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

drugs: 13.4%), to dose reduction of Lenvatinib in 68.8% of patients, and to interruption of Lenvatinib,
Pembrolizumab, or both drugs in 78.4% of patients.

In the Lenvatinib + Everolimus arm, adverse events of any grade led to discontinuation of Lenvatinib,
Everolimus, or both agents in 27.0% of patients (Lenvatinib: 22.0%, Everolimus: 24.8%, and both drugs:
18.9%), to dose reduction of Lenvatinib, Everolimus, or both agents in 73.2% of cases, and led to
interruption of Lenvatinib, Everolimus, or both drugs in 83.4% of the patients.

Finally, in the Sunitinib arm, the relative figures were: 14.4% for discontinuation, 50.3% for dose reduction,
and 53.8% for treatment interruption.

The combination of Pembrolizumab + Lenvatinib thus joined the other three above mentioned combination
as possible standards of care for the treatment of mRCC patients.

Avelumab + Axitinib (JAVELIN Renal 101)
In this study, 886 previously untreated mRCC patients were randomized to either the combination of the
[5]
anti-PD-L1 monoclonal antibody Avelumab with the VEGFR-TKI Axitinib, or Sunitinib monotherapy .

Avelumab was administered at a dose of 10 mg/kg of body weight as a 1 h intravenous infusion every 2
weeks, following premedication with an antihistamine and acetaminophen. Axitinib was administered
orally at a starting dose of 5 mg twice daily on a continuous dosing, while Sunitinib was administered at the
dose of 50 mg orally, o.d., on a 4 weeks-on, 2 weeks-off, schedule. Dose escalations and reductions for
Axitinib, and dose reductions for Sunitinib, were allowed per protocol.

Although the original primary objective of the study was PFS in all enrolled patients, during study
conduction, an amendment made PFS and OS among patients with PD-L1-positive tumors the study’s
novel co-primary endpoint, with key secondary end points being PFS in the overall population, ORR, and
safety.

Among the patients who had PD-L1-positive tumors (560, 63.2%), PFS was significantly longer among those
who received the immune-based combination, as compared to those who received Sunitinib monotherapy.
Indeed, the median PFS was 13.8 months (95%CI: 11.1-NE) with Avelumab + Axitinib, as compared with
7.2 months (95%CI: 5.7-9.7) with Sunitinib (stratified HR = 0.61; 95%CI: 0.47-0.79; P < 0.001).

As far as OS, among PD-L1-positive patients, deaths from any cause were observed in 37 patients (13.7%)
who received the combination vs. 44 (15.2%) who received Sunitinib (stratified HR = 0.82; 95%CI: 0.53-1.28;
P = 0.38).

Among the patients with PD-L1-positive tumors, the confirmed ORR was 55.2% (95%CI: 49.0-61.2) with
Avelumab + Axitinib vs. 25.5% (95%CI: 20.6-30.9) with Sunitinib, confirmed complete response rates being
4.4% and 2.1%, respectively.

In the overall population, median PFS was also significantly longer with Avelumab + Axitinib than with
Sunitinib: 13.8 months (95%CI: 11.1-NE) vs. 8.4 months (95%CI: 6.9-11.1), with HR for progression or
death being 0.69 (95%CI: 0.56-0.84; P < 0.001).