Kidney Cancer Journal 13
after 1–3 courses of therapy; such responding patients
likely may not require other long-term systemic treatments,
thus limiting prolonged treatment-related adverse
events (TRAE)s. By contrast, with targeted therapies
and perhaps also immune CPIs, longer-term treatments
are generally required, which can be associated with their
own set of potentially prolonged AEs.
With HD IL-2 therapy there appears to be a plateau
in terms of the proportion of patients with RCC achieving
objective response and CR. Although to date there
are no head-to-head comparisons, ORRs are often higher
with single-agent TKI therapies, but CR rates lower than
with HD IL-2. However, this paradigm may be shifting.
For instance, TKI plus immune checkpoint blockade as
upfront therapy (axitinib + pembrolizumab, axitinib +
avelumab) demonstrates ORR of 50–59% and CR rates of
3–6%.2 Interestingly, double immune checkpoint blockade
with nivolumab plus ipilimumab in the first-line setting
has resulted in ORR of 42% and CR rate of 9%. Thus,
it appears that immune modulation in advanced aRCC
is relevant to achieving clinical CR, and perhaps durable
CR, albeit the proportion of patients achieving this remains
low.3
An important question now is whether IL-2 can be
integrated with some of the newer approaches to further
improve treatment outcomes of RCC patients, given its
purported immunomodulatory mechanisms of action,
including enhanced expansion of antigen-specific clonal
T cells and cytotoxic CD8 cells, stimulation of large granular
lymphocytes (natural killer NK cells) and stimulation
of B cells to secrete antibodies. The intense treat-
ment schedule of HD IL-2, and the significant associated
toxicities, have made it difficult to readily incorporate
and test HD IL-2 with other treatments in combination
therapies. Although lower-dose IV IL-2 and subcutaneous
IL-2 have also been used to treat RCC, their anti-tumor
activities are even more modest than HD IL-2. The challenge
therefore has been to develop other formulations
of IL-2 that: a) can recapitulate the clinical efficacy associated
with HD IL-2, b) have lower side effects, c) be
given in an outpatient setting, and d) be safely combined
with other treatments to potentially improve anti-tumor
activity.
BEMPEG incorporates recombinant human IL-2 into
a polyethylene glycol moiety that favorably alters some
of the pharmacokinetic and pharmacodynamic properties
of HD IL-2. The gradual release of bound IL-2 from
pegylated chains after IV administration allows for IL-2
to reach peak serum concentrations more gradually over
24–48 hours after administration compared with the
rapid kinetics and short half-life of HD IL-2.2 BEMPEG
consequently has a 500-fold increase in AUC vs HD IL-
2.4 These properties allow for less frequent dosing, and
mitigate the rapid release of cytokines and hence cytokine
release-associated AEs that often occur with HD
IL-2 administration. Further, BEMPEG preferentially activates
the intermediate affinity IL-2 receptors (IL-2R
beta/gamma) over the high-affinity IL-2 receptors (IL-2R
alpha/beta/gamma), leading to preferential activation
and expansion of the desirable CD8+ T cells and NK cells
rather than the immunosuppressive CD4+ T-regulatory
(Treg) cells. It is the location of PEG chains at the
IL2/IL2Ra interface that interferes with binding to highaffinity
IL2Ra (CD25), while leaving binding to lowaffinity
IL2Rb (CD122). Its receptor-binding properties
also lead to decreased activation of the high-affinity IL-
2R on endothelial cells, and thus less likelihood of capillary
leak syndrome. Altogether, these properties suggest
that BEMPEG can be more readily incorporated into combination
therapies.
Dr Tannir: HD IL-2 was approved by the FDA in 1992
based on seven single-arm phase 2 trials showing consistent
ORRs of approximately 20% and CR rates of 7-10%,
with approximately 85% of the CRs being durable.1 Two
major limitations of HD IL-2 therapy have limited its
wide application: 1) significant toxicity, which in the
early years was associated with a 4% fatality rate and 2)
need for high-level training of healthcare providers to
administer this therapy in an inpatient setting with close
monitoring to manage challenging complications such
as capillary leak syndrome, refractory hypotension requiring
IV fluids, vasopressors, and intensive care unit
monitoring, liver and/or renal dysfunction, neurotoxicity,
sepsis, and gastrointestinal toxicity.5 The approvals
of targeted therapies (VEGF-directed agents, mTOR inhibitors)
have supplanted cytokine therapy, including
HD IL-2, although few centers continue to administer
HD IL-2 to selected patients who are candidates for this
therapeutic approach. The recent approval of immune
CPI- based therapies (e.g. nivolumab + ipilimumab, pembrolizumab
+ axitinib) as first-line therapies further
eroded the use of HD IL-2.
The limitations of HD IL-2 have spurred the development
of a more tolerable IL-2 therapy, which can harness
the benefits of the immune system while minimizing the
toxicity. BEMPEG was developed with these aims in
mind. The inactive 6-PEG prodrug compound yields two
active moieties after irreversible release in the circulation
and shifts signaling preferentially through the IL-2R beta
and gamma components, essentially acting as a CD122
agonist, away from the IL-2R alpha signaling that is responsible
for much of the toxicity of HD IL-2. Additionally,
the serum half-life of BEMPEG is 20 hours compared
with 20 minutes for HD IL-2. The more favorable toxicity
profile and longer half-life of BEMPEG allow for outpatient
administration; the recommended dose of BEMPEG
is on a three-week schedule.
Delineating the Pharmacologic Properties of BEMPEG
Dr Figlin: What are the results from the phase 1 monotherapy
trials that delineate the pharmacologic properties,
the AE profile, and how BEMPEG allows for inter-
mittent dosing in cancer?
Dr Tannir: BEMPEG has been evaluated in solid tumors as
a single agent in the phase 1 and phase 2 settings to establish
dosing and safety, and to assess initial activity. It
has been tested on an every-3-week schedule given IV;
five dose levels were evaluated ranging from 0.003–0.012
mg/kg, with the maximal tolerated dose identified as
0.009 mg/kg and the phase 2 dose defined as 0.006
mg/kg every 3 weeks. The dose-escalation phase included
28 patients.6 Among these, only one patient experienced