Novel MK-6482 Molecule Targeting HIF-2 Yields Responses in Clear Cell Renal Cell Carcinoma

Toni K. Choueiri, MD

The transcription factor HIF-2 has been known to be very difficult to target and was deemed undruggable, but the novel MK-6482 may play an unexpected role in this space. The molecule targets HIF-2 and has now demonstrated activity as treatment of patients with clear cell renal cell carcinoma (RCC) in a phase I/II clinical trial.

Approximately 55 patients with clear cell RCC enrolled in the study and had a median of 3 prior lines of therapy, representing a heavily pretreated patient population. The objective response rate was 24%, with 69% of patients experiencing tumor shrinkage.

The median progression-free survival (PFS) was 11 months with MK-6482, and investigators noted responses among patients who are considered poor-risk by the International Metastatic RCC Database Consortium.

The toxicity profile of MK-6482 appeared low among patients with clear cell RCC in this study. Anemia and hypoxia were observed as on-target toxicities, but other toxicities occurred at low levels. In response to these positive findings, MK-6482 will be evaluated in a phase III clinical trial as treatment of patients with clear cell RCC who are heavily pretreated.

In an interview with Targeted Oncology, Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, Dana-Farber Cancer Institute, and Jerome and Nancy Kohlberg Chair and professor of medicine, Harvard Medical School, discussed the findings from the phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell RCC, which were presented at the 2020 Genitourinary (GU) Cancers Symposium.

TARGETED ONCOLOGY: Do you want to provide some background to MK-6482?

Choueiri: I had the pleasure at GU 2020 to present the phase I/II results of this novel drug. It is an oral HIF-2 α inhibitor, a first-in-class and first-in-human called MK-6482 that targets the transcription factor HIF-2 α. Transcription factors, in general, are very hard and supposed to be undruggable except the androgen receptor. HIF-2 was a very interesting and important target in clear cell RCC. This is because clear cell RCC is defined by VHL alterations that lead to upregulations in HIF-2; an altered VHL protein cannot degrade HIF-2 in the proteasome, making HIF-2 activate lead to this transcription of many, many genes that have 2 governs, such as VGEF, the gene involved in angiogenesis.

TARGETED ONCOLOGY: What were the findings from this study?

Choueiri: We used this drug in 55 patients previously treated with clear cell RCC. The median number of prior lines of therapy was 3, so these patients are overall heavily pretreated patients. We saw a response rate of 24% with 69% of patients having tumor shrinkage, so this is a proof of principle. Interestingly enough, the median PFS despite this being a single-arm study was 11 months, and that is quite encouraging.

We saw responses in the poor-risk group. That is interesting, but what makes me particularly excited about this agent is the low level of toxicity compared to VEGF inhibitors, as well as different profiles. We don’t see hypertension, cardiovascular toxicity, significant fatigue, diarrhea, hand-foot-skin reaction. We see anemia that is on target because of the down-regulation of HIF-2. Anemia is usually easily treated with erythropoietin when it is symptomatic. We also saw hypoxia, which seemed to be another on-target toxicity managed with supplement oxygen, and usually, there was a pulmonary event underlying.

TARGETED ONCOLOGY: What are the next steps for this?

Choueiri: The next step, after we publish the manuscript, is launching a pivotal phase III trial of MK-6482 versus everolimus, and this trial just launched. We are opening the first few sites, and that trial will have PFS and overall survival as primary end points. We will enroll over 700 patients, and it will be in patients who progress on prior PD-1 and VGEF inhibitors with up to 3 prior lines of therapy.

TARGETED ONCOLOGY: Do you think this agent has potential to move into earlier lines of therapy?

Choueiri: I hope so. I think the low level of toxicity means that we can perhaps combine it. We can combine it hopefully with frontline regimens, like immunotherapy-immunotherapy or immunotherapy-VGEF. I think that would be a great idea after we hopefully prove the efficacy of this drug in a phase III trial. It is a possibility.

TARGETED ONCOLOGY: What do you hope the community takes from these findings?

Choueiri: The community and patients should know now that we have another target besides PD-1, PD-L1, CTLA4, VGEF, and MTOR. This is serious as it will open new avenues of research. HIF-2 can finally be targeted. This majority of patients on the study had prior VGEF inhibitor and PD-1 inhibitors, and that did not impede their response to the MK-6482. That is an important thing, so stay tuned and hopefully, our patients with clear cell RCC will have more options soon.

TARGETED ONCOLOGY: What were some of the exciting takeaways in RCC from the 2020 GU Cancers Symposium?

Choueiri: In kidney cancer besides this, there were some interesting data looking at cytoreductive nephrectomy in the immunotherapy era, although this was not a clinical trial that was prospective. However, I think we take this with a grain of salt. It is interesting work that we have been involved with. There was also an interesting study with tyrosine kinase inhibitor (TKI) nivolumab (Opdivo) in the post-TKI failure setting that showed some promising activity. There was an interesting study combining lenvatinib (Lenvima) and everolimus in a hard-to-treat population of non-clear cell RCC. It showed a 25% response rate and some responses in 44% in a small number of patients with a hard-to-treat tumor. It was quite an interesting meeting to see all of these data in San Francisco.

TARGETED ONCOLOGY: Are there any other trials you would like to highlight regarding lenvatinib in RCC?

Choueiri: The most important thing is to look at the pivotal phase III trial combining lenvatinib with everolimus or the PD-1 inhibitor pembrolizumab (Keytruda) versus sunitinib (Sutent). That is the clear study over 1,000 patients, which finished enrollment, and hopefully, we will see that in another meeting.