Figure 3. Tuning Receptor Selectivity
NKTR-214 preferentially stimulates proliferation of tumor-killing CD8+ effector T cells and
Natural Killer cells without activating immunosuppressive regulatory T cells.
risk group. This trial aims to enroll a total of 600 patients
at approximately 150 sites, although the vast majority
of patients will be recruited from countries other than
the US, Canada, and Western Europe. The co-primary
endpoints are ORR by blinded independent central review
(BICR) and OS. The key secondary endpoint is PFS
by BICR. Other secondary endpoints include incidence
of AEs, ORR using RECIST 1.1 by investigator and PD-L1
biomarker population, PFS by investigator and biomarker
population, OS in biomarker population, and quality of
life.
Dr Hussain: Recent phase 3 trials evaluating first-line therapies
in RCC have used sunitinib as the standard comparator
arm. The ongoing pivotal phase 3 trial with
BEMPEG plus nivolumab is somewhat unique in this regard
since the comparator arm is either sunitinib or
cabozantinib, depending upon physician choice. This
design takes into account the changing treatment patterns
of RCC. Currently, there are three single-agent TKIs
approved in the first-line setting, namely sunitinib, pazopanib,
and cabozantinib. Among these, sunitinib and
pazopanib are essentially similar in terms of treatment
outcomes, with perhaps some differences in their respective
side-effect profiles. Based on the CABOSUN trial,
cabozantinib may have greater activity compared to
sunitinib particularly among intermediate and poor risk
RCC patients, and consequently is also being increasingly
used as first-line monotherapy.9 In this respect, the
comparator arm ‘bar’ against which BEMPEG plus
nivolumab is being compared is perhaps higher than if
the comparator arm included only sunitinib.
A major challenge to the successful development of
BEMPEG plus nivolumab for RCC is that first-line therapies,
particularly some of the newer combination therapies
(nivolumab + ipilimumab, axitinib + pembrolizu-
mab, axitinib + avelumab), show significant and favorable
16 Kidney Cancer Journal
activity compared
with single-agent sunitinib.
The ongoing pivotal
phase 3 trial of BEMPEG
plus nivolumab must
show similar activity, and
perhaps even better activity,
compared with the
above combinations and
against a standard-of-care
arm that not only includes
sunitinib but also cabozantinib.
Dr Figlin: Do you believe
there are any tissue or laboratory
based biomarkers
that could identify the potential
beneficiaries of this
approach?
Dr Hussain: To date, no clear
biomarkers have been identified
that reliably predict
treatment outcomes to HD
IL-2 therapy. On the other hand, data across various malignancies
support PD-L1 expression patterns as a potential
predictor for response to immune checkpoint
targeting, although there is increasing recognition that
PD-L1 expression may not be adequately ‘captured’ during
testing of tumor specimens as it is a dynamic marker.
Further, although PD-L1 expression may identify subpopulations
of responding RCC patients, those without
significant PD-L1 expression can still respond to immune
CPIs. Consequently, current RCC immune CPI treatment
paradigms are essentially PD-L1 agnostic. It will be of interest
to study and further define the role of PD-L1 testing
in BEMPEG plus nivolumab RCC trials given that
BEMPEG can in fact alter/enhance PD-1 and/or PD-L1
expression. Whether relative quantification of immune
suppressor cells such as (myeloid-derived suppressor cells
(MDSCs) and Tregs or/and TILs within tumors can serve
as useful biomarkers to prognosticate or/and predict response
to therapy remain important questions. Although
exploratory, another open question would be whether
there are certain cytokine signature patterns (for instance,
within the circulation) at baseline and post therapy
that can identify and potentially inform treatment
outcomes for BEMPEG plus nivolumab or/and standard
of care TKI therapy.
Dr Tannir: Immune profiling of blood and tissue and nextgeneration
sequencing of tissue looking at prognostic
and predictive markers for response to BEMPEG plus
nivolumab and BEMPEG plus nivolumab and ipilimumab
are ongoing.
Future development of BEMPEG
Dr Figlin: What other diseases or combinations will you
be evaluating with respect to BEMPEG and its drug discovery
platform?
Dr Hussain: The success of immune CPIs in many differ-