HIF-2α Inhibitors and Other Targeted Therapies Appear Promising in VHL-Associated RCC

The role of immunotherapy, HIF-2α inhibitors, and CDK4/6 inhibitors appear encouraging for the treatment of patients with kidney cancer following recent research on targeting von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC).

Preclinical models demonstrated encouraging activity for a first-generation HIF-2α compound, PT2399, in VHL tumors, and CDK4/6 inhibitors are thought to induce promising findings in combination with HIF-2α inhibitors. The CDK4/6 inhibitors could also be used as a way to enhance immunotherapy in solid tumors.

Most recently, data were published in the Journal of Clinical Oncology, demonstrating an objective response rate (ORR) of 27.9% with the combination of the potent, selective, small molecule HIF-2α inhibitor MK-6482 as treatment of patients with VHL disease who had at least 1 measurable RCC tumor, did not have prior systemic therapy, and nor metastatic disease. Forty-three of 61 patients who received the therapy achieved stable disease with the HIF-2α inhibitor, and the median duration of response had not yet been reached.

Most treatment-related toxicities were grade 1/2 and were primarily anemia, fatigue, and headache. Grade 3 adverse events related to MK-6482 included fatigue and anemia. Overall, this therapy appears promising as a single agent in patients with pretreated clear cell RCC.

RCC is arising more frequently in patients with VHL, which makes this an important area of research, which was highlighted recently during a keynote address for the International Kidney Cancer Symposium.

In an interview with Targeted Oncology, William G. Kaelin Jr, MD, the 2019 Nobel Laureate in Physiology or Medicine, Sidney Farber Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, and an investigator at Howard Hughes Medical Institute, discussed latest updates and new avenues of research in the treatment paradigm for patients with kidney cancer.

TARGETED ONCOLOGY: What have been some of the most important updates for the treatment of patients with kidney cancer?

Kaelin: At this point, I think we've established the activity not only VEGF inhibitors but checkpoint inhibitors as well, and I think it's increasingly becoming clear that you can combine them safely and probably enhance efficacy. I would imagine that the combination of a checkpoint inhibitor and a VEGF inhibitor will be perhaps the new standard of care with the exception of perhaps some patients who might initially be treated with an immune checkpoint combination, such as an anti-PD-1 and anti-CTLA-4.

I've been closely involved with the development of the so-called HIF-2α inhibitors, and we now have a first in class HIF-2α inhibitor that I think has significant activity in phase 2 trials in kidney cancer patients as well as in a phase 2 trial that was done in patients who had VHL disease. It's particularly interesting because this was a patient population where to be on the trial, they had to have a measurable kidney tumor, but these were patients who were in careful surveillance programs in an attempt to delay or prevent the need for repeated surgeries. I think this gave us the first glimpse of whether a HIF-2α inhibitor might be able to do in a sort of quasi-frontline setting where patients had not failed prior lines of therapy and where the disease burden was less. I'm highly encouraged by the activity of the HIF-2α inhibitor. We're very hopeful that eventually, this drug will be approved not only for the treatment of VHL disease, but also for sporadic kidney cancer, where it's currently being tested in phase 3 trials and patients who have failed frontline therapies.

TARGETED ONCOLOGY: What is the rationale for exploring HIF-2α therapies in kidney cancer?

Kaelin: Melanoma is another highly immunogenic tumor, and at least there's a correlation with having a high tumor mutational burden, and so the current model is that a high mutational burden, perhaps, generates more antigens and [therefore] more likely to be recognized by the immune system. However, we've known for quite some time that kidney cancer, although immunogenic, does not have a particularly high mutational burden. There are a number of labs including mine trying to understand why kidney cancer might be immunogenic, and several labs have speculated that the cause for the immunogenicity in kidney cancer might be the promiscuous expression of endogenous retroviruses, which is something we're studying in my own laboratory, currently. We're very intrigued by this hypothesis that perhaps endogenous retroviral expression contributes to the immunogenicity of kidney cancer.

TARGETED ONCOLOGY: Could you discuss the current efforts to move new targets forward?

Kaelin: There was a paper we published recently where we found that cells lacking the VHL tumor suppressor protein, and of course, an activation of the VHL tumor suppressor, is a hallmark in kidney cancer, at least that's in clear cell type, which is the most common form of kidney cancer. We published that cells lacking VHL tumor suppressor protein seemed to have an increased requirement for CDK4/6. There is support for at least testing CDK4/6 inhibitors in patients with kidney cancer, and we hope to have a clinical trial started in patients who have with kidney cancer who have failed prior lines of therapy.