Optimal Systemic Therapy for Renal Cell Carcinoma Is Still Evolving

June 2023, Vol 14, No 3 - Online Only

Surgery is typically the gold standard for patients with biopsy-proven, clear cell, renal cell carcinoma (RCC) with no evidence of metastatic disease, said Eric Jonasch, MD, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, in a session during the 2023 National Comprehensive Cancer Network (NCCN) Annual Conference. In this setting, there is probably not a role for systemic neoadjuvant treatment, as response rates of 15% to 45% have been recorded with axitinib (Inlyta), sunitinib (Sutent), and other tyrosine kinase inhibitors (TKIs).

Locally Advanced RCC at Risk for Progression

Diligent postoperative surveillance is strongly warranted for patients with locally advanced RCC at increased risk for disease progression or recurrence, Dr Jonasch said. Systemic therapy options for RCC with clear cell histology now include adjuvant immunotherapy with pembrolizumab (Keytruda) or sunitinib, according to the updated NCCN Guidelines: Kidney Cancer (Version 4.2023).1

Most clinical trials of adjuvant systemic therapy following nephrectomy in patients with high-risk RCC have shown little benefit, he noted. The exception is sunitinib, which improved disease-free survival (DFS) by 24% in the S-TRAC study, but with no benefit in terms of overall survival (OS).

KEYNOTE-564 was a landmark phase 3, randomized, controlled clinical trial of adjuvant pembrolizumab versus placebo in patients with high-risk localized RCC tumors after resection. In an update of the study, with a median follow-up of 30.1 months, DFS was superior in the pembrolizumab arm (hazard ratio, 0.63), but data on OS were not yet mature. The results from the trial were the basis for the FDA approval of pembrolizumab in this setting. The indications for adjuvant pembrolizumab based on KEYNOTE-564 are tumor stage III to IV N0, TanyN1, and resected M1 RCC.

“We probably need better biomarkers ultimately to select which patients are at risk for progression, in addition to liquid biopsy/circulating tumor DNA to identify early recurrence,” Dr Jonasch said.

Oligometastatic Papillary and Nonclear Cell RCC

The approach to oligometastatic papillary RCC is surgery or ablative techniques, including stereotactic body radiotherapy (SBRT), as well as systemic therapy. SBRT allows for targeting the area with relatively little off-target side effects, he said. With clear cell histology, adjuvant pembrolizumab is recommended within 1 year of nephrectomy, according to the NCCN Guidelines.1

For relapsed or stage IV nonclear cell RCC, preferred systemic regimens, per the NCCN Guidelines, are cabozantinib (Cabometyx), sunitinib, and enrollment in a clinical trial.

Eric Jonasch, MD

“These [recommendations] are in a state of evolution,” Dr Jonasch explained. Other recommended regimens include doublets such as nivolumab (Opdivo) plus cabozantinib and lenvatinib (Lenvima) plus everolimus, as well as single-agent nivolumab and pembrolizumab.

Sunitinib was compared with everolimus in nonclear cell RCC, with no significant advantage found for sunitinib, and a progression-free survival (PFS) in the range of 5 to 6 months. The PAPMET study evaluated 4 agents in patients with papillary RCC. After an interim analysis, the study was consolidated into 2 arms (cabozantinib and sunitinib). An improvement in PFS with cabozantinib over sunitinib was observed, “making cabozantinib probably a more favored choice for individuals with papillary RCC,” Dr Jonasch said.

“We think of clear cell RCC as the only immunogenic tumor in the kidney cancer spectrum, but that’s probably not true,” Dr Jonasch went on to say. “Papillary RCC does have immune cell infiltrates, unlike chromophobe. The idea that using immunotherapy is reasonable was borne out by the KEYNOTE-427 study that had a clear cell and a nonclear cell arm.” In the arm that enrolled patients with nonclear cell RCC, the objective response rate (ORR) was 26.7%.

The combination of cabozantinib plus nivolumab was tested in patients with nonclear cell RCC, with an ORR of 47.5% for cohort 1, which consisted of patients with papillary or unclassified histology. Cohort 2, which enrolled patients with chromophobe RCC, was closed due to futility.

Among patients with oligometastatic disease, a subset will demonstrate a small number of lesions with slow growth kinetics.

“These patients can be observed initially, and local treatment can be applied to these lesions, but oligometastatic disease does lend itself well to surgery or SBRT,” Dr Jonasch said. “We’re still working our way toward getting strong data for systemic therapy in this grab bag of histologies [papillary, chromaphobe, medullary, translocation, etc]. It’s a very heterogeneous group of patients, with most being papillary or chromaphobe. Multidisciplinary input is critical, including neurosurgery, radiation oncology, and medical oncology, to come up with the best treatment choices.”

Dr Jonasch said that emerging evidence suggests cabozantinib monotherapy and immune-oncologic/TKI therapies are effective in papillary—and potentially in undifferentiated—histologic subsets. Significant efforts should be directed toward better defining treatment options for patients progressing or those refractory to frontline agents, he concluded.


  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Kidney Cancer. Version 4.2023. January 18, 2023. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed April 18, 2023.

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