(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 virtual annual meeting’s non-prostate cancer session included a presentation by Dr. Brian Rini discussing a new 3-arm phase 3 trial concept and design, which will randomize patients with advanced clear cell RCC in the first-line setting to either pembrolizumab + belzutifan + lenvatinib versus MK-1308A + lenvatinib versus pembrolizumab + lenvatinib. Despite advances in treatment, most patients with advanced clear cell RCC will eventually experience disease progression on treatment. Combination therapy with the PD-1 inhibitor pembrolizumab and the VEGF inhibitor lenvatinib showed activity in patients with advanced ccRCC in the phase III KEYNOTE-581/CLEAR trial.1 The HIF-2α inhibitor belzutifan (MK-6482) and MK-1308A, a coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab, have each shown antitumor activity in phase I/II trials. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in clear cell RCC.