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Page 8 of 14 Atmaja et al. J Cancer Metastasis Treat 2021;7:xx https://dx.doi.org/10.20517/2394-4722.2021.66

[61]
Sunitinib alone [59.3% vs. 35.7% and 15.1 months vs. 11.1 months (P < 0.001) respectively] . A recent
Bayesian network meta-analysis suggested that the Pembrolizumab plus Axitinib combination gives
[22]
optimum OS benefit for mRCC patients with intermediate and poor-risk disease .

Another combination treatment study, CheckMate 9ER, with Nivolumab plus Cabozantinib vs. Sunitinib, in
untreated advanced RCC, showed that at median follow-up of 18.1-month, the median PFS was 16.6
months vs. 8.3 months (HR = 0.51; 95%CI: 0.41-0.64; P < 0.001) and the median OS was not reached (HR =
0.60; 98.89%CI: 0.40-0.89; P = 0.001) with benefit across all IMDC risk and PD-L1 subgroups, and ORR was
[63]
55.7% vs. 27.1% with the median duration of response of 20.2 months vs. 11.5 months, respectively .
Recent data from the CLEAR study (study 307)/KEYNOTE-581 with a combination of Pembrolizumab plus
Lenvatinib or Lenvatinib plus Everolimus vs. Sunitinib in the setting of advanced RCC with no prior
systemic therapy showed a significantly better outcome in the combination cohorts compared to Sunitinib
alone, with a median PFS of 23.9 months in the Pembrolizumab plus Lenvatinib, 15 months in the
Lenvatinib plus Everolimus, and 9.2 months in Sunitinib cohort with benefit seen across all MSKCC or
IMDC risk groups. Similarly, the HR for OS in Pembrolizumab plus Lenvatinib vs. Sunitinib was 0.66, with
benefits seen across all MSKCC and IMDC risk groups, except for IMDC favorable risk. However, in the
OS, there was no statistical difference between Lenvatinib plus Everolimus and Sunitinib, pointing to the
important role of ICI in the combination strategy. The ORR was 71%, 54%, and 36%, with the complete
response rate in these groups being 16%, 10%, and 4%, respectively. These results demonstrated that
Pembrolizumab plus Lenvatinib is a meaningful alternative to Ipilimumab plus Nivolumab as a first-line
strategy for intermediate or poor-risk patients [68,69] .

However, there is a paucity of head-to-head randomized controlled trials directly comparing the
effectiveness of all available therapies. Given the variety of regimes available, it is a genuine challenge for
clinicians to identify the best treatment option for each patient. Several other first-line clinical trials with
combination agents (all in comparison with Sunitinib) are currently pending analyses, including
Atezolizumab/Bevacizumab (IMmotion151) [Table 2].
[70]

In a patient group for which immunotherapy is contraindicated (e.g., autoimmune disease or patients on >
10 mg baseline Prednisolone), targeted therapies can be considered as first-line. Cabozantinib is a VEGF,
MET and AXL inhibitor [Figure 1], and results from the randomized phase II CABOSUN trial demonstrate
improved PFS (8.2 months vs. 5.6 months) and superior ORR (46% vs. 18%) with Cabozantinib vs. Sunitinib
respectively. In addition, patients with osseous metastatic disease receiving Cabozantinib responded better
than those treated with Sunitinib .
[39]
Agents inhibiting mTOR pathways, such as Temsirolimus, can be used to treat patients with the poor-risk
disease. However, they are utilized less commonly than other therapies due to their limited efficacy and
laborious administration schedules, which involve weekly infusions . Although they can be considered for
[66]
patients unable to tolerate oral drugs and those with contraindications to ICIs.

Beyond first-line therapy
A high percentage of patients with mRCC will eventually have disease progression while on first-line
therapy, and switching to an alternative agent is recommended; however, the optimal therapy sequence is
still an active area of research. Whilst many clinicians choose second-line VEGF-targeted therapy based on
response to first-line therapy, a retrospective study of 464 patients receiving both first and second-line
VEGF inhibitors demonstrated no correlation between response .
[71]