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Page 6 of 12 Porta et al. J Cancer Metastasis Treat 2021;7:49 https://dx.doi.org/10.20517/2394-4722.2021.86

[15]
Study results have been recently updated at the 2021 Genitourinary Cancers Symposium .

Thus, the combination of Nivolumab + Cabozantinib was added to the previous standards of care for
mRCC patients, irrespective of IMDC risk groups (although a limited OS benefit for good risk patients was
showed).

Pembrolizumab + Lenvatinib (CLEAR study)
In this study, 1069 previosuly untreated mRCC patients were randomly assigned to receive Pembrolizumab
+ Lenvatinib, Lenvatinib + Everolimus, or Sunitinib .
[4]

In the Pembrolizumab + Lenvatinib group, the anti-PD1 monoclonal antibody and the multikinase
inhibitor were administered at the dose of 200 mg i.v., every 21 days, and 20 mg per os, on a continuous
dosing, respectively.

In the Lenvatinib + Everolimus group, Lenvatinib and Everolimus were administered at the dose of 18 mg
and 5 mg o.d. per os, while Sunitinib was administered at the dose of 50 mg orally o.d. on the classical 4:2
schedule.

The primary end point was PFS, secondary endpoints being OS, ORR, and safety.

At a median follow-up of 26.6 months, median PFS as determined by independent review was significantly
longer in the Pembrolizumab + Lenvatinib arm than in the Sunitinib arm: 23.9 months (95%CI: 20.8-27.7)
vs. 9.2 months (95%CI: 6.0-11.0), leading to a HR of 0.39 (95%CI: 0.32-0.49; P < 0.001). Furthermore,
median PFS was also significantly longer in the Lenvatinib + Everolimus than in the Sunitinib arm: 14.7
months (95%CI: 11.1-16.7) vs. 9.2 months (95%CI: 6.0-11.0), leading to a HR of 0.65 (95%CI: 0.53-0.80; P <
0.001).

In the OS analysis, 79.2% of the patients treated with the immune-based combination, 66.1% of the patients
in the non-ICI-containing combination, and 70.4% of the patients in the Sunitinib group were alive at 24
months, although median OS was not reached with any of the three treatments.

OS was significantly longer with Pembrolizumab + Lenvatinib than with Sunitinib (HR = 0.66; 95%CI: 0.49-
0.88, P = 0.005), while it was not the case when the combination of Lenvatinib + Everolimus was compared
with Sunitinib (HR = 1.15; 95%CI: 0.88-1.50; P = 0.30).

ORR was 71.0% with Pembrolizumab + Lenvatinib, 53.5% with Lenvatinib + Everolimus, and 36.1% with
Sunitinib. The relative risk of mortality with the immune-based combination vs. Sunitinib was thus 1.97
(95%CI: 1.69-2.29), while it was 1.48 (95%CI: 1.26-1.74) for the Lenvatinib + Everolimus combination vs.
Sunitinib. The percentage of patients achieving a complete response was 16.1% in the Pembrolizumab +
Everolimus arm, 9.8% in the Lenvatinib + Everolimus arm, and finally 4.2% in the Sunitinib arm.

Almost all patients in each group had adverse events of any cause: 99.7% in both the Pembrolizumab +
Lenvatinib and Lenvatinib + Everolimus arm, and 98.5% in the Sunitinib arm. Grade 3 or higher adverse
events of any cause occurred in 82.4% of the patients who received Pembrolizumab + Lenvatinib, in 83.1%
of the patients who received Lenvatinib + Everolimus, and in 71.8% of the patients who received Sunitinib.
In the ICI-containing combination, adverse events of any grade led to discontinuation of Pembrolizumab,
Lenvatinib, or both agents in 37.2% of the treated cases (Pembrolizumab: 28.7%, Lenvatinib: 25.6%, and both