Belzutifan beat everolimus in progression-free survival (PFS) and response rate, but hardly anyone uses it alone, mostly used in combination with Lenvatinib.
It is yet another option for renal cell cancer patients.
Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies.
In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response).
A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P=0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P=0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively.
Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.)
Adjuvant pembrolizumab improves overall survival (reduced mortality by 38%). We need to make sure that urologists are also aware so those patients with a high risk of recurrence can get this medication.
An intriguing study from the UK, patients had 24 weeks of sunitinib or pazopanib followed by a continuation or treatment holiday. Non-inferiority could not be established, but there was seemingly no meaningful reduction in OS (28 vs. 27 months overall), with a noticeable improvement in toxicity in the treatment break group. This may be a realistic strategy for patients with a focus on QOL or cost-effectiveness.
Pembrolizumab remains the only adjuvant option for high risk RCC after curative surgery. The OS curves seem to be beginning to separate and hope to be positive with longer f/u. The ongoing Durvalumab + Tremilumumab will be an interesting adjuvant study for RCC when the results are available.
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