Toni K. Choueiri, MD, discusses new data with adjuvant belzutifan plus pembrolizumab for the treatment of patients with clear cell RCC.
Belzutifan (Welireg) will likely become a key component of the clear cell renal cell carcinoma (ccRCC) treatment landscape across multiple lines of therapy, including the adjuvant setting, following the promising data the agent displayed in combination with pembrolizumab (Keytruda) in the phase 3 LITESPARK-022 trial (NCT05239728), according to Toni K. Choueiri, MD.
Findings from the phase 3 LITESPARK-022 trial presented by Choueiri during the
“[LITESPARK-022] was the first trial to build on adjuvant pembrolizumab in this [patient population]. We’re pushing the envelope [and] more patients are going to be around for the next generation of drugs,” Choueiri, the director of the Lank Center for Genitourinary Oncology and the medical director of International Strategic Initiatives at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts, said in an interview with OncLive®. “[We are] quite happy with these data, and I’m sure this is not the end. There will be more data coming out of LITESPARK-022.”
In the interview, Choueiri discussed the background and design of LITESPARK-022, the clinical significance of the data presented during ASCO GU, and how he sees belzutifan plus pembrolizumab fitting into the ccRCC treatment landscape.
Choueiri: [Data from the phase 3] KEYNOTE-564 trial [NCT03142334] were presented in 2021 at the American Society of Clinical Oncology Annual Meeting, and in 2024, we presented OS data at ASCO GU.2,3 Based on those findings, we wanted to build on that success.
Belzutifan is a HIF-2α inhibitor that is well tolerated and
The primary end point was DFS, and it was met with an HR of 0.72. This is the first study that builds on adjuvant pembrolizumab. The safety profile showed that there was more toxicity with 2 drugs compared with 1, but we know how to manage the adverse effects [AEs] associated with belzutifan and pembrolizumab. There was not a significant amount of treatment discontinuation in either arm due to AEs.
OS still needs to be followed because we currently have only 28 months of follow-up. One important point is that the forest plot for DFS showed an HR generally below 1 across subgroups, indicating that patients do benefit [across the board].
Most of the patients included had intermediate-high risk disease or high-risk disease with M1 NED [metastasis with no evidence of disease]. This population is similar to the population enrolled in KEYNOTE-564 in terms of eligibility criteria, although this is a larger study and it compares the combination against an active control of pembrolizumab.
We’re very pleased that this study met its primary end point. Many [investigators] will now be looking at biomarkers, because in any adjuvant setting, there is always concern about overtreating some patients. Others will want to see more mature OS data. Another question will be what to use upon progression once this combination becomes available, because it creates a space where there is not yet a clear standard. Overall, it is an exciting time for patients.
When you add belzutifan [into the mix], the 2 AEs we focus on are anemia and hypoxia. Anemia is a hallmark AE of belzutifan and occurs more frequently compared with pembrolizumab alone.
Management of belzutifan-related anemia mainly involved dose reductions or treatment interruptions. We did not use erythropoiesis-stimulating agents [ESAs] or transfusions very often, although that may change with time. Hypoxia occurred in fewer than 10% of patients, but it is a known risk. It can be managed with supportive measures such as oxygen and dose adjustments.
Fortunately, belzutifan has been available for some time in the metastatic setting, so we already have experience managing these AEs.
Historically, oncologists did not have many options in this space. It will be important for community oncologists to become familiar with the safety profile of belzutifan. Overall, it is generally well tolerated, and we are seeing it move into earlier disease settings.
For example, the [phase 3] LITESPARK-011 study [NCT04586231] in the post–PD-1 and VEGF setting also met its primary end point. Now we have an adjuvant trial with LITESPARK-022.
Belzutifan is becoming a drug that will remain part of [RCC] treatment. Additional studies are underway as well. Because of this, it is very important for oncologists to become familiar with the drug, as it will likely become a regular part of the RCC treatment journey.
With more than 1800 patients enrolled, the subgroup analyses should have reasonable statistical power. If you look at the forest plot overall, there is no strong signal suggesting that the combination should not be used in most patients.
There is some variability in the very high-risk M1 NED subgroup based on the HR, but the confidence intervals are wide. That indicates instability in the estimate because the subgroup is relatively small.
At this point, I would not exclude patients based on that signal alone. However, we cannot completely rule out biological differences that could influence benefit. More research will help clarify that.
Urologists and medical oncologists should work closely together. At many centers, including ours, urologists have been excellent at referring patients for discussion of adjuvant treatment options.
However, LITESPARK-022 does not address every patient population. One group I often see referred includes patients with non–clear cell histology. HIF-2α inhibitors have primarily been studied in clear cell, VHL-driven malignancies.
If I have a patient with papillary RCC, for example, where we do not have data supporting belzutifan even in the metastatic setting, I would not use the combination today. The same applies to most non–clear cell histologies.
One exception could be tumors with sarcomatoid features. Those represented approximately 11% of patients in the [investigational arm of the] study, and we plan to analyze that subgroup in more detail.
In future presentations, we plan to examine additional important end points beyond OS. One of those is distant metastasis-free survival, which I believe is very important. Metastases are typically managed with additional systemic therapy or localized therapy, so it will be important to analyze those outcomes while we wait for the OS data to mature.
There are many aspects of the data we can explore before OS matures, and those analyses will be presented in future updates.
The main takeaway is that oncologists should become familiar with belzutifan because it will likely become part of the treatment armamentarium across multiple lines of therapy, including the adjuvant setting.
We should remember the 2 key AEs: anemia and hypoxia. It’s important to understand how to manage these through dose reductions, treatment interruptions, and supportive measures such as ESAs or blood transfusions, if needed.
