Page 111 - Read Online

Page 8 of 11 Kotecha et al. J Cancer Metastasis Treat 2021;7:67 https://dx.doi.org/10.20517/2394-4722.2021.163

Table 2. Select phase III ongoing clinical trials for systemically treatment-naïve RCC
Clinical trial
Treatment regimen Comparator
information
Ipilimumab + Nivolumab Nivolumab CA209-8Y8,
NCT03873402
Ipilimumab + Nivolumab, followed by Nivolumab (CR), *Select patients only (non-CR, non-PD to PDIGREE, NCT03793166
Cabozantinib + Nivolumab/Nivolumab (SD/PR), or Cabozantinib induction with Ipilimumab + Nivolumab):
(PD) Nivolumab vs. Nivolumab + Cabozantinib
Cabozaninib + Ipilimumab + Nivolumab Ipilimumab + Nivolumab COSMIC-313,
NCT03937219
Lenvatinib + Pembrolizumab + Belzutifan Lenvatinib + Pembrolizumab MK6482-012,
Lenvatinib + Pembrolizumab + Quavonlimab NCT04736706
Bempegaldesluekin + Nivolumab Sunitinib or Cabozantinib PIVOT-09,
NCT03729245
Systemic therapy (Ipilimumab + Nivolumab, Axitinib + Continued systemic therapy PROBE/SWOG1931,
Pembrolizumab, or Axitinib + Avelumab) followed by cytoreductive NCT04510597
nephrectomy based upon response (PR/SD)

*Adaptive trial design: all patients are treated with ipilimumab + nivolumab initially, then assigned to treatment arms per their treatment
response: PD - cabozantinib monotherapy; CR - nivolumab maintenance, to complete 1 year; non-CR/non-PD: randomization nivolumab vs.
nivolumab + cabozantinib. CR: Complete response; PR: partial response; SD: stable disease; PD: progressive disease.

Building upon this framework, other promising therapeutic agents with strong clinical activity in the
treatment-refractory setting are also being poised for a position in the triplicate space with combinations
still under early investigation. For example, bempegaldesleukin (NKTR-214) is a pegylated first-in-class IL-2
receptor that potently binds to the CD122 surface to stimulate proliferation and mobilization into the tumor
microenvironment . Bempegaldesleukin was previously tested in a phase I/II study in patients with
[40]
systemically treatment-naïve ccRCC and was found to have an ORR of 64% (7/11 patients) with responses
[41]
seen regardless of PD-L1 expression . Based upon these encouraging results, a global phase III study of
bempegaldesleukin in combination with nivolumab vs. investigator’s choice TKI (sunitinib or cabozantinib)
remains ongoing with results forthcoming (NCT03729245) . In addition to this, an early phase I/II study
[42]
(NCT04540705) tests this novel agent in combination with ICI and VEGFR TKI therapy (axitinib and
cabozantinib, on separate arms) in the treatment-naïve setting. Other agents, including MEDI5752, a
monovalent bispecific antibody co-targeting PD-1 and CTLA-4, paired with axitinib, similarly explore the
triplicate combination of the mechanism of action for therapy of TKI and PD-1/CTLA-4 inhibition
(NCT04522323) . As more triplicate combinations are developed, it will be helpful to discriminate these
[43]
additional strategies within the known context of angiogenesis and immune activation to optimize
synergism and limit overlapping toxicities.

CONCLUSION
The treatment paradigm for patients with systemically untreated ccRCC has significantly evolved, and
multiple ICI-based combination therapies are the new standard for all eligible patients. Current first-line
combinations have entered the arena in rapid succession, and while it is increasingly difficult to select
amongst these available options, certain clinical situations and the clinician’s treating experience may guide
the selection of one regimen over another. Doublet therapy has become the standard comparator for clinical
trials, but regimen choice will likely remain investigator-dependent and within the context of prognostic
risk stratification. As triplicate regimens become a new reality, management of treatment-related adverse
events will also become increasingly complex, and a key question is whether an achieved gain in efficacy
justifies added toxicity. All this constitutes an urgent call for biomarker-driven studies and innovative trial
designs with an overarching goal to incorporate molecular profiling and identify determinants for response,
resistance, and ideally adverse effects, with adaptive study designs that offer the ability to intensify and de-