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Targeting HIF-2 Has the Potential to Improve Outcomes for Patients with Clear-Cell Renal-Cell Carcinoma

TOP - January 2021 Vol 14, No 1

In a keynote address during the virtual 2020 International Kidney Cancer Symposium, William G. Kaelin Jr, MD, Sidney Farber Professor of Medicine, Dana-Farber Cancer Institute, Boston, MA, provided an update on treatment strategies aimed at improving outcomes for patients with clear-cell renal-cell carcinoma (RCC) caused by inactivation of the VHL gene. Promising therapies include immunotherapies, hypoxia-inducible factor (HIF)-2α inhibitors, and cyclin-dependent kinase (CDK)4/6 inhibitors.

Loss of VHL function is the initial or truncating event in the pathogenesis of clear-cell RCC. In other forms of cancer, targeting the truncal mutations, such as HER2/neu in breast cancer and BRAF in melanoma, has been successful in improving outcomes.

“To exploit gene–gene interactions, in which late mutations are only tolerated because of early mutations, we should be targeting VHL,” Dr Kaelin said. “You can start to dream what an eventual kidney cancer curative combination will look like. I suspect that it will contain a VEGF [vascular endothelial growth factor] inhibitor, an immune checkpoint inhibitor, maybe a HIF-2α inhibitor, maybe a CDK 4/6 inhibitor, [and] maybe even a MET [mesenchymal-epithelial transition] inhibitor,” he added.

HIF-2α is a transcription factor that is a key oncogenic driver in clear-cell RCC. HIF is a master regulator of hundreds of genes that promote adaptation to a low-oxygen environment, “perhaps the best studied of which is VEGF,” said Dr Kaelin. “We’re now up to 7 FDA-approved for the treatment of kidney cancer. So that’s the good news. The bad news is that some patients don’t respond to these, and even those patients who do respond eventually progress. So how can we do better?” he asked.

Targeting HIF itself, specifically HIF-2α, is one possibility. An early HIF-2α antagonist, PT2399, was shown to decrease HIF-2α–dependent transcription in selected VHL-deficient clear-cell RCC models. In other preclinical models, tumor formation by some VHL-/- kidney cancer cell lines were not inhibited by PT2399, although a pharmacodynamic response to the drug was observed. Differential sensitivity to PT2399 in preclinical studies and in clinical trials and the development of resistance with prolonged treatment suggested a need for complementary approaches.

Agents that demonstrate synthetic lethality, such as CDK4/CDK6 inhibitors, may be a viable approach. The synthetic lethality observed with CDK4/CDK6 inhibitors appears to be HIF-independent, noted Dr Kaelin. Adding a CDK4/CDK6 inhibitor to PT2399 synergistically suppressed VHL-/- cell growth in HIF-2–sensitive cell lines, and palbociclib (Ibrance) alone and in combination with PT2399 suppressed orthotopic xenograft growth.

According to Dr Kaelin, recent studies have shown that HIF-2α can be targeted by a class of orally bioavailable, selective inhibitors. One such agent targeting HIF-2α is MK-6482 (belzutifan), which was evaluated in an open-label phase 2 clinical trial of 61 patients with von Hippel Lindau disease who had at least 1 measurable RCC tumor. Patients were administered 120 mg of MK-6482 orally once daily until disease progression or intolerable toxicity. Those who received MK-6482 had a confirmed objective response rate of 27.9%, which included 17 partial responses. Eight additional patients (13.1%) had an unconfirmed partial response. Responses were also observed in patients with central nervous system, retinal, and pancreatic lesions. The median duration of response had not yet been reached.

A total of 43 (70.5%) patients achieved stable disease with MK-6482. Notably, most of the patients (86.9%) had a reduction in the size of their target lesions. At 12 months, the progression-free survival rate was 98.3% and median progression-free survival had not been reached.

All 61 patients were included in the safety analysis of the study. Adverse events (AEs) of any grade occurred in 100% of patients, and treatment-related AEs occurred in 59 patients (96.7%). Of the AEs observed, 19.7% were grades 3 to 5 in severity. Grade 3 treatment-related AEs were observed in 6 patients (9.8%) and there were no grade 4/5 treatment-related AEs observed. The most common any-grade AEs experienced by patients in the study were anemia (86.9%), fatigue (57.4%), headache (36.1%), dizziness (31.3%), and nausea (24.6%). Grade 3 AEs included fatigue (4.9%), anemia (3.3%), arthralgia (1.6%), and weight gain (1.6%).

Based on these data, the FDA granted a breakthrough therapy designation to MK-6482 for the treatment of patients with VHL disease–associated RCC who have nonmetastatic tumors <3 centimeters, unless immediate surgery is necessary.

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