Treatment Approaches for Renal Cell Carcinoma: Insight From the 2022 Genitourinary Cancers Symposium

Oncologists gathered for the 2022 American Society of Clinical Oncology (ASCO®) Genitourinary (GU) Cancers Symposium in San Francisco, California, and virtually to discuss the latest research, insights, and innovations in GU cancer care. This year’s symposium provided expert perspectives on the latest clinical and scientific advances in the field. The program included multidisciplinary panels and case-based discussions as well as daily oral and poster abstract sessions.
 
Robert Dreicer, MD, discussed research on RCC presented at the meeting and highlighted key takeaways. Dr Dreicer is deputy director of University of Virginia (UVA) Cancer Center in Charlottesville. He serves as the director of solid tumor oncology within the division of hematology/oncology and is a professor of medicine and urology at University of Virginia Health in Charlottesville, Virginia.

Which presentations from ASCO’s GU Cancers Symposium had the greatest clinical impact or interested you most?

The past year has been a relatively quiet one for kidney cancer research, and this was reflected at the meeting. To put that into context, we are still awaiting the final results of KEYNOTE-564 (ClinicalTrials.gov identifier: NCT03142334), a phase 3 study of adjuvant treatment of patients with clear cell renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy with or without resection of metastatic lesions. At the ASCO GU Symposium, 30-month follow-up results of KEYNOTE-564 showed that adjuvant pembrolizumab maintained a significant disease-free survival  benefit compared with placebo in this high-risk population. The 24-month disease-free survival was 78.3% with pembrolizumab and 67.3% with placebo, and no new safety signals were observed. Not enough overall survival (OS) events have been observed to draw conclusions, so additional follow-up is needed regarding this key secondary endpoint.¹
 
Additionally, Dr Michael Benjamin Atkins of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, presented final results of a phase 2 study of nivolumab as primary therapy in metastatic clear cell RCC or ipilimumab plus nivolumab as a salvage therapy in patients who had received prior immunotherapy (ClinicalTrials.gov Identifier: NCT03117309). The study demonstrated that activity of monotherapy with nivolumab is maintained in patients who are treatment-naive. However, combination therapy with nivolumab plus ipilimumab appears to be less efficacious in patients with intermediate or poor risk RCC, as defined by the International Metastatic RCC Database Consortium, than in patients with favorable risk RCC (objective response rate, 25% vs 57.1%).² The findings suggest that patient selection is important when considering salvage therapy with ipilimumab plus nivolumab following immunotherapy with nivolumab.
 
Overall, the results presented on RCC treatment represent incremental progress.

Identification of biomarkers in RCC was also discussed during the ASCO GU Symposium. Were any clinically meaningful findings presented regarding identification and use of biomarkers to guide treatment selection for patients with RCC?

This continues to be an area of active investigation, but none of the data presented at this meeting supported demonstrable progress toward routine clinical use. One study of patients with localized RCC at high risk of relapse following nephrectomy evaluated several potential biomarkers as an exploratory endpoint following neoadjuvant treatment with avelumab plus axitinib. The investigators assessed expression of programmed death-ligand 1 (PD-L1), CD8+, CD8+/granzyme B, Foxp3+ cells, CD8+/CD39+, and major histocompatibility complex I in pretreatment biopsy and nephrectomy samples from 34 patients (ClinicalTrials.gov Identifier: NCT03341845). They found that post-treatment samples had upregulated programmed death-ligand 1 expression (P <.0001) and total CD8+ densities (P <.01) compared with pretreatment biopsies. In addition, post-treatment samples from patients who did not experience recurrence showed significantly higher CD8+ densities compared with patients who did experience recurrence (P <.05). In other comparisons, however, no clear differences were observed.³ At this time, there is still no routine clinical use of any specific biomarker in kidney cancer.

The hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is a novel therapy under investigation for the treatment of RCC. How does this treatment option fit in with others that we have discussed and where might it be used in combination therapy?

Belzutifan is approved by the US Food and Drug Administration (FDA) for adult patients with von Hippel-Lindau disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery. Belzutifan is now being evaluated as monotherapy and in a variety of combinations in ongoing clinical trials as frontline and salvage therapy. The approval for frontline therapy of von Hippel-Lindau-associated syndromes was an important step. The important question of its impact on treatment of the more common RCCs is still unanswered, so more work remains to be done.

What are key challenges and unmet needs in the treatment of RCC?

Well, there are a range of challenges. The biggest unmet need is the lack of a curative treatment for metastatic kidney cancer. Most patients do not respond to immune-based therapies, and most patients who respond to treatment will experience disease progression. Development of therapies that are active in patients with primary or secondary immune resistance is a critical unmet need.

We also need predictive biomarkers to determine who is more likely to respond to an immune-based therapy. Although newer immune-based therapies are available for first-line use, we need new drugs and strategies that enable patients to overcome treatment resistance. After receiving immune-based therapy, most patients with RCC receive targeted therapy with tyrosine kinase inhibitors that target vascular endothelial growth factor receptor. These are toxic therapies. Ultimately, we need better treatment options and better ways to identify which patients are more likely to benefit from a certain regimen.

What are some other potentially practice-changing trials to watch for?

Several ongoing trials could inform or even alter current clinical practice in the RCC space, depending on their outcomes. As I mentioned, the most important trial presented at ASCO’s GU Cancers Symposium was the update from the KEYNOTE-564 study of adjuvant pembrolizumab, which has been approved for patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. We are waiting for the OS results; if they show that earlier integration of therapy with an immune checkpoint inhibitor in the adjuvant setting allows people to live longer, that will be practice-altering. Right now, the findings inform practice and suggest that this therapy should be considered for selected patients. An OS benefit would likely make this treatment approach a standard of care.