Page 14 - Read Online

Atmaja et al. J Cancer Metastasis Treat 2021;7:xx https://dx.doi.org/10.20517/2394-4722.2021.66 Page 9 of 14

Table 2. Selected clinical trials investigating combination therapies in the first-line setting
Comparison of median
No. of Comparison of OS (months
Study Treatment vs. control PFS (months vs.
patients months) vs. months)
CheckMate 214 [26] Nivolumab/Ipilimumab vs. Sunitinib 1096 11.2 vs. 8.3 Median OS 48.1 months vs.
26.6 months (HR = 0.65;
95%CI: 0.54-0.78)
KEYNOTE-426 [61] Pembrolizumab/Axitinib vs. Sunitinib 861 15.1 vs. 11.1 12-months OS: 89.9% vs.
78.3% (HR = 0.53; P < 0.0001)
JAVELIN Renal-101 [62] Avelumab/Axitinib vs. Sunitinib 886 13.8 vs. 7.0 (in PD-L1 OS not yet reported
positive population)
13.3 vs. 8.0 (in overall
population)
IMmotion151 [69] Atezolizumab/Bevacizumab vs. 915 11.2 vs. 7.7 (in PD-L1 OS not yet reported
Sunitinib positive population)
CheckMate 9ER [63] Nivolumab/Cabozantinib vs. Sunitinib 636 16.6 vs. 8.3 OS not yet reported
CLEAR (Study Pembrolizumab/Lenvatinib vs. 1069 23.9 vs. 14.7 vs. 9.2 OS not yet reported
307)/KEYNOTE-581 [68,69] Everolimus/Lenvatinib vs. Sunitinib

For patients progressing on first-line ICIs, a TKI can be considered. In the phase III METEOR trial, 658
patients, previously treated with a VEGF TKI or ICI, were randomly assigned to receive Cabozantinib or
Everolimus. PFS improvement was seen in the Cabozantinib group (7.4 months vs. 3.8 months) with a HR
[40]
of 0.58 (95%CI: 0.45-0.75; P < 0.001) . Another phase III study, investigating the use of Tivozanib (a novel
EGFR-TKI) vs. Sorafenib in the third or fourth-line setting, showed a PFS benefit with Tivozanib across all
groups, including approximately 25% of patients previously treated with VEGF-TKI/ICI combination .
[72]

If a single-agent TKI is used as frontline therapy in mRCC, Nivolumab has recently been approved as a
second-line option. The CheckMate 025 trial compared Nivolumab with Everolimus in 821 patients after
previous antiangiogenic therapies. The study established that Nivolumab was associated with a significant
[27]
improvement in OS (25.0 months vs. 19.6 months; HR = 0.73) and an increased ORR (25% vs. 5%) .
The combination of Guadacitabine, a DNA hypomethylating agent, and Durvalumab, a PD-L1 inhibitor, in
the setting of advanced ccRCC, has recently been investigated in a single-arm phase Ib/II trial. The first
cohort consisted of patients unexposed to ICI and 0 or 1 previous treatments. Recently published data from
this cohort of 42 patients, including 36 from phase II with metastatic disease, showed at a median follow-up
of 20.1 months, best RECIST 1.1 response was partial response (PR) in 9 patients (22%), stable disease (SD)
in 25 patients (61%) and progressive disease in 7 patients (17%), with 1 non-evaluable patient. Sixty-six
percent of patients derived clinical benefit, which was defined as PR or SD ≥ 6 months with median OS not
reached and median PFS being 17 months .
[73]

Hypoxia-inducible factor (HIF-2α) is a transcription factor that is a key oncogenic driver in RCC. MK-6482
or Belzutifan, a first-in-class small molecule HIF-2α inhibitor, has been shown to induce tumor regression
in mouse xenograft RCC models. The NCT02974738 phase I/II trial investigating Belzutifan in the setting of
advanced clear-cell RCC with ≥ 1 prior therapy has shown promising results. In 55 treated patients, with a
median number of prior therapies of 3, the ORR was 25%, and the median PFS was 14.5 months. The
disease control rates for IMDC favorable risk (n = 13) and intermediate or poor risk (n = 42) were 92% and
76%, respectively .
[74]