Belzutifan Generates Promising Responses and Safety in Advanced Stage Clear Cell RCC

Eric Jonasch, MD

The novel hypoxia-inducible factor (HIF)–2α inhibitor belzutifan (Welireg) elicited an encouraging overall response rate (ORR) with a manageable safety profile in patients with advanced clear cell renal cell carcinoma (RCC), according to data from the phase 1 LITESPARK-001 trial (NCT02974738) presented at the 2022 ASCO Annual Meeting.¹

Notably, responses were observed in patients irrespective of International Metastatic Renal Cell Database Consortium (IMDC) risk category and prior treatment with immunotherapy and/or a VEGF inhibitor, according to Eric Jonasch, MD, who served as the lead author of the study.

In patients with clear cell RCC who had a median of 3 prior lines of therapy (range, 1-9; n = 55), the ORR was 25%, with 1 complete response and 13 partial responses. The disease control rate (DCR) was 80%. In patients with favorable risk (n = 13), the ORR was 31% with a DCR of 92%, and in patients with intermediate or poor risk (n = 42), the ORR was 24% with a DCR of 76%.

“These were decent numbers for a pretreated population,” Jonasch said. “In the end, what we see here is that this is a safe agent and one that’s also effective in this highly pretreated population.”

In an interview with OncLive^®, Jonasch, a professor in the Department of Genitourinary Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the efficacy and safety of belzutifan observed in the LITESPARK-001 trial for patients with advanced clear cell RCC and the next steps for investigating belzutifan in this patient population.

OncLive^®: Could you expand on the rationale for conducting the LIGHTSPARK-001 trial?

Jonasch: This study looked at a novel HIF-2α inhibitor in individuals with previously treated advanced RCC. This drug blocks the interaction between the transcription factor HIF-2α with HIF-1β, and it essentially prevents [HIF-2α] from acting as a transcription factor.

The downstream consequences of that are decreased levels of various prometabolic and proangiogenic genes. [Because clear cell] RCC subvariants [typically have] an inactivation of the von Hippel-Lindau [VHL] protein, either through mutation or other modifications, it makes a lot of sense to test this drug in this patient population.

How was belzutifan investigated in this trial?

This was a non-randomized, phase 1/2 study where the primary end point was safety, and secondary end points [were ORR, DCR, progression-free survival, and duration of response]. The trial accrued patients in a variety of different centers, and patients had to have had prior treatment with standard-of-care treatment for advanced RCC.

In the analysis [presented at the 2022 ASCO Annual Meeting], there were 55 patients in the study. These patients had a median of 3 prior treatments and a median follow-up of 41 months, making it a relatively long follow-up.

What key data were presented from the study?

Looking at the end points, we saw that this agent was quite safe. The most common adverse effect [AE] was anemia. There was grade 3 anemia in 24% of patients, and this is an on-target effect, because one [the hormones regulated by] HIF-2α is erythropoietin [EPO]. If you effectively block the transcription of HIF-related genes, you would expect EPO levels to go down, and we did see this [lead to] anemia. This anemia was manageable with EPO, blood transfusions, or dose modification, so it wasn’t a major problem.

From an efficacy perspective, regardless of how you looked at it, this agent was active. We saw a 25% ORR. This follow-up study looked at this [treatment] from a variety of ways. One of the ways was to ask the question of whether the IMDC risk category influenced the probability of response. For patients with favorable or intermediate/poor risk, the ORR was 31% and 24%, respectively.

The other important metric was to see progressive disease as best response, and it’s very low at 8% and 17% [for patients with favorable- and intermediate- or poor-risk disease], respectively. So, this is an active agent [in these patients].

We [also] looked at prior therapy and whether patients had received prior immunotherapy or VEGF therapy, or prior immunotherapy and VEGF therapy. The ORR was 38% for prior immunotherapy or VEGF, and 21% for patients who received prior combination therapy.

Was there anything surprising about the data?

The biggest surprise with these data was the relative universality of clinical benefit, regardless of whether we looked at this from a standpoint of risk group or the number of prior therapies patients had received.

The other point that I raised before about progressive disease as best response being quite low [was also surprising]. The DCR that we saw in the overall population was 80%.

What are the next steps for investigating belzutifan in patients with RCC?

These exciting data have led to the randomized phase 3 LITESPARK-005 trial [NCT04195750], which has completed accrual. We are hoping to get results from that study in the next year or 2.

Moreover, there are a number of other studies looking at belzutifan in combination, either with immunotherapy or TKIs. This is an agent that’s going to find its place in the RCC treatment armamentarium, but we still need to determine the best way to use it. As monotherapy, it will be an addition to our treatment regimens, but as a combination therapy it could further improve upon the benefit we’ve seen with this agent.

What would you like your colleagues to take away from this research?

The big take-home message is that the journey of discovery that has led to the development of this drug is quite amazing. [We have gone] from the discovery of the VHL gene at the NIH in 1993, to the work from Drs William G. Kaelin Jr, Peter J. Ratcliffe, and Gregg L. Semenza that led to the Nobel Prize [in Medicine] being awarded to them in 2019, to understanding how VHL regulates HIF and other factors, to the development of this drug by a group that began at UT Southwestern. This was a huge, combined effort, not forgetting the patient advocacy groups and the VHL Alliance, that was spurring them along all the way.

This is an amazing example of science that’s properly motivated that’s led to highly effective therapy for this disease.

Are there any further efforts with belzutifan to highlight?

At the 2022 ASCO Meeting, I also presented the follow-up data on the [phase 2] LITESPARK-004 trial [NCT03401788], which is a study of belzutifan in patients with [VHL disease–associated RCC]. We demonstrated that the data there with this agent in this hereditary patient population continue to improve. This is exciting for the patients with VHL disease, seeing that this agent is finally providing an effective treatment option for this devastating hereditary disorder.

Reference

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