Experts from the American Association for Cancer Research and the American Society of Clinical Oncology (ASCO) have teamed up again this year to present the latest in bench-to-bedside advances.

Kidney cancer is not a single disease but made up of a number of different diseases, most caused by different genes, and responding to different therapies. Renal cell carcinoma (RCC) treatment has advanced in recent years, but greater understanding is still needed. This joint session provided an update on advances in the treatment of RCC, exploring the identification of novel targets and the development of new therapies.

AACR-ASCO Joint Session: Targets in the Treatment of Renal Cell Cancer was one of the On Demand sessions, and its related live panel session took place Tuesday April 13. Registrants can watch replays of these sessions through June 21, 2021.

Targeting the genetic basis

According to W. Marston Linehan, MD, National Cancer Institute, all of the genes known to cause kidney cancer are fundamentally in the same pathway. They are all involved with the cell’s ability to respond to changes in oxygen, iron, nutrients, or energy sensing. Decades of research led to the identification of two genes at cause for a number of kidney cancers: VHL and hypoxia inducible factor (HIF).

These discoveries resulted in the development and approval by the FDA of nine agents targeting the VHL/HIF pathway for patients with advanced clear cell RCC.

Linehan also discussed abrogation of HIF-2 alpha degradation and its role in tumorigenesis, and the more recent discovery of fumarate hydratase in hereditary leiomyomatosis renal cell carcinoma (HLRCC), a hereditary form of type 2 papillary kidney cancer.

“It is our hope that by understanding the genetic basis of kidney cancer that this will provide a foundation for development of forms of therapy for all patients with this form of cancer,” Linehan said.

Use of checkpoint inhibition

Padmanee Sharma, MD, PhD, University of Texas MD Anderson Cancer Center, discussed mechanisms of response and resistance to immune checkpoint therapy in RCC.

“Immune checkpoint therapy revolutionized the way we treat cancer including patients with metastatic RCC,” Sharma said.

To date, single-agent nivolumab is approved in the second-line setting for metastatic clear cell RCC and multiple combinations of immunotherapies are approved in the front line. However, several key research questions remain, including questions about biomarkers and other possible pathways to target to improve clinical outcomes.

Sharma discussed the status of several biomarkers that have been examined in RCC, including PD-L1 and CD8 T cells.

Despite the need for better biomarkers, immune checkpoint therapy has joined the ranks of surgery, radiation, and chemotherapy as a pillar of cancer treatment, and combination strategies are the future.

Multiple immune checkpoints exist and are dynamic in their expression, Sharma said. They should be evaluated in both pre- and on-treatment human samples to guide therapeutic decisions.

The organ-specific microenvironment will also need to be considered in order to understand immunological subsets and subsequent immune responses against cancer cells in these organs. For example, Sharma discussed response to immune checkpoint therapy in bone metastases versus soft tissue metastases.

Pre-surgical and tissue-based clinical trials provide a feasible platform to study biological effects in patients, which provide insights into mechanisms that can be targeted for rational combination therapies.

Consider clinical nuances

Ulka N. Vaishampayan, MBBS, University of Michigan, discussed clinical nuances in advanced renal cancer.

Recent advances in kidney cancer research suggest that there are many clinical factors—both patient-related and disease-related—that must be considered when choosing front-line therapy, including age, histology (clear cell, medullary, papillary, sarcomatoid), sites of metastases, autoimmune disease, and organ dysfunction. Vaishampayan detailed these factors and how they might weigh into treatment decisions or the decision to recommend active surveillance.

In addition to these factors, biomarkers would also be useful to aid in treatment decisions. PD-L1 status, of course, should be considered and evaluated, but so far in kidney cancers, it has not proven to have predictive value. Additionally, genomic biomarkers such as 3p loss, HIF2alpha/HIF1alpha, PBRM1, or BAP-1 have not been validated prospectively for clinical decision-making use. There is still a paucity of predictive genomic biomarkers, Vaishampayan said.

Historically, when interferon was used as systemic therapy, cytoreductive nephrectomy resulted in an overall survival benefit compared with systemic therapy alone. Now, Vaishampayan said, things have changed, and nephrectomy is no longer standard in metastatic RCC. Recent studies such as CARMENA and SURTIME have provided evidence for targeted therapy-based approaches that might eliminate the need for surgery in this type of cancer, Vaishampayan said.

Novel targets

Howard “Skip” Burris, MD, Sarah Cannon Research Institute and Tennessee Oncology, closed the session by discussing some novel targets for RCC therapy. Recent advances include the development of the HIF-2 alpha inhibitor belzutifan, which has shown good activity and duration of treatment alone and in combination with cabozantinib in on-going clinical trials. Belzutifan is also being investigated with a number of different agents, such as everolimus, pembrolizumab, and lenvatinib, in other phase II or phase III clinical trials.

Burris also discussed the desire to have agents that affect metabolism, particularly glutaminase inhibition. The glutaminase inhibitor telaglenastat is being looked at alone and in combination with cabozantinib and has shown promising results to date. However, results of the CANTATA trial that looked at telaglenastat plus cabozantinib compared with cabozantinib alone indicate that the study did not achieve the primary endpoint; full results are not yet available.

Burris revisited interleukin-2 (IL-2), which came to trials decades ago and had dramatic and durable responses in a small number of patients but was considered a toxic regimen. Now there are a number of IL-2 immuno-oncology candidates under development. Burris spoke specifically about bempegaldesleukin (NKTR-214). One study of this drug in combination with nivolumab showed an overall response rate of 71.4 percent in first-line RCC and 28.6 percent in second-line RCC. The PIVOT-09 study will compare bempegaldesleukin plus nivolumab with sunitinib or cabozantinib.

Personalized medicine approaches under investigation include use of antibody-drug conjugates, including two in clinical trials (BA-3021 targeting CAB-ROR2 and DS-6000a targeting CDH6), and MET inhibitors. However, more novel targets are needed especially for papillary, chromophobe, and medullary subtypes.