MK-6482 Showcases Promising Clinical Activity in VHL Disease–Associated RCC

Eric Jonasch, MD

MK-6482 showed favorable efficacy and tolerability in patients with Von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), according to Eric Jonasch, MD, sparking hope for a population known to have a shortened life expectancy.

In this open-label, phase 2 study (NCT03401788), investigators sought to determine the efficacy of MK-6482, a potent, selective, small molecule HIF-2α inhibitor, in patients with VHL disease who have at least 1 measurable RCC tumor, received no prior systemic anticancer therapy, have no metastatic disease, and an ECOG performance status of either 0 or 1.

In the trial, data were collected from 61 adult patients who received 120 mg of oral MK-6482 once daily until progression or intolerable toxicity. Results showed that treatment with the agent led to a confirmed objective response rate (ORR) of 27.9% (95% CI, 17.1-40.8), and 8 other patients (13%) experienced an unconfirmed partial response (PR).

Moreover, the median duration of response with the agent was not yet reached and 95% of patients remain on study treatment. Notably, the majority of patients, or 86.9%, experienced a decrease in the size of their target lesions.

With regard to safety, any-grade treatment-related adverse effects (TRAEs) occurred in 96.7% of patients. TRAEs were mostly grade 1 or grade 2 (83.6%) and primarily anemia (83.6%), fatigue (52.5%), and headache (36.1%). Grade 3 TRAEs were reported in 9.8% of patients, and were primarily fatigue (4.9%) and anemia (3.3%).

“This [research] provides hope for patients with VHL disease; these are individuals who literally, in some cases, have had dozens of surgeries throughout their lives to help deal with their CNS, as well as renal and adrenal manifestations of disease,” said Jonasch, who was also lead study author. “[The results of this study] have brought joy to some of our patients; they're finally seeing a light at the end of the tunnel. This has really been amazing and beautiful to see.”

In an interview with OncLive, Jonasch, who is also a professor in the Department of Genitourinary Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the favorable clinical activity of MK-6482 in patients with VHL disease–associated RCC and next steps for research with the agent.

OncLive: Could you share some background on MK-6482 and its mechanism of action?

Jonasch: The VHL gene creates a protein which, under normoxic conditions, regulates the transcription factors, HIF-1α and HIF-2α. If you have a hypoxic situation, VHL will back off and HIF-1α and HIF-2α will result in the transcription of genes that are associated with factors such as angiogenesis, cell metabolism, etc. Under normoxic conditions, VHL will grab onto the HIF-2α proteins that have been produced, drag them off into the proteasome, and that will result in degradation. If you have broken VHL, you essentially have a pseudohypoxic state where you end up getting unbridled transcription of HIF-1α and HIF-2α genes. Highly angiogenic tumors and tumors that have other selective advantages may result.

As such, coming up with a drug to block HIF-2α would be wonderful. The best thing to do would be to fix broken VHL, but that's more of a challenge. The next best thing would be to block HIF-2α or HIF-1α. It looks like HIF-2α is potentially more important than HIF-1α, but transcription factors are tough to develop compounds against because they tend to be slippery molecules. MK-6482, has been the first to successfully block the HIF-2α’s heterodimerization with its partner, HIF-2β, preventing that transcription.

What are some data that have already been reported with this agent in RCC? What was did the prior activity look like and how did that lead to the phase 2 study?

[The phase 2 trial] is 1 of 2 trials that have studied this compound. The first trial was done in patients with metastatic RCC, which demonstrated an intriguing 24% ORR in heavily pretreated patients with metastatic sporadic disease.

[The phase 2] is different because it [examined the agent in] individuals who have hereditary, inherited germline-mutated VHL and these individuals develop pleiotropic manifestations, includinghemangioblastomas in the eye, brain, and spine; multifocal bilateral RCCs, which will require resection at some point in time; pheochromocytomas; pancreatic neuroendocrine tumors; among others.

In this trial, the primary end point was to test the hypothesis that we could achieve shrinkage in the RCCs in those with VHL disease. It was a relatively small study, with only 61 patients involved. The trial did meet its primary end point of ORR, with a confirmed ORR of 27.9%. However, an additional 13% of individuals had unconfirmed PR. We expect that, because we don’t see idiosyncratic changes in these tumors over time, these [responses] will be confirmed. The rate of change and [tumor] shrinkage with this drug, unlike TKIs, is modest in terms of its continued improvement. As such, we expect that we're going to have other patients who are going to convert to PRs over time.

Not only do we see these responses in these RCCs, but we've also seen responses in hemangioblastomas, and my presentation demonstrated a pictorial representation of the response in cerebellar and spinal hemangioblastomas. The data for the central nervous system (CNS) manifestation responses is not yet mature but will be presented at future congresses as well as in publication form.

What is the safety profile of MK-6482? What are the best ways to manage any adverse events that are associated with this agent?

The most common adverse event (AE) [observed] with this agent is anemia, and that's not surprising because erythropoietin is a HIF-2α client gene. As such, anemia is an on-target, expected AE. We saw this event in 86.9% of patients; only 3.3% were grade 3 and no grade 4 or 5 [events were reported]. The majority of patients didn't require any sort of intervention, but a subset of individuals did require either exogenous erythropoietin and a few patients underwent transfusion. Erythropoietin works very well for control of this [event] and we see that, even in individuals who don't undergo exogenous erythropoietin, there is a gradual improvement of the anemia over time. Fatigue is the second most common AE but it’s tough to tell if the event was from the therapy specifically. There's no randomization in this trial so it's hard to tell whether it’s a true AE or just a bystander effect.

What are the next steps for this research?

The big question in this rare patient population is, ‘Does this trial require a randomized study [moving forward] to confirm [what we’re seeing and] result in approval, or are these data sufficient?’ As a physician who has been treating individuals with VHL disease for almost 20 years now, it would break my heart to have to randomize individuals at this point in time. We would hope that there could be some type of approval mechanism based on these data. We’ll see whether that is going to be possible.

Moving forward, another question is, ‘Would this drug be helpful from a prevention perspective? ‘We know these individuals develop lesions over time. If they were to be on this therapy, which is fairly well tolerated, could we prevent the development of lesions? Also, are there partners with which this drug should be combined to further enhance response? In the metastatic setting, this is being tested. Toni Choueiri, MD, of Dana-Farber Cancer Institute, is leading a study that is evaluating the [agent in] combination with cabozantinib (Cabometyx). The question of whether this [agent] should be combined with immunotherapies is more of a metastatic RCC question rather than a VHL question. However, these are examples of [areas of research that could be] important next steps [for the agent].

Reference

Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5003. doi: 10.1200/JCO.2020.38.15_suppl.5003