ESMO 2022: Invited Discussant: Results of the Phase 2 LITESPARK-003 Trial

He began by summarizing LITESPARK-003, a study of belzutifan and cabozantinib. As of today, the first-line treatment of aRCC is a immune checkpoint inhibitor-based combination regime with either dual checkpoint inhibition or combination with a VEGF inhibitor. Summarizing data available thus far, he noted that the trials with longer follow-up have truly demonstrated meaningful survival differences for patients with intermediate and poor-risk disease.

In contrast, in those with favourable risk disease, not only has the combination approach not show survival benefits, the CheckMate 214 trial showed a shorter median progression-free survival for patients receiving the dual immune checkpoint inhibitor combination than sunitinib alone. Thus, the question arises as to how we should expand therapeutic options in first-line treatment for aRCC.

There are certainly a number of approaches. In the COSMIC-313 trial which was also presented at this year’s ESMO meeting, the investigators sought to assess the value of adding a third agent to the dual checkpoint inhibitor backbone. However, numerous other approaches including novel medications with discrete mechanisms and tailored treatment paradigms have also been assessed.

Emphasizing the development of novel agents, he noted that belzutifan, a potent and selective HIF-2 inhibitor, has demonstrated encouraging activity in patients who are heavily pre-treated. Based on pre-clinical data, anti-VEGF treatment increases HIF2 concentrations. Thus, there is a mechanistic rationale for the combination assessed in this trial. LITESPARK-003 assessed this combination with cohort 1 including previously untreated patients.

In 35 patients evaluable to date, 94% of patients had reductions in target lesions and, in terms of the primary endpoint of objective response rate, this was 57%. It was somewhat higher in favourable (62%) than intermediate/poor-risk disease (50%).

Dr. Fay contextualized these results by comparing them with results from other trials in the first-line aRCC setting. As seen in the figure below, thes results from LITESPARK-003 appear to provide a ORR that is somewhat lower than seen in most trials of a combination of VEGF with IO.

In the favourable risk population (ORR 62%), the cross-trial comparison shows relatively comparable results to other studies and treatment approaches in this space. He noted that there may be rationale that favourable risk disease is more angiogenic-driven.

Moving forward, he considered the potential role for belzutifan. Clearly, this will be better delineated by numerous ongoing clinical trials.

He noted that this report showed no new signals of toxicity, though we need to be vary of hypoxia. Summarizing, he noted that the combination of cabozantinib and belzutifan demonstrates encouraging activity. However, longer follow-up is needed for survival outcomes and randomized trials will better help to delineate the role of this treatment approach. However, it raises the question of sequencing approaches, particularly as it is currently being investigated as adjuvant therapy.