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. Author manuscript; available in PMC: 2022 Dec 22.
Published in final edited form as: Nat Rev Urol. 2022 Nov;19(11):631–632. doi: 10.1038/s41585-022-00651-9

The shifting treatment paradigm of metastatic renal cell carcinoma

Yasser Ged 1,✉, Mark C Markowski 1, Nirmish Singla 2, Steven P Rowe 3
PMCID: PMC9774042  NIHMSID: NIHMS1850241  PMID: 36064785

Abstract

The treatment landscape of renal cell carcinoma is rapidly evolving, especially with the introduction and approval of immune checkpoint inhibitor combination therapies. Clinical trial data show substantial improvements in patient outcomes, and now results in the real-world setting support the use of these combinations.

Over the past two decades, considerable advances have been made in understanding clear cell renal cell carcinoma (ccRCC) biology, which, in turn, has led to the approvals of multiple new systemic therapies1. Currently, immune checkpoint inhibitors (ICIs) blocking programmed cell death protein 1 (PD1) or its ligand (PDL1) or cytotoxic T lymphocyte-associated protein 4 (CTLA4) are the backbone of front-line systemic therapy in metastatic ccRCC, either as doublet ICI combinations or ICI plus vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations, of which four have been approved by the FDA2.

Survival has improved with these agents; furthermore, increased rates of complete response (CR) and durable remissions are setting new treatment end-point benchmarks. Based on results from previous studies, CR rates have improved from <5% with VEGFR-TKIs to 10–16% with ICI combinations3. The latest ICI plus VEGF–TKI combination to be approved by the FDA was lenvatinib plus pembrolizumab (which led to a CR rate of 16% based on the CLEAR phase III clinical trial4) in August 2021. However, as we move into using these combinations in the real-world practice setting, uncertainty exists concerning whether such high CR rates will be observed in a non-clinical trial population5. Real-world observations suggest that high CR rates are a possibility; for example, a 67-year-old woman with metastatic ccRCC experienced a remarkable CR after 4 months of treatment with first-line standard-of-care lenvatinib plus pembrolizumab, including complete resolution of an 8 cm anterior mediastinal mass (FIG. 1). This case and others that we see in our day-to-day practice give further support to using these combinations in the real-world practice setting.

Fig. 1 |. Dramatic treatment response to systemic therapy in metastatic renal cell carcinoma.

Fig. 1 |

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A 67-year-old woman with metastatic renal cell carcinoma at baseline (parts a and b) and after 4 months of therapy with the combination of lenvatinib plus pembrolizumab (parts c and d). Axial arterial-phase CT through the chest demonstrates a large mediastinal mass with heterogeneous arterial enhancement (arrow), as well as a partially visualized right humerus pathological fracture with a large enhancing soft-tissue component (arrowhead) (part a). Axial arterial-phase CT also demonstrates metastatic disease to the left upper lobe (arrow) (part b). Follow-up imaging shows complete radiographic response with resolution of all visible sites of disease (parts c and d).

Future large-scale, observational cohort and registry studies are needed to provide insight into the extension of clinical trial data of ICI therapies to more diverse real-world patient populations6. Multiple multi-institutional registry observational studies are currently ongoing, including an observational study of avelumab plus axitinib in metastatic RCC in the UK (NCT05394493) and the outcomes database to prospectively assess the changing therapy landscape in renal cell carcinoma (ODYSSEY RCC) observational phase IV study in the USA (NCT04919122). However, despite these advances, multiple challenges still remain in the management of metastatic RCC, including the discovery of therapies with novel mechanisms of action, the identification of biomarkers predictive of treatment responses and toxic effects, and understanding mechanisms of resistance to RCC treatments7,8. Several studies are currently ongoing both in the front-line and treatment-refractory settings to investigate novel therapies and treatment strategies in RCC. Belzutifan (which is a highly specific hypoxia-inducible factor 2α inhibitor with promising activity and tolerability in patients with metastatic ccRCC who have received multiple previous treatments)9,10 is one of the most promising novel therapies in RCC. Belzutifan is currently being studied in a phase III first-line study of triplet therapy in combination with lenvatinib and pembrolizumab (NCT04736706).

To conclude, the treatment landscape of RCC is rapidly evolving, which has resulted in considerable improvements in patient outcomes both in the clinical trial and real-world practice setting. Multiple studies are currently ongoing to address the current challenges in RCC and uncover new therapeutic strategies and interventions.

Footnotes

Competing interests

The authors declare no competing interests.

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