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Page 6 of 11 Kotecha et al. J Cancer Metastasis Treat 2021;7:67 https://dx.doi.org/10.20517/2394-4722.2021.163

trials which escalate and de-escalate immunotherapy based upon an individualized response to minimize
risk while attempting to achieve durable benefit.

Three previously reported adaptive trials (TITAN, OMNIVORE, HCRN-GU-260) had explored a novel
stepwise scheme of adjusting the intensity of ICI therapy per radiographic response. All three studies
enrolled ICI-naïve patients with clear cell histology and initially started with the anti-PD1 monotherapy
nivolumab. Subsequently, per response assessment during the initial months of therapy, treatment was
matched to the degree of therapeutic benefit observed, incorporating varying strategies with de-escalation
(to active surveillance) vs. intensification (with the addition of ipilimumab) vs. continuation of nivolumab
alone. The three studies varied in study population (distribution of risk status and prior treatment
exposure), length of nivolumab induction and the type of risk adaptation escalation; hence, the results must
be viewed within the context of the individual study design. For instance, nearly half the patients on TITAN
had received prior therapy, and radiographic responses in the first 4 months were achieved in 22.7% of
patients. At that point, those with SD or PD received up to 4 cycles of ipilimumab/nivolumab with
additional responses observed in 12% of previous non-responders (n = 12/104 patients) . In OMNIVORE,
[31]
where half the patients had received TKI therapy, patients were initially treated with nivolumab
monotherapy for up to 6 months; those who achieved a response had treatment discontinued altogether,
[32]
while those who did not were treated with 2 cycles of ipilimumab . The 6-month ORR was 14%, and 5
patients sustained a treatment-free interval for more than a year. For non-responders, the addition of 2
cycles of ipilimumab for salvage therapy applied after 6 months led to a response rate of only 4% (n = 2/57
patients). Lastly, in the HCRN-GU-260 study, all patients were treatment-naïve and underwent therapy
with escalating doses of nivolumab (240 mg × 6 doses, 360 mg × 4 doses, and 480 mg monthly). Patients
who experienced disease progression prior to or stable disease at 48 weeks were then offered salvage
ipilimumab and nivolumab for 4 cycles . In this schema, induction nivolumab was associated with PRs
[33]
and CRs of 26% and 5.7% of patients, respectively (ORR = 31.7%), and the addition of salvage ipilimumab
led to an added response in 4/30 patients (13.3%). Expectedly, high-grade immune-mediated adverse events
were more frequent during the salvage ipilimumab portion of each study, but data in terms of escalating
toxicities with the additional ipilimumab for those who sustained minor adverse events has not been
reported. The relatively small number of patients whose treatment was escalated/de-escalated on these trials
make it challenging to appreciate the nuances of how patients fair with individualized treatment intensity.
Nonetheless, one can make valuable observations across all three studies. First, the addition of ipilimumab
to nivolumab monotherapy could convert non-response to at least PR in all three trials, albeit in only a
small proportion of patients (4%-13% of patients); and second, the composite ORR across all treated
patients receiving individualized treatment on these three trials, and particularly the reported CR rates raise
concern that the sequence of PD-1 to combination CTLA-4 directed combination therapy comes at the
price of lost efficacy. As we await ongoing prospective efforts to formally assess the differences between
ipilimumab plus nivolumab vs. nivolumab alone in the systemically untreated setting (NCT03873402), the
low conversion and CR rates on OMNIVORE, TITAN and HCRN-GU-260 argue against the broad use of
sequenced nivolumab/ipilimumab and support the use of combination therapy in the upfront setting.

Another effort is accepting upfront ipilimumab/nivolumab as the standard frontline regimen but tailoring
treatment beyond the initial imaging assessments. For example, in the pivotal phase III PDIGREE study
(NCT03793166), systemically untreated IMDC intermediate-poor risk ccRCC patients undergo treatment
with induction ipilimumab and nivolumab therapy per standard schedule. Those who sustain PD are shifted
towards cabozantinib monotherapy. Patients who achieve a CR to induction ipilimumab/nivolumab
continue standard nivolumab maintenance up to 1 year. Patients who achieve a partial response or stable
disease are randomized to receive nivolumab monotherapy or combination cabozantinib/nivolumab