Dr. Michiel Strijbos, a medical oncologist at GZA Wilrijk, and Dr. Peter Schatteman, a urologist at OLV Aalst, discussed key aspects of the LITESPARK trials presented at the ESMO meeting. Their conversation began with the phase 2 LITESPARK-003 study, which explored belzutifan in combination with the multi-kinase inhibitor cabozantinib for patients with advanced ccRCC. The patients in this study were either treatment-naïve (Cohort 1) or had previously received immunotherapy (Cohort 2).
One notable point of discussion was the absence of a cohort combining belzutifan with immunotherapy in the first line. Both experts found this surprising, given that immunotherapy is the standard first-line treatment for most ccRCC patients. Dr Schatteman acknowledged that for tumours primarily driven by angiogenesis, the combination of belzutifan (targeting the HIF pathway) and cabozantinib (targeting the VEGF pathway) could be effective.
Dr. Strijbos was particularly impressed by the high response rates observed in the study, which he noted were among the highest he had seen. There was also a significant PFS benefit. However, in the cohort of pretreated patients, the benefit appeared less clear, mainly resulting in stable disease.
The experts also discussed the dosage of cabozantinib used in the study. They both recognised the challenges associated with cabozantinib monotherapy, especially its tolerability. They were surprised that the study included a 60 mg dose of cabozantinib in the first line, in combination with belzutifan. They suggested that a 40 mg dose might be more reasonable, as toxicity often becomes problematic after 2-3 months. Additionally, with the combination of belzutifan, they anticipated an increased risk of anaemia, potentially leading to higher toxicity in a real-life setting. Nevertheless, they both agreed that the approach showed promise, with a potential synergy between the two drugs. They expressed curiosity about the results of the phase 3 trial.
The conversation briefly touched on the LITESPARK-013 study, which compared belzutifan at doses of 200 mg and 120 mg in advanced ccRCC patients who had progressed on anti-PD-1/L1 therapy. Previous phase 1 studies did not determine the maximum tolerated dose of belzutifan. However, this study yielded negative results, with no significant differences in efficacy outcomes between the two dosage groups. The 200 mg dose of belzutifan was associated with a higher rate of overall dose modifications and drug discontinuation. As a result, the experts continued to support the use of belzutifan at a 120 mg once-daily dose for ccRCC patients.
References:
Toni Choueiri – Phase 2 LITESPARK-003 Study of Belzutifan in Combination With Cabozantinib for Advanced Clear Cell Renal Cell Carcinoma (ccRCC). ESMO23 – LBA87
Neeraj Agarwal – Safety and Efficacy of Two Doses of Belzutifan in Patients (pts) With Advanced RCC: Results of the Randomized Phase 2 LITESPARK-013 Study. ESMO23 – 1881O
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