation in mRCC, supported by preclinical
data suggesting biological synergism and by the proven
clinical efficacy of each therapeutic approach independently.
Multiple early-phase clinical trials have demonstrated
favorable anti-tumor activity and manageable
safety profiles of combination therapies, and five large
randomized phase III studies involving distinct treatment
combinations are ongoing in treatment-naïve mRCC patients.
The combination of atezolizumab plus bevacizumab
has achieved one of its co-primary endpoints of
improving PFS in patients with PD-L1+ tumors. With regulatory
review of atezolizumab plus bevacizumab expected
in the near future, results of survival data in
follow-up will be key in further informing the role of this
combination in the treatment of mRCC patients. Efficacy
and safety results from four additional randomized phase
III trials of VEGFR TKI plus anti-PD-1/PD-L1 therapy are
also forthcoming. Ultimately, these studies have tremendous
potential to transform the standard-of-care treatment
for advanced RCC from one of sequential therapies
to one of combination regimens that meaningfully improves
the lives of kidney cancer patients.
Acknowledgments
Many thanks to David McDermott, MD for the helpful
discussion and comments in the preparation of this manuscript.
References
1. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized
Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated
Metastatic Renal Cell Carcinoma (mRCC). J Clin Oncol. 36, 2018
(suppl 6S; abstr 578).
2. Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell
Carcinoma. N Engl J Med .2017;376:354-66.
3. Gao X, McDermott DF. Combinations of Bevacizumab With Immune
Checkpoint Inhibitors in Renal Cell Carcinoma. Cancer journal.
2018;24:171-9.
4. Senbabaoglu Y, Gejman RS, Winer AG, et al. Tumor immune microenvironment
characterization in clear cell renal cell carcinoma identifies
prognostic and immunotherapeutically relevant messenger RNA
signatures. Genome Biol. 2016;17:231.
5. Turajlic S, Litchfield K, Xu H, et al. Insertion-and-deletion-derived tumour
specific neoantigens and the immunogenic phenotype: a pancancer
analysis. Lancet Oncol. 2017;18:1009-21.
6. Cancer Genome Atlas Research N. Comprehensive molecular characterization
of clear cell renal cell carcinoma. Nature. 2013;499:43-9.
7. Gnarra JR, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor
gene in renal carcinoma. Nat Genet. 1994;7:85-90.
8. Kaelin WG, Jr. The von Hippel-Lindau tumour suppressor protein:
O2 sensing and cancer. Nat Rev Cancer. 2008;8:865-73.
9. Schaaf MB, Garg AD, Agostinis P. Defining the role of the tumor vasculature
in antitumor immunity and immunotherapy. Cell Death Dis.
2018;9:115.
10. Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and
emerging role of angiogenesis inhibitors as immunotherapeutics. Semin
Cancer Biol. 2017.
11. Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular