Choueiri Spotlights Activity With Novel HIF-2a Inhibitor in Heavily Pretreated RCC

Toni K. Choueiri, MD

Recent findings from a phase 1/2 trial demonstrated promising single-agent activity with the novel hypoxia-inducible factor (HIF)-2α inhibitor MK-6482 in patients with heavily pretreated clear cell renal cell carcinoma (RCC), said Toni K. Choueiri, MD, who added that the benefit was seen across International Metastatic RCC Database (IMDC) risk groups.

"Transcription factors in general are very hard to target," said Choueiri, who is the director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute. "They are thought to be undruggable, except for the androgen receptor. As such, HIF-2α is really an interesting and important target in clear cell RCC."

An overall response rate (ORR) of 24% and a disease control rate of 80% was observed in the 55 patients enrolled in the dose-escalation/expansion cohort. The ORR consisted of 13 confirmed partial responses. Additionally, the median progression-free survival (PFS) for the total population was 11.0 months. At 12 months, 49% of patients remained progression free.

The regimen was well tolerated among patients, said Choueiri. At a median follow-up of 13 months, the most common all-grade, all-cause adverse events (AEs) occurring in at least 20% of patients were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%).

The most common grade 3 AEs were anemia (26%) and hypoxia (15%). Two-thirds of patients had grade 3 to 5 AEs, and about one-third had grade 3 to 5 treatment-related AEs.

A phase 3 trial (NCT04195750) investigating MK-6482 versus everolimus (Afinitor) in individuals with advanced clear cell RCC who have progressed on prior PD-1/PD-L1 inhibitors or VEGF inhibitors is currently enrolling patients.

In an interview with OncLive, Choueiri, who is also the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, discussed the findings from the phase 1/2 trial, the clinical implications of targeting HIF-2α in kidney cancer, and the potential utility of MK-6482 in clear cell RCC.

OncLive: Could you provide some background on MK-6482? What is the mechanism of action of the agent?

Choueiri: At the 2020 Genitourinary Cancers Symposium, I had the pleasure of presenting the phase 1/2 results with the novel agent MK-6482. It is an oral, first-in-class, first-in-human HIF-2α inhibitor that targets the transcription factor HIF-2α.

Clear cell RCC is defined by VHL alterations that lead to upregulation in HIF-2α. An altered VHL protein cannot degrade HIF-2α. The proteins making HIF-2α accumulate, dimerize, and lead to the transcription of many genes that HIF-2α governs, such as VEGF, as well as genes involved in angiogenesis, glycolysis, and proliferation. It is almost as though a truncal event is set up.

Some elegant crystallographic work showed that small molecules could get into 1 of the pockets of HIF-2α to inhibit heterodimerization. That led to the investigation of molecules, such as MK-6482.

How was this trial designed?

We gave this drug to 55 patients with previously treated clear cell RCC. The median number of prior lines of therapy was 3, which indicates that these patients were overall heavily pretreated.

What were the results of the phase 1/2 study?

We saw a response rate of 24% and a tumor shrinkage rate of 69%. This was considered a proof-of-principle study. Interestingly, despite this being a single-arm study, the median PFS was 11 months. That is quite encouraging. Additionally, we saw responses in patients with poor-risk disease, according to the IMDC model.

How was the agent tolerated? Were there any safety signals?

What makes me particularly excited about this agent is the low level of toxicity compared with VEGF inhibitors. In addition, the toxicity profile of [the agent] differed [from those of VEGF inhibitors]. We do not see hypertension, cardiovascular toxicities, significant fatigue, diarrhea, or hand-foot skin reactions [with MK-6482].

We do see anemia, which is believed to be an on-target toxicity and a result of having to downregulate HIF-2α and erythropoietin. The anemia is usually easily treated with erythropoietin when it becomes symptomatic.

We saw hypoxia, which also seems to be an on-target toxicity. Hypoxia is managed with supplemental oxygen and often, there was a pulmonary event underlying [in patients who developed hypoxia].

What are the next steps with MK-6482?

Regarding next steps, a pivotal phase 3 clinical trial with MK-6482 as monotherapy versus everolimus was just launched. The trial is being opened at a few of the first sites. That trial will have PFS and overall survival as its coprimary endpoints. We [are planning] to enroll over 700 patients who have progressed on prior PD-1 and VEGF inhibitors and have had up to 3 prior lines of therapy.

Does this agent have the potential to move into earlier lines of therapy?

I hope so. The low level of toxicity could mean that we can combine it with current first-line regimens. Combinations of immunotherapeutic agents or immunotherapy plus VEGF inhibitors may be great ideas. Hopefully, after we prove the efficacy of the HIF-2α inhibitor in the phase 3 trial, those combinations will become a possibility.

What do you hope the field takes away from these findings?

The community, as well as the patients, should know that we now have another target besides PD-1/PD-L1, CTLA-4, VEGF, and mTOR. This [new pathway] has the potential to open new avenues of research exploring modalities that target HIF-2α. It gives us hope, especially knowing that prior exposure to VEGF inhibitors and PD-1 inhibitors didn't impede patients' response to MK-6482 on the trial.

We have to stay tuned for more data. Hopefully our patients and our physicians who treat patients with clear cell RCC will have [more] options soon.

Choueiri TK, Plimack ER, Bauer TM, et al. Phase 1/2 study of the oral HIF-2α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl_6; abstr 611). doi:10.1200/JCO.2020.38.6_suppl.611