Combination Immunotherapy and Targeted Therapy:
Will New Combinations Raise the Tail of the Survival Curve?
Xin Gao, MD
Medical Oncologist
Claire and John Bertucci Center
for Genitourinary Cancers
Massachusetts General Hospital
Cancer Center
Boston, Massachusetts
linical trials investigating combinations of antibodies
against the immune checkpoints PD-1 or PD-L1 plus
targeted therapies against VEGF/VEGFR have shown
C
promising anti-tumor activity over single-agent therapy in
renal cell carcinoma (RCC). In addition to their proven clinical
efficacy as single agents, each class of drugs has a distinct
and potentially synergistic mechanism of action relevant to
RCC biology. Several combinations are now in phase III evaluation
in treatment-naïve metastatic RCC patients. This report
summarizes the preclinical and clinical rationale underlying
the use of such combination therapies and describes the
latest combination trials, which may be transformative for the
treatment of advanced RCC.
The therapeutic landscape for advanced renal cell carcinoma
(RCC) has evolved rapidly in recent years, and additional
clinical trials investigating combinations of
immune checkpoint inhibitors with anti-angiogenic therapies
are poised to continue to redefine the treatment paradigm.
A randomized phase III study of the programmed
death-ligand 1 (PD-L1) antibody atezolizumab in combination
with the vascular endothelial growth factor
(VEGF)-targeted antibody bevacizumab has already
demonstrated clinical efficacy for a subset of patients with
metastatic RCC (mRCC).1 Furthermore, results from four
large randomized phase III trials investigating various
combinations of monoclonal antibodies against programmed
cell death protein 1 (PD-1) or PD-L1 plus small
molecule tyrosine kinase inhibitors (TKIs) of VEGF receptor
76 Kidney Cancer Journal
(VEGFR) are highly anticipated as combination approaches
work their way through rigorous review toward
potentially reshaping the conventional sequential approach
in the treatment of mRCC.
Combined targeting of PD-1/PD-L1 and VEGF/VEGFR
is grounded in the basic biology of RCC. The highly immunogenic
and vascular nature of RCC are wellknown,
2,3 and it is logical that immunotherapeutic and
anti-angiogenic approaches have yielded clinical success
against this remarkably chemo-resistant neoplasm. The
predominant histologic subtype – clear cell RCC (ccRCC)
– is characterized by high proportions of immunogenic
insertion and deletion mutations as well as increased immune
infiltration compared to other human cancers.4,5
Furthermore, a mutation in or inactivation of the von
Hippel-Lindau (VHL) tumor suppressor gene is present in
the vast majority of ccRCCs, leading to aberrant signaling
via the hypoxia-inducible factor (HIF) transcriptional
complex.6,7 Altered expression of a multitude of HIF
downstream genes, including VEGF, results in an adaptation
to hypoxia through the formation of new blood vessels,
increased glycolysis, and enhanced tumor proliferation
and survival.8
While immunotherapies and anti-angiogenic therapies
have individually become standard-of-care treatments
for advanced RCCs, intriguing preclinical data
have emerged in recent years to suggest beneficial effects
of angiogenesis inhibitors on anti-tumor immunity.
Tumor-associated blood and lymphatic vascular formation
likely play key roles in promoting an immunosuppressive
phenotype by modulating the recruitment,
adhesion, trafficking, and function of immune cells in
the tumor microenvironment.9 Data from preclinical
studies have built a framework for understanding the interaction
between angiogenic signaling and anti-cancer
Keywords: Combination therapy, PD-1/PD-L1, immunotherapy,
VEGR/VEGFR, anti-angiogenic therapy
Corresponding Author: Xin Gao, MD, Massachusetts General Hospital
Cancer Center, Yawkey Building, Suite 7E, 55 Fruit Street, Boston,
MA 02114 Tel: 617-724-4000 Fax: 617-643-1740