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Personalizing First-Line Treatments for Metastatic Renal Cell Carcinoma
Advances in immunotherapy and targeted therapies have revolutionized the treatment of metastatic renal cell carcinoma (mRCC), according to Kelly Fitzgerald, MD, and Chung-Han Lee, MD, PhD, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (JNCCN. 2022; doi:10.6004/jnccn.2022.7003). These advances include immune checkpoint inhibitors (ICIs) and new tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor.
Several regimens incorporating these agents have been approved for the first-line treatment of RCC. Nevertheless, most of these regimens have not been directly compared, which makes choosing a first-line treatment regimen for specific patients challenging. Making such a choice depends on many factors, such as the cancer’s histopathologic and clinical features and the patient’s comorbidities.
“Historically, treatment options for advanced RCC have been severely limited,” wrote Drs Fitzgerald and Lee, adding, “This review discusses current standards of care in the systemic treatment of advanced RCC and describes an approach to personalizing patient care in the modern era.” Drs Fitzgerland and Lee wrote, “We begin with a summary of the approved regimens for the first-line management of RCC and conclude with a discussion of patient and disease characteristics that may guide an individualized approach to first-line treatment selection.”
For selected patients with clear cell RCC, high-dose interleukin-2 (IL-2) is still listed as an option in National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Kidney Cancer (NCCN Guidelines). Nevertheless, Drs Fitzgerald and Lee recommend against using IL-2 instead of ICIs, which are more tolerable and effective. They include ipilimumab, nivolumab, and pembrolizumab.
In NCCN Guidelines, ipilimumab plus nivolumab is the only preferred first-line treatment for clear cell RCC when immunotherapy is used alone. For patients with non–clear cell RCC who have contraindications to treatment with TKIs, pembrolizumab plus nivolumab can be considered, but the efficacy of this combination is limited.
Single-agent TKI therapy may be appropriate for patients who prefer the convenience of oral therapy or wish to avoid the potential toxicities of immunotherapy-based regimens. Agents approved for first-line use in RCC include sunitinib, pazopanib, axitinib, lenvatinib, and cabozantinib. However, in NCCN Guidelines, cabozantinib is the only TKI monotherapy listed as a preferred treatment for patients with intermediate- or poor-risk clear cell RCC, and cabozantinib and sunitinib are the only preferred first-line treatment options for non–clear cell RCC.
Combinations of TKIs with immunotherapies include axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab, which are all approved for the first-line treatment of metastatic clear cell RCC.
Regarding factors to consider in selecting a first-line treatment regimen, an accurate understanding of histologic subtype is crucial, as is determining the genomic features underlying the disease. The distribution and size of metastases and potential for organ crisis can also guide choice of therapy. Regarding comorbidities, relative contraindications to immunotherapy include active autoimmune disease or any condition requiring immunosuppressive therapy.
“In light of the multiple approved therapies with lack of direct comparisons among them, the initial management decision becomes highly personalized and depends on all of the patient-specific factors discussed herein,” Drs Fitzgerald and Lee concluded.
