Kidney Cancer Journal 17
ent cancer types has established a paradigm for modulating
the immune system for therapeutic benefit. Although
IL-2-based treatments have, to date, focused
primarily on melanoma and RCC, based on the immunomodulatory
and potentially complementary effects
of IL-2 with immune CPIs in reactivating and enhancing
the immune system, this suggests that an approach integrating
reformulated forms of IL-2 such as BEMPEG
may have a broader role in treating malignancies beyond
RCC. This may be a particularly viable approach if BEMPEG
is integrated with immune CPIs or/and vaccinebased
therapies in disease states where there is already a
defined role for these latter treatments. It is of interest
that pivotal phase 2/3 registrational trials are being carried
out with BEMPEG and immune CPIs in other solid
tumors, including melanoma, NSCLC, and urothelial
cancers, which may provide a platform for further investigation
into some of these other cancer types. It should
be noted that metastatic prostate cancer is currently the
only solid tumor for which a vaccine, sipuleucel-T, has
been approved by the FDA. This autologous dendritic
cell-based vaccine has been shown to improve OS, but
not necessarily PFS, and significant room for improving
upon this vaccine treatment remains. Whether BEMPEG
or a CPI or both can be incorporated with sipuleucel-T
to improve treatment outcomes in advanced prostate
cancer is another potential area to consider.
As noted above, VEGF/VEGFR has been established as
a pivotal axis in RCC angiogenesis and pathogenesis, targeting
of which has led to significant improvements of
RCC patients. Importantly, this axis not only enhances
angiogenesis but also stimulates myeloid-derived suppressor
cells (MSDCs) that contribute to an immunosuppressive
and tumor-permissive environment. Thus, tar-
geting VEGF/VEGFR can enhance anti-tumor immune
responses by increasing T-cell trafficking into tumors, decreasing
MDSC and Treg activity, and producing immunosuppressive
cytokines. The clinical relevance of tar-
geting VEGF/VEGFR concurrently with immune modulation
has now been well established in RCC based on
several phase 3 trials that have shown positive outcomes
with bevacizumab plus atezolizumab, axitinib plus pembrolizumab,
and axitinib plus avelumab.10,11 Thus, the
VEGFR axis and the immune checkpoint axis provide a
relevant framework in the context of BEMPEG, including
exploratory co-targeting approaches that could evaluate
BEMPEG plus VEGFR targeting, or even BEMPEG plus
CPI plus VEGFR targeting in RCC and other solid tumors.
Recent work has identified a key role for PI3K -based
signaling in immune cell function, particularly in immunosuppressive
cells such as MDSCs. Targeting PI3K
in combination with BEMPEG offers another potential
opportunity to explore. In addition to the above, there
have been significant efforts to modulate the metabolome,
particularly glutamine metabolism, in RCC and
other cancer types in combination strategies with TKIs
and immune CPIs that could also inform further development
of BEMPEG in the future.
Finally, although BEMPEG is being evaluated with
nivolumab in the first-line setting in RCC via a pivotal
ongoing phase 3 trial, another important and relevant
aspect is to also explore and define a possible role for BEMPEG
in the second-line or beyond settings in RCC patients
progressing on initial immune CPI- or/and TKIbased
therapies. For instance, is there any role or benefit
to further immune modulation by BEMPEG among previously
treated patients, either as single-agent therapy or
more likely in combination with another targeting agent
(e.g. PI3K inhibitor, glutaminase inhibitor, others)?
Dr Tannir: That is an accurate summary. I also would like
to add that the two tumor types other than RCC where
there is already promising preliminary data with the doublet
of BEMPEG plus nivolumab are melanoma and
urothelial carcinoma. In the melanoma expansion cohort
of the PIVOT-02 trial, the ORR was 53% and CR
34%.
At the 2019 ASCO GU meeting, data were presented
on the combination of BEMPEG and nivolumab from the
PIVOT-02 cohort of first-line treatment of 41 patients
with metastatic urothelial cancer who were cisplatin-ineligible
or cisplatin-eligible and refused standard of care.
The doublet of BEMPEG plus nivolumab was well tolerated.
The most common TRAEs were Grade 1 and 2 flulike
symptoms, fatigue, rash, and pruritis. Six patients
experienced a Grade 3 TRAE, which led to discontinuation
of therapy in four patients (10%). There were no
Grade 4 or 5 AEs. Among 27 evaluable patients for response,
13 patients had a complete or partial response
for an ORR of 48%: 5 patients had CR and 8 patients had
a partial response. Responses were noted in patients with
PD-L1 <1% and in patients with PD-L1 1%. In metastatic
UC (mUC), responses were observed in patients with
PD-L1-negative and CD8-TIL low tumors (4/8 or 50%)
and CD3-TIL low tumors (3/7 or 43%).14 The combination
of BEMPEG plus NIVO is being evaluated in several
other tumor types, including RCC, melanoma, UC, and
NSCLC.
Conclusion
Results from pivotal clinical trials have demonstrated the
immunomodulatory and potentially complementary effects
of IL-2 with CPIs in reactivating and enhancing the
immune system. A novel therapeutic approach, integrating
reformulated forms of IL-2 such as BEMPEG with the
checkpoint inhibitor nivolumab may have translational
impact as first-line therapy in treating RCC. Although
BEMPEG is being evaluated with nivolumab in the firstline
setting in RCC via a pivotal ongoing phase 3 trial,
another important and relevant aspect is to also explore
and define a possible role for BEMPEG in the second-line
or beyond settings in RCC patients progressing on initial
immune CPI- or/and TKI-based therapies.
Disclosure: The roundtable participants (authors) were invited
to participate in this discussion by the journal. This
article was supported in part through independent funding
to the journal from Nektar Therapeutics. This article
was peer-reviewed and the final content and article is the
sole work of the authors. Nektar is the owner of BEMPEG
(NKTR-214) which is an IND-stage compound that has
not been approved by the FDA or any other counterpart
regulatory agency in any country for renal cell carcinoma
or for any other indication.