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Christopher Wallis: Hello, and thank you for joining us for the UroToday Journal Club. Today we are discussing a recent paper entitled, Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: A phase one trial and biomarker analysis. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent publication in Nature Medicine. Based on [inaudible 00:00:32] work out of the NIH, we've come to understand the importance of the VHL pathway in clear cell renal cell carcinoma. VHL is lost in over 90% of patients with clear cell renal cell carcinoma, whether they have underlying genetic causes or a sporadic tumor. In this context, the most relevant function of VHL is as an E3 ubiquitin ligase, which mediates HIF-2 alpha degradation.

As you can see in the pathway here, how this interacts with angiogenesis and the mTOR pathway as well. And so under conditions of normoxia, HIF-2 alpha is ubiquitinated by VHL and undergoes proteasomal degradation. However, under hypoxic conditions, heterodimer rises and translocates to the nucleus. While there, it acts as a transcription factor and promotes the transcription of hypoxia-inducible genes, and these lead to a range of different outcomes that contribute to the carcinogenesis pathway including angiogenesis, increased cell survival, and a variety of other characteristics highlighted here. And so the loss of VHL function, whether again, through underlying genetic causes or through somatic changes is associated with a pseudo-hypoxic state, thus targeting of HIF-2 alpha represents a novel treatment approach for VHL driven diseases, such as clear cell renal cell carcinoma. And this adds to the complement of treatment options in this pathway.  We can already see highlighted here, including mTOR inhibition and tyrosine kinase inhibitors.

In order to target HIF-2 alpha, I want you to consider its molecular structure. And so the HIF-2 alpha protein contains a PAS-A and a PAS-B ligand-binding domain. And synthetic small molecules can occupy the pocket and cause conformational changes which disrupt a dimerization of HIF-2 alpha. The first among these was MK-3795. But more recently, MK-6482 was discovered. This is a second-generation HIF-2 alpha inhibitor, which is significantly more potent than the first-generation alternatives. So the objective of this initial study is to identify the maximum tolerated dose of belzutifan and evaluate the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity than it had for patients with advanced solid tumors, including clear cell renal cell carcinoma. And so this was the first-in-human phase one study that included adult patients who had a histologic or cytologic diagnosis of locally advanced or metastatic tumors.

And then the dose-escalation cohort included patients with any solid tumors. And the dose-expansion cohort was limited to patients with renal cell carcinoma who had a clear cell renal cell carcinoma subtype, as well as one prior line of therapy. Patients had to have measurable metastatic disease according to RECIST criteria, and ECOG performance status of zero to one. The primary objective was to determine the maximum tolerated dose of belzutifan, as well as to determine the recommended phase two-dose, which is later going to be abbreviated RP2D. There are a number of secondary objectives, including safety, pharmacokinetics, pharmacodynamics, and assessment of anti-tumor activity. In patients in the dose-escalation phase, this included any patient with advanced solid tumors. There were sequential dose cohorts of approximately three to six patients per cohort, and a standard three plus three design was used.

Belzutifan was started at 20 milligrams orally once daily. And in each cohort, the dose increased 100% with each step up until toxicity was reached. And dose-limiting toxicities were considered grade three to four adverse events, which occurred in the first three weeks. At that point in time, smaller increases were used until the maximum tolerated dose was determined. Within the dose-expansion phase, this cohort was limited to those with previously treated advanced clear cell renal cell carcinoma. And these patients received belzutifan at the RP2D. And treatment here was continued until treatment-related toxicity or unequivocal disease progression.

In terms of assessment, there were a variety of approaches taken in keeping with the multiple objectives of the study. In terms of PK analysis, there were multiple tests made. And so week one and week three, there was pre-treatment testing as well as multiple blood draws after infusion. Weeks two, four, five, seven, nine, 13, and 17 had just a pre-treatment assessment. In terms of PD analysis, again, we see a difference in approach between weeks one and three, and the remainder all the way up to 49 weeks. Safety assessment was performed continuously and included assessment for adverse events, laboratory testing, vital sign testing, and ECG monitoring. Tumor imaging was performed with axial imaging at baseline. Then within seven days proceeding week nine, and then every eight weeks thereafter. The images were assessed in progressional response determined according to RECIST criteria.

In terms of the sample size for the dose-escalation, the authors plan to establish the maximum tolerated dose. And given that this is the first-in-human study, they estimated that this could take between three and 48 patients. In terms of the dose-expansion portion of the study, up to an additional 50 patients are planned to be enrolled. Safety was assessed in all patients who received at least one dose of study treatment. Pharmacokinetic analyses were performed according to non-compartmental analysis.

At this point in time, I will pass it over to Zach to take us through the results of this study.

Zachary Klaassen: Thanks Chris. So this is the patient disposition for this trial. As you can see here, they screened 107 patients and enrolled 95 patients. On the left of this table is the dose-escalation phase of 43 patients, and on the right is the dose-expansion phase of 52 patients. So generally, there were roughly six patients that were treated with either 20, 40, 80, 120, 160, or 240 milligrams daily of belzutifan and six patients that were treated with 120 milligrams b.i.d. Ultimately, the selected dose for the dose-expansion phase was 120 milligrams daily.

There were, in the dose-escalation phase, several malignancies of which clear cell renal cell included three patients. These were added to the dose-expansion phase which was all clear cell renal cell carcinoma patients for a total of 55 patients. This table looks at the baseline demographics and disease characteristics. On the far right is the clear cell RCC cohort of 55 patients. And in the middle is the dose-escalation cohort of 43 patients. The median age was roughly similar, 63 in the escalation cohort and 62 in the RCC cohort The majority of patients in each cohort were male, 65% in the dose-escalation cohort, and 80% in the RCC cohort.

The most common ECOG performance was ECOG 1 with 65% in the dose-escalation group and 62% in the clear cell RCC group. As I mentioned previously, there were 51% of patients in the dose-escalation cohort that were RCC, but you can see that there were also 12% of patients that have brain cancer and 7% that have lung cancer, and a smattering of other cancers noted in the table. In terms of prior systemic therapies, the median was three for each group. 60% of patients in the dose-escalation cohort had greater than or equal to three prior systemic therapies compared to 62% in the RCC cohort. The most common prior anticancer therapies were checkpoint inhibitors in the escalation cohort at 60% and were VEGF/VEGF receptor therapies at 91% in the RCC cohort. The majority of patients, 76% of patients in the RCC cohort were intermediate or poor IMDC risk category.

These figures look at the mean plasma concentration of belzutifan. On the left is week one, in the middle is week three, and on the right is all weeks. Looking specifically at week three and all weeks, you can see that 120 milligrams b.i.d. had the highest plasmic concentration with 120 milligrams daily, sort of in the mid-range. And this was selected for the dose-escalation cohort.

This is a table looking at the incidents of all-cause adverse events in more than or equal to 20% in the clear cell RCC cohort. We will focus on the grade three adverse events as there were only two grade four adverse events. Specifically of interest for this study is anemia which had 27% grade three adverse events, and hypoxia at 16% grade three adverse events.

This table looks at the best objective response rate per RECIST criteria in the clear cell RCC cohort. You can see here in this table that the objective response rate was 25% with zero complete responses and 25% partial responses. 54% of patients had stable disease and the disease control rate defined as complete response plus partial response and stable disease was at 80%. 15% of patients had progressive disease in this trial.

This waterfall plot looks at the maximum change from baseline in target lesions in the RCC cohort. As you can see here, 67% of patients with a target lesion had a reduction from baseline. 30% of patients had a greater than 30% reduction in the baseline as you can see here in the orange, patients with partial response. This plot looks at the duration of treatment, and you can see on the left that 35% of patients were treated beyond 12 months with a median duration of response that was not reached. And 71% of patients having a duration of response for greater than or equal to six months. This is the progression-free survival Kaplan-Meier estimate. The median progression-free survival in this trial was 14.5 months with a 95% confidence interval of 7.3 to not reached.

So several discussion points from this trial in this study, belzutifan had promising anti-tumor activity and was well tolerated amongst these patients. The maximum tolerated dose was not reached and the RP2D of 120 milligrams once daily was determined based on pharmacokinetics, pharmacodynamics, and safety. We noted in this trial that belzutifan had a distinct toxicity profile compared to that of other drugs in the second-line setting for clear cell RCC.  And we saw that in the dose-expansion cohort, the most common grade three adverse events were hypoxia and anemia, likely secondary to the mechanism of action of belzutifan. The objective response rate of 25% and disease control rate of 80% in the clear cell RCC court provided the rationale to evaluate belzutifan monotherapy versus everolimus in an ongoing phase three trial of previously treated patients with advanced clear cell RCC.

So in conclusion, belzutifan had a favorable safety profile and showed promising anti-tumor activity in heavily pre-treated patients with clear cell renal cell carcinoma. And this study validates the growing pre-clinical and clinical evidence that HIF-2 alpha inhibition might offer an effective and well-tolerated treatment for patients with advanced clear cell RCC. Belzutifan demonstrates anti-tumor activity by targeting the underlying pathophysiology of clear cell RCC, which makes it an attractive agent for future combination therapy trials.

Thank you very much, and we hope you enjoyed this UroToday Journal Club.