Belzutifan Improves Survival in Patients With RCC and VHL


Eric Jonasch, MD, further discussed the 2 posters he presented in regard to belzutifan at 2022 ASCO.

Belzutifan (Welireg), a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, demonstrated positive results when given as treatment to patients with Von Hippel-Lindau (VHL) disease and renal cell carcinoma (RCC).1,2

Previously, in August 2021, belzutifan was approved by the FDA for adult patients with VHL disease who require therapy for RCC, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery.3 Since its approval, multiple studies examining the HIF-2α inhibitor have begun and made strides in the VHL and RCC spaces, including LITESPARK-001 (NCT02974738), LITESPARK-004 (NCT03401788), and LITESPARK-022 (NCT05239728).

At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Eric Jonasch, MD, presented the findings of both the phase 1 LITESPARK-001 and phase 2 LITESPARK-004 studies which examined belzutifan in different patient populations.1,2

In LITESPARK-001, the efficacy and safety of belzutifan in addition to pembrolizumab (Keytruda) vs the combination of placebo plus pembrolizumab was compared as treatment in patients with clear cell RCC (ccRCC) post nephrectomy. LITESPARK-004, an open-label, phase 2 study, evaluated the efficacy and safety of belzutifan in patients with VHL disease.

While these recent studies of belzutifan continue to show promise and investigators are able to prolong survival—something that was not demonstrated 10 years ago—unmet needs remain in this space. According to Jonasch, his hope is to be able to provide patients with a complete and durable response.

In an interview with Targeted OncologyTM, Jonasch, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas (UT) MD Anderson Cancer Center, further discussed the 2 posters he presented in regard to belzutifan at 2022 ASCO.

Can you describe the posters you presented at ASCO this year?

Jonasch: There were 2 posters on belzutifan, which is a HIF-2α inhibitor. This is a drug that has arisen out of several decades of work, starting with the discovery of the VHL gene in 1993, then with work by doctors Peter Ratcliffe, Gregg Semenza, and William Kaelin that the led to the Nobel Prize in 2019 of how VHL regulates HIF-1α and HIF-2α. This then led to the efforts to target HIF as a treatment target, the challenge there being that small molecule inhibitors of transcription factors are historically hard to develop.

The team at UT Southwestern came up with an initial foray into that which then led the development of a company called Peloton that created the precursor drugs and the current drug that is now known as belzutifan and the trials that that we presented the updates on at ASCO. They're called the LITESPARK-001 spark, which is looking at the phase 1b/2 study in RCC, and LITESPARK-004, which is the registrational study and VHL disease, which led to the approval of belzutifan in VHL disease.

Could you discuss the background and the basis of LITESPARK-001?

LITESPARK-001 is a phase 1b/2 study, which did dose-escalation to find the optimal dose of belzutifan and focused on the RCC patient population. Fifty-five patients with RCC were enrolled in this trial.

The primary end point was safety with the phase 1 study and the secondary end points were progression-free survival [PFS], objective response rate [ORR], and duration of response per RESIST 1.1. The trial was a multicenter study, and we accrued these patients relatively rapidly. This presentation is now a median 41-month follow-up of data that we have previously published.

What safety and efficacy findings were discovered in LITESPARK-001 for patients with RCC?

What was exciting was that both from a safety perspective, as well as from an efficacy perspective, the data continue to hold up. Safety shows that anemia was the most common adverse event in the metastatic advanced RCC, at 24%, patients who did have grade 3 anemia. This is an on-target effect because HIF-2α is the transcription factor that regulates urethral potent. So if you knock down HIF-2α, you would expect less production, and indeed, that's what happened. This is something that's manageable either with exogenous erythropoietin blood transfusions, or dose adjustments.

Hypoxia is a relatively rare adverse event and about 13% of individuals developed that as well. Unclear mechanism, but something that's also quite manageable with dose adjustments. From an ORR perspective, we see that this has continued to hold up. The ORR in this follow-up of 41 months is 25%, as it was before, and there are some subset analyses that have been formed looking at whether or not this is different in favorable vs intermediate and poor risk. It really doesn't look like there's a major difference, it's 31% in the favorable vs 24% in the intermediate/poor risk.

The other thing we looked at was the 3 prior therapies received in this patient population, so heavily pretreated. Those who did not receive either prior IO [immunotherapy] or VEGF [inhibition], the ORR was 38%. For those who had received prior IO and VEGF, the ORR was 21%. Again, small numbers in this but still very interesting to see that this is quite effective, regardless of what prior therapies people have received.

The median PFS was 14.5 months, so from a metastatic RCC perspective, we're seeing that even as a single agent in this heavily pretreated patient population, the data continue to hold up that this drug those who defend it is active in this patient population. I'm looking forward to seeing this being an approved agent and advanced renal cell carcinoma.

What did you look at in LITESPARK-004?

LITESPARK-004 is in patients with VHL disease, and we did get approval for belzutifan in patients with VHL disease. The basis of this 61-patient study, which was published last year in the New England Journal of Medicine—but this is an immediate 29-month follow-up. With the metastatic RCC patient population, we're seeing that these data not only are holding up but they're improving with time.

The primary end point was ORR in RCC from these patients. We're seeing now that those numbers have gone up to an ORR of 59%. There is now a 3% CR [complete response] rate and a 56% partial response rate, so even better than we've seen before.

We see that of the number of patients that remain on study with nearly 30 months follow-up, 50 out of 61 patients remain on study and only 4 patients came off because of a progressive disease. Even more excitingly, we're seeing that RCCs are responding with pancreatic lesions. There's an 80% ORR. If you look at pancreatic neuroendocrine tumors, it's a 90% response rate. For CNS hemangioblastomas, there's now a 38% response rate and we're seeing CRs in all of these.

What do these findings mean for this patient population?

This is really amazing for this group of individuals who face a lifetime of surveillance, imaging, surgical intervention for these lesions as they reach various danger points. We are seeing, already in the study, that for those individuals who were on this trial across the population of study, there were about 20 procedures per year being performed on these patients. Since getting on the study in the entire population, there have only been 3 procedures. This is really game changing in terms of how many surgical procedures these patients have to be subjected to after starting those effects.

How do you think the findings of both LITESPARK-001 and LITESPARK-004 will impact the future of this space?

For patients with VHL, I think it's going to be a question of what is the ideal patient? When should we use this study? In the LITESPARK-004 study, there were no brakes built into the study, so should we treat it to maximal benefit and then take breaks? We don't know. Should we be starting this in patients as a prevention strategy? Obviously, a clinical study would have to be designed to do that. These are the sorts of questions that are being asked in the VHL world.

What are the determinants of resistance? Again, there's so few patients that have demonstrated resistance. It's hard at this point in time to answer that, but I think it's going to become easy. Unfortunately, it is easier as more people inevitably progress. I think for advanced RCC, the big questions are, how do we use this drug optimally? Do we use it as monotherapy, which I think is already likely to be effective, but can we improve this by adding a tyrosine kinase inhibitor or by adding IO? What should we be doing to really optimize the use of this drug?

Is belzutifan currently being examined in any other spaces?

It is being tested in other diseases. As of now, at least in the data that we have, there have not been extremely strong signals elsewhere. I think that is more due to a lack of data as opposed to a clear sign that it's not effective. I think the next steps are going to be finding the ideal combination [and] determining how to optimally use this drug in conjunction with other agents in the treatment landscape.

What unmet needs still exist in the advanced renal cell carcinoma space?

We need curative therapy. We are getting better at prolonging survival, which was something that 10 years ago wasn't even consistent, so we're getting there with regards to improving survival. But what we want is to be able to get people to have a CR that is durable, where we can even stop therapy for a while and allow them to enjoy a treatment-free interval. That is the new Holy Grail. Ten years ago, saying CRs would be our goal was perhaps fanciful, but now because we're seeing that in a small but significant group of patients, I think that is what we should be pushing forward to get. [And getting] that depth of response and to get that durability of response so we can have people living much longer.

What would you recommend for community oncologists working with patients in these patient populations?

If you have patients with VHL disease in your practice, my recommendation is that you work together with the clinical care centers that are around the country to optimize the management of these individuals.

For patients with advanced RCC in your practice, I would say stay tuned. This is not yet FDA approved for that indication, but I am really hopeful to see this as a choice for advanced RCC in the relatively near future.

1. Jonasch E, Iliopoulos O, Rathmell WK, et al. LITESPARK-004 (MK-6482-004) phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease: Update with more than two years of follow-up data. J Clin Oncol. 2022;40(suppl 16):4546. doi:10.1200/JCO.2022.40.16_suppl.4546
2. Jonasch E, Bauer TM, Papadopoulos KP, et al. Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: Update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up. J Clin Oncol. 2022;40(suppl 16):4509. doi:10.1200/JCO.2022.40.16_suppl.4509
3. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed June 21, 2022.

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