Plenary session 4 report: The VHL mechanism and IMT-based management for RCC

To kickstart Plenary session 4, Prof. W. Marston Linehan (US) presented the Society of Urologic Oncology (SUO) lecture “The VHL kidney cancer gene: Discovery, oxygen sensing and therapy”.

To identify kidney cancer genes, Prof. Linehan and his team studied hereditary forms of renal cancer by following nearly 2,400 patients from over a thousand families with clear cell, papillary, chromophobe, and oncocytic renal cell cancer (RCC), then proceeded to focus on the von Hippel-Lindau (VHL) disease, the most well-known form of hereditary clear cell RCC (ccRCC) at the time.

Over the years, the team developed an overall approach for the management of renal tumours based on the genotype:

1. 1. For patients with VHL disease, Chromosome 3 Translocation, BAP1, hereditary papillary renal carcinoma (HPRC), or Birt-Hogg-Dubé (BHD), the recommendation is active surveillance then surgical intervention if the largest tumour reaches 3 cm in size.
   2. For patients with hereditary leiomyomatosis and renal cell cancer (HLRCC), translocation, and succinate dehydrogenase (SDH) renal cancer, upfront surgery with wide margins is recommended.

To find the gene for ccRCC, they conducted genetic linkage in families affected with VHL disease.  They localised the gene to the short arm of chromosome 3 and with physical mapping identified the VHL gene.

“The VHL gene is a two-hit, loss-of-function, tumour-suppressor gene. When we place these cells from a human RCC into a mouse, it grows into a tumour just like it does in our patients. However, when we put a normal copy of that gene back in, there was either no tumour or a very small tumour growth,” stated Prof. Linehan.

He cited the study of Dr. William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Dr. Gregg L. Semenza, who were awarded the 2019 Nobel Prize in Physiology or Medicine. They discovered how cells can sense and adapt to changing oxygen availability, and identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen.

“In ccRCC, when the VHL gene is mutated, VHL can’t bind its partners or it can’t bind and degrade hypoxia-inducible factor (HIF). Either way, HIF accumulates even when the oxygen levels are normal. Understanding this pathway provided the foundation for the development of the 9 FDA-approved therapies targeting the downstream VHL/HIF pathway,” said Prof. Linehan.

He added, “HIF-2α was found to be critical for ccRCC tumorigenesis. These findings led to the development of agents such as Belzutifan targeting HIF-2α transcription. A multi-centre clinical trial is currently being conducted to evaluate the effect of HIF-2α inhibition with Belzutifan on VHL-associated clear cell kidney cancer.  At the recent ASCO meeting, remarkable responses were reported by Dr. Ramaprasad Srinivasan and his colleagues: 49% response with 49% stable disease in which 92% of patients had a decrease in the size of the targeted lesions in kidney cancer. In a trial with patients with sporadic non-familial ccRCC, Dr. Toni K. Choueiri and his colleagues recently reported that there was an 80% partial response or stable disease in patients with advanced disease, in which 69% experienced tumour shrinkage targeting the VHL/HIF pathway.

“We hope that understanding the pathway of each kidney cancer gene will provide the foundation for the development of more effective forms of diagnosis, management, and therapy for all patients with this disease,” concluded Prof. Linehan.

IMT-based management

In his presentation “State-of-the-art lecture: Immunotherapy-based management of metastatic clear-cell and variant RCC: What can we achieve?”, Dr. Ignacio Duran (ES) stated that IMT-based combinations can provide a long-term benefit in a substantial percentage of patients with metastatic clear cell RCC.

Furthermore, if decreasing tumour burden is the priority, immuno-oncology (IO)-tyrosine kinase inhibitors (TKI) doublets provide a higher chance of objective response rate, although probably at the cost of increased toxicity or, possibly, worse quality of life.

He added that deep and long-lasting responses are achieved with both IO-IO and IO-TKI. However, the more extensive follow-up data available is from IO-IO.

“A subgroup of patients may not derive a clear benefit from IO-based combinations and could be treated with the single-agent TKI. However, this is still a work in progress. We may need a longer follow-up,” said Dr. Duran.

Sarcomatoid RCC patients, in particular, benefit from IMT-based combinations versus traditional alternatives for this patient population.

To watch and/or review all Plenary Session 4 presentations and case-based debates in full, you can access them via the On Demand feature of the EAU21 Virtual Platform.