Long-Term Benefits of Tivozanib: Insights From the TIVO-3 Study

Katy Beckermann, MD, PhD, of Vanderbilt-Ingram Cancer Center, and Thomas Hutson, DO, PharmD, FACP, of Baylor University Medical Center, summarize the TIVO-3 study for patients with relapsed or refractory advanced RCC, the recently reported long-term follow-up data, and what subgroup analyses tell us about the benefit of this treatment approach when factoring age and prior immunotherapy exposure.

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Dr. Beckermann: I will briefly introduce the TIVO-3 study, and then we will quickly delve into what the more recent longer-term data follow-up showed. Just as a reminder, TIVO-3 was a randomized phase 3 trial for patients with metastatic RCC who had progressed on prior therapy. About two-thirds of patients had 2 prior lines of treatment, while the remaining had 3 prior lines of treatment. This contextualizes that this is a pretty refractory patient population. Tivozanib, a novel TKI at that time, was compared to sorafenib, and the primary endpoint was PFS, which it met with a PFS of 5.6 months compared to 3.9 months with sorafenib. This led to its FDA approval in 2021, and certainly, I have been using it in the clinic since then.

I think what this paper, on which we are both co-authors, aimed to do was to understand in the longer term whether patients in the refractory setting were able to have long-term benefit. So, maybe starting there, Dr. Hutson, I wonder if you could summarize some of that and discuss how it supports what we do in clinic or how we think of it in the treatment landscape.

Dr. Hutson: I think what is most important about this study is that it included a population that we would consider modern. They were exposed to what we would consider best practice or standard of care today. This addresses some of the limitations in previous studies of other agents, where one could end up extrapolating to a dated population. It was great to see this drug demonstrate a degree of activity that we could confidently use in clinic, knowing we had this dataset to support it.

What was significant about the data was the clear separation of the curves in some of the efficacy endpoints, particularly in PFS. We also observed overall survival hazard ratios indicating a positive benefit. Importantly, in the long term, we see that patients are not harmed, but rather continue to benefit. Tracking the PFS curves, we observe a maintained separation, indicating ongoing benefit even with post-progression therapy. Ultimately, exposure to tivozanib provided a long-term benefit to these patients for the rest of their lives.

As we move patients into later lines of therapy, the goals of therapy shift, focusing more on disease control rather than significant tumor shrinkage. This dataset is refreshing, demonstrating this sustained benefit even in later lines of therapy. This has implications as we look at newer agents, which may alter the treatment landscape. Tivozanib, with its mature dataset, is well positioned to remain a standard therapy option, potentially within the first 4 lines of therapy, which encompasses the bulk of therapy. While newer agents may emerge in the refractory setting, they may eventually be combined earlier in therapy.

Dr. Beckermann: Yes, and I agree. Maybe to highlight one other thing you mentioned as we transition to discussing where this ends up in the treatment options, what this data showed, now with longer follow-up, is that in this refractory patient population, the goal is a durable benefit that is well tolerated. While not explicitly quality of life, we did observe patients able to remain on treatment for 11 months compared to sorafenib, which was closer to the 4 or 5-month range. Additionally, the incidence of grade 3 treatment-related adverse events was lower with tivozanib than with sorafenib. It is important to highlight these aspects because these patients, having gone through multiple prior treatment options, often experience side effects and symptoms from their cancer, detracting from their quality of life. It is also reassuring to see that even in the most elderly patients, those over 75, there was not an increased rate of discontinuation or dose reduction, suggesting good tolerability.

Dr. Hutson: The conclusions, especially when looking at the group of responding patients and following them out over 4 years, show a clinically meaningful benefit. The conclusion statements of the article are absolutely true. This benefit was seen across all age groups regardless of prior therapies or immunotherapy exposure. These are important factors to consider, and we have a subgroup of patients who truly benefit long-term after exposure to this drug.

View their further comments on Next-Generation Therapies in RCC.