Renal cell carcinoma (RCC) is one of the top 10 most common cancers, although incidence rates have been stable over the past decade. It is more common in men than women and rates are higher among African American, American Indian, and Alaska Native patient populations.

Despite RCC being classified as an orphan disease before 2005, significant advances have been made in this field in the past 2 decades. Among these are the development of vascular endothelial growth factor (VEGF) inhibitor tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and checkpoint inhibitors that target both the PD-1 axis and CTLA-4 axis.

Single-agent drugs kicked off the era of clinical developments and their efficacy was based on improvements in progression-free survival (PFS). Later, an overall survival (OS) advantage was demonstrated by single-agent drugs such as nivolumab (Opdivo) and cabozantinib (Cabometyx).

Beginning in 2018,2 novel combination regimens of 2 immuno-oncology (IO) agents or an IO agent paired with a TKI started to appear. Soon 5 combination regimens were available or recommended for use in patients with RCC:

Axitinib (Inlyta) plus pembrolizumab (Keytruda) 

The trials conducted in the combination space used International Metastatic RCC Database Consortium (IMDC) criteria for risk grouping and stratification. The criteria were used in routine practice for risk grouping and treatment selection.

Results from all the combination studies (CheckMate 214 [NCT02231749], KEYNOTE-426 [NCT02853331], JAVELIN Renal 101 [NCT02684006], CheckMate 9ER [NCT03141177] and CLEAR [NCT02811861]) consistently demonstrated the value of the single-agent TKI, sunitinib (Sutent), in the favorable-risk group. However, patients in the Immunotherapeutic Targets and Therapy for Renal Cell Carcinoma group benefitted at large from these combinations. The current NCCN clinical practice guidelines include sunitinib and pazopanib (Votrient) for patients with RCC who have favorable-risk disease. Additionally, the combination regimens of axitinib plus pembrolizumab and cabozantinib plus nivolumab are included as preferred regimens.

The use of IMDC risk grouping has been more prevalent since 2018. The IMDC-risk scoring can be calculated by using the 6 factors: time from diagnosis to treatment of less than 1 year, Karnofsky performance status less than 80%, hemoglobin level less than the lower limit of normal, calcium level greater than the upper limit of normal (ULN), absolute neutrophil count greater than the ULN, and platelet count greater than the ULN. Risk grouping categorizes patients into favorable (0 factors), intermediate (1 or 2 factors), or poor (3 to 6 factors) status. The NCCN clinical practice guidelines for selecting first-line treatment for patients with RCC are shown in TABLES 1 AND 2.

High-dose IL-2 and temsirolimus are seldom used in this setting today because there are more efficacious drugs that can produce better outcomes.

TABLE 1. International Metastatic Renal Cell Carcinoma Database Consortium Criteria3

TABLE 2. NCCN First-line Recommended Therapy Options for Patients with Clear Cell Histology3

IO combinations have resulted in improvements in OS and health-related quality of life (QOL) for patients with advanced RCC, with the expected median OS now exceeding 4 years based on long-term follow-up data from CheckMate 214.5 Investigators are expected to present mature data for additional IO-TKI combinations soon.

Consider Comorbidities in Selecting Treatment 

Five combination regimens in addition to single agent pazopanib and sunitinib is an embarrassment of riches and could make it challenging to choose a frontline treatment option. Fortunately there are seldom dilemmas in selecting the best first drug.

TKI or TKI-based combinations should be avoided as the first treatment option for patients with uncontrolled hypertension, congestive heart failure, ischemic heart diseases, and other peripheral arterial diseases. In such situations it is best to use a single-agent PD-1 inhibitor or an IO-IO combination.

for patients with uncontrolled hypertension, congestive heart failure, ischemic heart diseases, and other peripheral arterial diseases. In such situations it is best to use a single-agent PD-1 inhibitor or an IO-IO combination.

If patients present with pathological fractures and if surgical intervention such as open reduction and internal fixation is likely indicated, it is best to avoid a TKI or TKI-based combination regimen as the first drug because of potential risks with wound healing and surgical complications resulting from the vascular targeting by such agents. In such situations, TKI-based therapies could be used as second-line therapies.

Finally, in patients who present with multiple uncontrolled or innumerable brain metastases, it is better to avoid TKI-based regimens because of the increased chance of hemorrhage in uncontrolled brain lesions. These scenarios also make it safer to use single-agent IO or IO-IO combinations as the first treatment.

Novel drugs and IO combinations make it possible for patients to live many years, therefore it is important to use the appropriate regimen to support maximal QOL and survival.

The guidance outlined here can help with selecting personalized first-line options for patients with advanced RCC. Additionally, discussing difficult cases in a multidisciplinary tumor board and consulting with other specialists as needed is recommended.

When optimally used, these new treatment options make it possible for patients to maintain or even improve health-related QOL and for clinicians to begin viewing RCC as a chronic illness.

SEER cancer stat facts: kidney and renal pelvis cancer. National Cancer Institute. Accessed May 6, 2021. https://seer.cancer.gov/statfacts/html/kidrp.html

Hematology/oncology (cancer) approvals and safety notifications. FDA. May 5, 2021. Accessed May 6, 2021. https://www.fda.gov/drugs/resources-information- approved-drugs/hematologyoncology-cancer-approvals- safety-notifications

NCCN. Clinical Practice Guidelines In Oncology. Kidney cancer, version 4.2021. Accessed May 6, 2021. https://www.nccn.org/professionals/physician_gls/pdf/ kidney.pdf

Motzer RJ, Jonasch E, Boyle S, et al. NCCN guidelines insights: kidney cancer, version 1.2021. J Natl Compr Canc Netw. 2020;18(9):1160-1170. doi:10.6004/jnccn.2020.0043

Albiges L, Tannir N, Burotto M, et al. Nivolumab plus ipilimumab (N+I) vs sunitinib (S) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214: 4-year follow-up and subgroup analysis of patients (pts) without nephrectomy. Ann Oncol. 2020;31(suppl 4): S559-S560. doi:10.1016/j.annonc.2020.08.783

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Renal cell carcinoma is one of the top 10 most common cancers, although incidence rates have been stable over the past decade. It is more common in men than women and rates are higher among African American, American Indian, and Alaska Native patient  populations.

Saby George, MD, FACP, Roswell Park

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