Final analysis of the LITESPARK-005 study

Prof Brian Rini, a medical oncologist at Vanderbilt Ingram Cancer Center, Nashville, TN presented an update on the LightSpark005 trial, which compared belzutifan to everolimus in patients with previously treated advanced ccRCC. Belzutifan, an oral HIF inhibitor, prevents HIF dimerization, disrupting downstream signalling, including VEGF pathways. In prior phase II trials, belzutifan showed a 20% response rate, long PFS and good tolerance, which led to this phase III trial.

The updated results, first presented at last year’s ESMO and recently published in NEJM, confirmed a sustained PFS advantage for belzutifan. While both arms showed similar median PFS of 5.6 months, the belzutifan arm eventually separated, with a significant PFS hazard ratio of 0.75. The response rate for belzutifan was 23%, with complete responses in some patients, compared to just 3.5% for everolimus. Despite this, OS was not statistically significant, with a hazard ratio of 0.92 favouring belzutifan but not meeting the threshold for significance.

Belzutifan is well-tolerated, with manageable side effects like anaemia and occasional hypoxia, making it preferable to VEGF inhibitors in some cases. Its tolerability and efficacy make it a strong option for third- or fourth-line treatment in patients with indolent, low-volume disease, where its slower response time (around four months) is less of a concern. The drug may perform better in patients with favourable characteristics, such as lower disease burden and better performance status, though biomarkers are still under investigation.

Ongoing trials are exploring belzutifan in combination therapies, including with lenvatinib and pembrolizumab, in earlier lines of treatment. These studies, expected to report in the coming years, may clarify belzutifan’s role, potentially shifting its use earlier in the disease course, especially given kidney cancer’s angiogenic nature in its early stages. For now, it remains a promising monotherapy for refractory cases, with clear clinical activity and excellent tolerability.