Selecting Frontline and Subsequent Treatment Options for Metastatic RCC
Key Points
- In metastatic renal cell carcinoma (RCC), standard frontline treatment options are immune checkpoint inhibitor plus a tyrosine kinase inhibitor (TKI) or double immune checkpoint inhibitor combinations.
- Frontline immunotherapy and TKI combinations are preferred for many patients, although dual immunotherapy regimens may be more effective for patients with sarcomatoid features.
- Cabozantinib monotherapy is a favored second-line option for patients who did not receive nivolumab plus cabozantinib in the first line.
- Subsequent options after second-line cabozantinib include lenvatinib plus everolimus, tivozanib, axitinib, and belzutifan combinations.
Metastatic RCC Treatment Options and Considerations
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with genitourinary medical oncologist Pedro Barata, MD, MSc, FACP, of University Hospitals, to discuss two cases of metastatic RCC as part of the Challenging Cases series. The doctors focused on frontline treatment options in the metastatic setting, as well as standard sequencing and emerging options for subsequent lines of therapy.
Frontline Treatment of Metastatic Clear Cell RCC
The first case described a 71-year-old man with a past history of smoking who presented with right flank pain and weight loss over a 2-month period. The patient had mild chronic kidney disease, and was on amlodipine for hypertension and metformin for type 2 diabetes. CT imaging identified multiple bone lesions, lung nodules, and a right renal mass measuring 9 cm. A lung biopsy analysis confirmed a diagnosis of grade 3 metastatic clear cell RCC. Further workup showed anemia and hypercalcemia.
The standard frontline treatment for a patient with metastatic RCC is one of three immunotherapy-plus-TKI combinations (nivolumab plus cabozantinib, pembrolizumab plus axitinib, or pembrolizumab plus lenvatinib) or dual immunotherapy with ipilimumab plus nivolumab. Among these options, current data support that immunotherapy plus TKI combinations have more favorable response rates, tumor control, and a lower risk of progressive disease compared with dual immunotherapy for most patients, said Dr. Barata. However, ipilimumab plus nivolumab may be favored for patients with sarcomatoid features.
Among immunotherapy-plus-TKI combinations, Dr. Barata often uses nivolumab plus cabozantinib or pembrolizumab plus lenvatinib in his practice, based on data showing lower rates of progressive disease. Nivolumab plus cabozantinib also offers a good balance of efficacy and tolerability. In real-world practice, it may be effective for oncologists to become comfortable with a single regimen and to optimize tolerability, dose adjustments, and side-effect management as much as possible, said Dr. Barata.
Later Lines of Treatment for Metastatic RCC
The second case the doctors discussed involved a 74-year-old patient who previously underwent a right radical nephrectomy, but was diagnosed with metastatic clear cell RCC after presenting with left adrenal metastasis and pulmonary nodules. For frontline therapy, the patient was started on nivolumab plus ipilimumab and had a partial response for 14 months. After further progression with new hepatic lesions, the patient received cabozantinib for 10.5 months and showed shrinkage of pulmonary nodules with stable hepatic lesions until restaging scans identified progressive disease.
For patients already treated with cabozantinib in the first or second line, third-line treatment options include lenvatinib plus everolimus, tivozanib, axitinib, and belzutifan. Dr. Barata tries to ensure patients receive both cabozantinib and lenvatinib at some point during the course of treatment, so lenvatinib plus everolimus is a frequent choice—although he maintains a low threshold to drop everolimus and continue lenvatinib as monotherapy. Otherwise, tivozanib is a strong choice based on data from the TIVO-3 trial.
Data are also emerging for belzutifan combinations as early as the second line, such as the LITESPARK-011 trial on lenvatinib plus belzutifan. However, belzutifan is associated with unique side effects like hypoxia, and oncologists may need to implement new management strategies when using belzutifan. Ultimately, the choice of therapy across treatment settings should be a shared decision based on what patients can tolerate and their treatment goals, the doctors agreed.