LITESPARK-024 Trial to Examine HIF-2α and CDK4/6 Inhibition With Belzutifan Plus Palbociclib in Advanced RCC

David F. McDermott, MD

The combination of the first-in-class HIF-2α inhibitor belzutifan (Welireg) with the CDK4/6 inhibitor palbociclib (Ibrance) makes for an ideal pairing given the tolerability of belzutifan and preclinical data showing potential activity with the two treatment classes, according to David F. McDermott, MD. The activity of the combination will be further evaluated in patients with pretreated advanced renal cell carcinoma (RCC) in the phase 1/2 LITESPARK-024 trial (NCT05468697).

In a presentation at the 2023 Kidney Cancer Research Summit McDermott noted that belzutifan has shown promising activity in patients with previously treated advanced clear cell RCC (n = 55), yielding a 25% objective response rate (ORR) and 14.5-month median progression-free survival (PFS) in a first-in-human phase 1 study (NCT02974738).¹

“[LITESPARK-024] is a randomized phase 2 trial [of] patients who are required to have been exposed to VEGF blockade and PD-1 blockade, so it’s a second- or third-line study population,” McDermott said. “But otherwise, [the trial has] the standard eligibility criteria—patients have to have metastatic clear cell kidney cancer, a good performance status, and normal laboratory values.”

LITESPARK-024 will enroll patients with unresectable stage IV RCC with a clear cell component who have previously been treated with at least 2 systemic regimens, including anti–PD-1/PD-L1 immunotherapy and a VEGF-directed TKI. Eligible patients also need to have a Karnofsky performance status of at least 70%, no history of or known central nervous system metastasis, and have experienced disease progression on or after treatment with their most recent regimen.²

In part 1 of the trial, oral belzutifan will be given at a dose of 120 mg daily plus oral palbociclib daily for 21 days followed by 7 days off in up to 3 dose groups with approximately 3 to 10 patients per group. After determination of the recommended phase 2 dose of palbociclib, approximately 150 patients will be randomly assigned 2:1 to receive belzutifan plus palbociclib or belzutifan monotherapy. Sites in the United States, Australia, and Israel are recruiting patients, with additional sites to be added in Europe and Latin America.

The coprimary end points in part 1 are dose-limiting toxicities, adverse effects (AEs), and treatment-related discontinuations. In part 2, the primary end point is investigator-assessed ORR and secondary end points include clinical benefit rate, PFS, duration of response, overall survival, and safety.

In an interview with OncLive^®, McDermott, a professor of medicine at Harvard Medical School, and the director of Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center in Boston, Massachusetts, discussed how combining HIF-2α inhibition with CDK4/6 inhibition could be an effective treatment regimen in patients with RCC and shared additional details of LITESPARK-024.

OncLive: What was the rationale for initiating the LITESPARK-024 trial?

McDermott: Kidney cancer, particularly clear cell kidney cancer, is often driven by increased expression of the transcription factor HIF-2α. We now have agents in the clinic that can target this transcription factor that can produce some impressive antitumor activity, but the agents don’t work in all patients. The question for this trial is: How can we improve the activity of a HIF-2α inhibitor like belzutifan [by combining it with other] targeted therapies?

The preclinical data from Dana-Farber Cancer Institute suggest that combining HIF-2α blockade with CDK4/6 inhibition might be an effective strategy. Both approaches are already FDA approved, but we don’t know how well they work together in combination, so we’re exploring them in this randomized trial where every patient gets a HIF-2α inhibitor, belzutifan, and some of the patients get the combination of HIF-2α and CDK4/6 blockade.

Given what’s known about the safety profile of each agent alone, what safety signals will investigators be monitoring during LITESPARK-024?

It’s interesting because the HIF-2α class of drugs have a novel and somewhat narrow safety profile based on what we’ve seen so far. They can cause some fatigue which is often related to anemia [and] that can be reversed with erythropoietin injections; hypoxia which sometimes is symptomatic, and patients need to have their treatment held; [and] mild constitutional symptoms.

In general, HIF-2α [inhibitors] are better tolerated than other agents for kidney cancer as they have a narrower spectrum of toxicities than say VEGF inhibitors. They’re in some ways a good candidate for combination approaches.

The CDK4/6 class has a broader list of AEs. They can affect bone marrow [as well as] the GI tract, causing diarrhea, for example. We have to be concerned that there might be some overlapping toxicity, that’s why we’re spending time trying to find the right dose of these 2 agents together before we randomly assign patients [to treatment].

What is the incentive for a community oncologist to refer patients to this trial?

It gives patients a completely novel option for therapy that they wouldn’t get at the moment outside of a clinical trial. Right now, HIF-2α inhibitors are in late-stage phase 3 trials, but they’re not yet FDA approved for clear cell kidney cancer. This gives a completely different approach that the tumors have not seen. These agents have shown some activity with a response rate of 25% and increased the number of patients with prolonged stable disease. We’re hopeful this will be a new approach to kidney cancer [treatment]. We haven’t confirmed it yet, but it’s a way of gaining access to this new approach before FDA approval.

What were some of the highlights of the 2023 Kidney Cancer Research Summit?

This is an exciting meeting where folks who are doing translational and basic science get together with clinicians, and we try to accelerate what we’re learning in the laboratory to [reach] our patients [faster]. We’re learning a lot—for example, the session about how we better select patients for treatment [was helpful because with] the resistance pathways for the treatments we have [there is the question of] how we overcome those pathways. This is a great meeting for building collaborations, developing novel approaches, and trying to understand why our current treatments work or don’t work. Hopefully this will speed clinical development ahead for our patients.

References

1. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor 2 α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. doi:10.1038/s41591-021-01324-7
2. McDermott DF, Peer A, Agarwal N, et al. LITESPARK-024: randomized phase 1/2 study of belzutifan with or without palbociclib for treatment of advanced renal cell carcinoma. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023. Boston, MA. Abstract 68.