Table 1 Current targeted molecular agents recommended for the treatment of advanced/metastatic ccRCC

Pembrolizumab

Monoclonal antibody

PD-1

First-line for advanced ccRCC when used in combination with TKI lenvatinib or axitinib. Higher PFS and OS for pembrolizumab + lenvatinib, with more serious adverse events than pembrolizumab + axitinib or nivolumab + cabozatinib [13]. Combination with lenvatinib has higher incidences of blood, lymphatic system, metabolism, and vascular disorders, while the combination with axitinib has higher incidence of cardiac and hepatobiliary toxicity, axitinib has a shorter half-life [14], usually with more easily manageable toxicities.

Nivolumab

Monoclonal antibody

PD-1

First-line therapy when used in combination with TKI cabozantinib or ipilimumab. Nivolumab + cabozantinib has slightly superior PFS, OS than nivolumab + ipilimumab, with more serious adverse events [13].

Ipilimumab

Monoclonal antibody

CTLA-4

First-line for intermediate- and poor-risk advanced ccRCC when combined with nivolumab, lower rate of severe adverse events than more potent combinations [13].

Avelumab

Monoclonal antibody

PD-L1

First-line for PD-L1 positive advanced ccRCC when used in combination with TKI axitinib. Avelumab is cleared faster and has a shorter half-life than other anti–PD-L1 antibodies, such as atezolizumab and durvalumab [15].

Lenvatinib

TKI (multi-kinase)

VEGFR, FGFR, (others)

First-line for advanced ccRCC when used in combination with pembrolizumab. Very potent TKI. Less selective. Higher PFS and OS for pembrolizumab + lenvatinib, with more serious adverse events than pembrolizumab + axitinib or nivolumab + cabozatinib [13].

Axitinib

TKI

VEGFR

Highly selective for VEGFR, the first line for advanced ccRCC when combined with avelumab or pembrolizumab. Better ORR, OS, and PFS compared to sunitinib [16]. Shorter half-life compared to other TKIs.

Cabozantinib

TKI (multi-kinase)

VEGFR (others)

First-line for advanced ccRCC when combined with nivolumab and used alone when ICI therapies are not indicated. Prolonged PFS compared with sunitinib for intermediate- or poor- risk advanced RCC [17]. Very potent TKI. Less selective. In combination with nivolumab, it has lower rates of serious adverse events compared with lenvatinib or axitinib in combination with pembrolizumab.

Sunitinib

TKI

VEGFR

Widely used previously as a first-line agent. Inferior performance alone compared to most first-line combinations of ICI-TKI or ICI-ICI. Option for patients for whom ICI therapy is not indicated. Superior to Sorafenib in PFS, with a similar OS [18].

Pazopanib

TKI

VEGFR

An alternative when ICI therapy is not indicated. Developed as a newer, more selective agent. Better patient-reported outcomes over sunitinib [19].

Sorafenib

TKI

VEGFR

An alternative when ICI therapy is not indicated. Inferior to sunitinib in PFS, with a similar OS. Superior to tivozanib considering OS [20].

Tivozanib

TKI

VEGFR

Alternative to relapsed or refractory advanced RCC following at least two prior systemic therapies. Superior PFS and ORR but inferior OS when compared to sorafenib [20].

Everolimus

Small molecule inhibitor

mTOR

Everolimus with lenvatinib was superior to sunitinib alone, considering PFS, without OS benefit [21] and can be recommended after first-line treatments.