ROUNDTABLE DISCUSSION
Reinventing the Paradigm of IL-2 Therapy:
Pivotal Trial Could Change the Landscape of
Combination Strategies in Advanced RCC
Objectives of the Roundtable Discussion
This roundtable discussion held on January 15, 2020 explores
the potential impact and innovative clinical strategy
of the PIVOT-09 trial involving bempegaldesleukin
(BEMPEG: NKTR-214) combined with nivolumab as a
novel combination therapy for renal cell carcinoma
(RCC). In this discussion, three RCC cancer experts analyze
the landscape of interleukin-2 (IL-2) therapy, and
they also outline how a novel re-designed IL-2 molecule,
comprising a PEGylated version of IL-2 (bempegaldesleukin;
BEMPEG; NKTR-214), may deliver promising immunomodulatory
capabilities. One of the goals of the
PIVOT-09 trial is to evaluate the synergistic effect of BEMPEG
with the checkpoint inhibitor (CPI) nivolumab
(NIVO) in IMDC intermediate- or poor-risk patients and
IMDC all-risk patients with previously untreated advanced
renal cell carcinoma (aRCC). The discussion is
led by Robert A. Figlin, MD, Editor-in-Chief of Kidney
Cancer Journal. The panel members are Nizar Tannir, MD,
Professor, Department of Genitourinary Medical Oncology,
Division of Cancer Medicine, The University of
Texas MD Anderson Cancer Center, Houston, Texas, and
Arif Hussain, MD, Professor of Medicine, University of
Maryland Greenebaum Comprehensive Cancer Center,
University of Maryland School of Medicine, Baltimore,
Maryland.
The Development of NKTR-214 (BEMPEG)
Therapy: A Historical P erspective
Dr Figlin: Please describe the development of NKTR-214
and the properties that make it different from the historical
IL-2 therapies that were developed in the 1990s.
Dr Hussain: Before we consider the development of NKTR-
214, it is important to first review the background of IL-
2 therapy and how it relates to recent treatment
advances. The clinical treatment landscape of advanced
RCC with a component of clear cell histology has been
evolving dramatically over the last 14 years, since the approval
of the first targeted therapies which target angiogenesis
factors or further downstream factors at the level
of the mammalian target of rapamycin (mTOR) complex.
12 Kidney Cancer Journal
The approval of these newer agents was based on the
findings from randomized phase 3 trials that included
various primary endpoints such as progression-free survival
(PFS; e.g. sorafenib, sunitinib) or overall survival
(OS; e.g. temsirolimus). The subsequent progress has
been steady, both for initial treatment of patients presenting
de novo with advanced disease, and those progressing
after initial systemic therapies. These additional
therapies have continued to build upon further targeting
of receptor kinases (primarily vascular endothelial
growth factor receptor VEGFR, but potentially other
targets as well such as MET, AXL, among others), demonstrating
that progression on one tyrosine kinase inhibitor
(TKI) does not preclude responses to other tyrosine kinase
targeting agents. In the last few years, an additional
approach has also been incorporated into the treatment
landscape of RCC with the demonstration of a positive
impact of immune checkpoint inhibitor (CPI)-based
therapy: a) in patients failing TKI-based treatments
(nivolu-mab), or b) in patients as first-line therapy
(nivolumab + ipilimumab). Furthermore, recent trials
have also established a role for combination therapies in
the first-line RCC setting that include TKI plus CPI (e.g.
axitinib + pembrolizumab, axitinib + avelumab).
The role of IL-2 in RCC needs to be put in context
with the current evolving treatments for metastatic renal
cell carcinoma (mRCC) or aRCC, keeping in mind that
HD intravenous IL-2 was in fact the first FDA-approved
therapy for RCC (approved in 1992). The basis for use of
HD IL-2 was a phase 2 pooled study in which approximately
12% of mRCC patients achieved a partial response,
with 9% achieving complete response (CR).1
Further, some of the responding patients could be converted
into long-term cancer-free survivors upon resection
of residual disease. Although the high incidence of
significant side effects, including those related to capillary
leak syndrome (CLS), necessitates close inpatient
monitoring of high-dose interleukin-2 (HD IL-2) treatment,
treatment by experienced providers and appropriate
medical support can allow for successful admini-
stration of HD IL-2. The potential advantage of this approach
is that if one is destined to respond, they do so
Robert A.
Figlin, MD
Nizar Tannir, MD Arif Hussain, MD