Belzutifan improves PFS, response in advanced renal cell carcinoma
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Key takeaways:
- Belzutifan improved PFS and objective response compared with everolimus for patients with advanced renal cell carcinoma.
- Rates of treatment-related grade 3 or higher adverse events appeared similar in each group.
Belzutifan significantly improved PFS and objective response compared with everolimus for patients with advanced renal cell carcinoma, according to results of a randomized phase 3 trial.
Researchers reported comparable rates of treatment-related grade 3 or higher adverse events in each treatment group; however, individuals assigned belzutifan (Welireg, Merck) required fewer treatment interruptions or discontinuations due to adverse events.
“Participants who received belzutifan had a longer time to confirmed worsening of disease-specific symptoms and deterioration in health-related quality of life than participants who received everolimus, which provides further support for the use of belzutifan in advanced clear-cell renal-cell carcinoma,” Toni K. Choueiri, MD, director of Lank Center for Genitourinary Oncology and director of the kidney cancer center at Dana-Farber Cancer Institute, and colleagues wrote.
Background and methods
First-line treatment with antiangiogenic and immune checkpoint inhibitors have improved outcomes for patients with advanced clear cell renal cell carcinoma, according to study background. VEGF receptor tyrosine kinase inhibitor monotherapy, as well as the combination of lenvatinib (Lenvima, Eisai) and everolimus, are among the options used after disease progression.
However, more effective treatment options are needed.
Belzutifan is an oral HIF-2alpha inhibitor approved in the U.S. for multiple indications, including previously treated patients with advanced kidney cancer or those with certain von Hippel-Lindau disease-related tumors.
Choueiri and colleagues conducted the LITESPARK-005 trial to compare belzutifan with everolimus for 746 adults with stage IV clear-cell renal cell carcinoma whose disease progressed after PD-1/PD-L1 checkpoint inhibitor and VEGFR-TKI therapy, either in sequence or in combination.
Researchers randomly assigned 374 patients (median age, 62 years; 79.4% men; 79.4% white) to 120 mg oral belzutifan daily. The other 372 patients (median age, 63 years; 76.3% men; 78.2% white) received 10 mg oral everolimus daily.
A comparable percentage of patients in the belzutifan and everolimus groups had received at least three prior lines of therapy (45.2% vs. 40.3%).
PFS and OS served as dual primary endpoints. Objective response, duration of response, and safety served as secondary endpoints.
Results and next steps
After median follow-up of 18.4 months, results showed median PFS of 5.6 months in each group. However, nearly three times as many patients assigned belzutifan remained progression free at 18 months (24% vs. 8.3%; P = 0.002).
Additionally, more patients assigned belzutifan achieved objective response (21.9% vs. 3.5%; P < 0.001).
Researchers conducted the OS analysis after median follow-up of 25.7 months.
Results showed no significant difference in median OS (21.4 months vs. 18.1 months) or 18-month OS (55.2% vs. 50.6%; HR = 0.88; 95% CI, 0.73-1.07) between the belzutifan and everolimus groups.
Investigators reported comparable rates of treatment-related adverse events (any grade, 89% vs. 89.4%; grade 3 or higher, 38.7% vs. 39.4%) and any-cause serious adverse events (42.2% vs. 38.1%) between the belzutifan and everolimus groups.
Fewer patients assigned belzutifan experienced any adverse events that led to treatment interruption (43.5% vs. 48.1%), treatment discontinuation (5.9% vs. 14.7%) or death (3.5% vs. 5.3%). They also experienced fewer treatment-related adverse events that led to discontinuation (2.7% vs. 10.6%) or death (0.3% vs. 0.6%).
The most common adverse events for both groups included anemia and fatigue. Anemia was the most common grade 3 or worse adverse event in each group, followed by hypoxia in the belzutifan group and hyperglycemia in the everolimus group.
Researchers acknowledged study limitations, including the use of everolimus as the comparator therapy and the fact LITESPARK-005 enrolled a more heavily pretreated population than prior trials.
“Studies investigating belzutifan combinations as compared with other therapies are ongoing,” researchers wrote.
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