medwireNews: Treatment with belzutifan achieves significantly better progression-free survival (PFS) and response than everolimus in heavily pretreated patients with advanced renal cell carcinoma (RCC), show phase 3 data.
Noting that the hypoxia-inducible factor (HIF)-2α inhibitor has been approved in the USA, the investigators say: “The LITESPARK-005 trial introduced HIF-2α inhibition as an active therapeutic mechanism and established belzutifan as a treatment option in patients with advanced renal-cell carcinoma after both immune checkpoint and antiangiogenic therapies.”
In the trial, 746 patients with stage IV clear-cell RCC who had received up to three prior lines of therapy – including a PD-1 or PD-L1 inhibitor and a VEGFR–tyrosine kinase inhibitor, in sequence or in combination – were randomly assigned to received either belzutifan 120 mg/day or everolimus 10 mg/day until disease progression or unacceptable toxicity.
At the first interim analysis, conducted at a median follow-up of 18.4 months, the median duration of the co-primary endpoint of PFS was identical in both treatment arms, at 5.6 months.
However, the estimated proportion of patients alive and free of progression at landmark timepoints was significantly higher in the belzutifan than everolimus group, at 46.6% versus 42.5% at 6 months, 33.4% versus 17.1% at 12 months, and 24.0% versus 8.3% at 18 months.
The objective response rate was similarly significantly higher with belzutifan than everolimus, at 21.9% and 3.5%, respectively, equating to a between-group difference of 18.4 percentage points, report Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and collaborators in The New England Journal of Medicine.
The second interim analysis was conducted at a median follow-up of 25.7 months, and this showed a trend in favor of belzutifan with respect to the other primary endpoint of overall survival (OS), but the difference did not reach statistical significance. Specifically, the median OS duration was 21.4 months in the belzutifan group and 18.1 months in the everolimus group, giving a nonsignificant hazard ratio for death of 0.88.
The researchers note that “[r]esults of the final protocol-specified analysis are pending.”
Turning to the safety, they say that “[t]he percentage of participants with adverse events [AEs] from any cause, both of any grade and of grade 3 or higher, was similar in the two treatment groups, although fewer participants in the belzutifan group than in the everolimus group discontinued treatment because of an adverse event.”
Any-cause AEs of grade 3 or worse occurred in 61.8% of patients in the belzutifan arm and 62.5% of those in the everolimus arm. The corresponding rates of treatment-related AEs of at least grade 3 were 38.7% and 39.4%, with the most common event in both groups being anemia (32.5 and 18.1%, respectively).
A total of 14.0% of the belzutifan group and 14.7% of the everolimus group needed a dose reduction due to AEs, while a respective 5.9% and 14.7% discontinued study treatment. AEs led to death in 3.5% and 5.3% of participants, respectively.
Hypoxia from any cause is “a known adverse event associated with belzutifan treatment,” note Choueiri et al, and the AE was reported in 14.5% (grade ≥3, 10.5%) of belzutifan-treated patients and 1.1% (all grade ≥3) of everolimus-treated patients.
And they conclude: “Belzutifan has a safety profile distinct from other available late-line therapies for clear-cell renal-cell carcinoma. Attention to the management of adverse events such as anemia and hypoxia will be required as belzutifan is incorporated into clinical practice.”
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