The phase 3 TiNivo-2 trial has revealed that combining nivolumab with tivozanib does not improve outcomes compared to tivozanib monotherapy in patients with immuno-oncology (IO)-refractory clear cell renal cell carcinoma (RCC), according to data presented at the European Society for Medical Oncology Congress 2024.
Key Trial Findings
The study compared tivozanib monotherapy at 1.34 mg daily against a combination of tivozanib (0.89 mg) with nivolumab in patients who had progressed on prior immunotherapy. The progression-free survival (PFS) analysis showed a hazard ratio of 1.1 (95% CI, 0.84-1.43; P = .49), indicating no significant benefit from the combination approach.
Both treatment arms demonstrated comparable efficacy with identical objective response rates of 19%. Notably, the duration of response reached 15.8 months in the combination arm, while it was not yet reached in the tivozanib monotherapy arm at the time of analysis.
Patient Population and Treatment History
The trial enrolled a diverse patient population, with the majority having received only one prior line of therapy. Approximately one-third of participants had received IO/IO therapy (PD-1 and CTLA-4 inhibition) in the frontline setting, while others had experienced either sequential therapy or IO/TKI combinations.
A distinctive feature of the TiNivo-2 trial was its inclusion of patients who had received intervening tyrosine kinase inhibitor (TKI) therapy, representing about 30% of the study population. Among those who received third-line treatment, cabozantinib was the predominant second-line therapy choice.
Subgroup Analysis and Treatment Outcomes
The trial revealed interesting trends in different patient subgroups. Patients who received tivozanib monotherapy immediately following immune checkpoint inhibitor therapy showed particularly promising results, achieving a median PFS of 9.2 months. However, patients in the third-line setting demonstrated more modest outcomes, with both treatment arms showing a median PFS of approximately 3.7 months.
Treatment Options in IO-Refractory Setting
The findings come at a time when the treatment landscape for IO-refractory RCC continues to evolve. Current options include various TKIs such as axitinib, the combination of lenvatinib and everolimus, the novel mechanism agent belzutifan, and tivozanib. The NCCN guidelines acknowledge the growing prominence of IO therapy in frontline treatment but note the absence of preferred regimens in the refractory setting due to limited sequential therapy studies.
Safety Considerations
The study design notably incorporated FDA guidance regarding potential hypertension risks, leading to a reduced tivozanib dose in the combination arm. This methodological approach highlights the importance of careful dose optimization when combining targeted therapies with immunotherapy.
