Updated Appraisal of Late-Line Tivozanib in Advanced Clear-Cell RCC

Pavlos Msaouel, MD, PhD, University of Texas MD Anderson Cancer Center, spoke with our sister site GU Oncology Now to highlight his study from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024 on the efficacy, safety, and tolerability of tivozanib in heavily pretreated patients with advanced clear-cell renal cell carcinoma.

What does the study data and overall understanding of VEGF-TKIs tell us about which patients are optimal candidates for tivozanib?

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Why did you decide that an updated appraisal of tivozanib for patients with advanced ccRCC was necessary?

Dr. Msaouel: The rationale behind this, both practical and clinical, stems from the approval of a new TKI following the TIVO-3 randomized controlled trial, which compared tivozanib with sorafenib. Tivozanib, being the new TKI, was approved based on TIVO-3, which enrolled patients in later lines of therapies. However, given that TIVO-3 was conducted years ago when therapy standards differed significantly, particularly at MD Anderson, where patient treatment evolved notably between 2018 and 2019, it became crucial to assess the efficacy of tivozanib in a contemporary cohort. Such an assessment would aid in positioning tivozanib for future clinical practice not only at MD Anderson but also at similar centers.

We analyzed a heavily pretreated cohort of 30 patients who received tivozanib after a median of 4 prior therapies. This sizable number underscores the increasing availability of lines of therapies in the contemporary setting. All patients had previously received checkpoint inhibitors, with most having also been treated with potent TKIs like cabozantinib or lenvatinib. Notably, 93% had received at least one of these TKIs, with nearly half having received both. This scenario presents an ideal opportunity to evaluate the efficacy of tivozanib, its duration of response, and its target population.

What were your findings for tivozanib in terms of safety, overall survival, and objective response rate relative to other treatment options?

Dr. Msaouel: Our findings largely confirm the anticipated behavior of tivozanib in this setting, aligning with impressions from both our group and other practices. Given tivozanib’s focused inhibition of the VEGF pathway, observed side effects were predominantly VEGF pathway-related, such as hypertension. Thirteen percent of patients experienced any grade hypertension, with 6 of them experiencing severe hypertension, including grade three or higher cardiovascular side effects like congestive heart failure, observed in 3 patients.

Other observed adverse events included GI disturbances, GI perforation, and mucositis. Notably, there were no unexpected safety signals, consistent with observations with other TKIs like axitinib.

Understanding such safety profiles is crucial, especially considering the typically frail health status of patients in later-line therapies. This knowledge can help clinicians in the decision-making process when choosing between tivozanib and recently approved agents like belzutifan, particularly concerning factors like hypertension, congestive heart failure, and wound healing.

What does the study data and overall understanding of VEGF-TKIs tell us about which patients are optimal candidates for tivozanib?

Dr. Msaouel: Despite the study’s limitations, analysis of the data suggests that the most suitable candidates for tivozanib are patients heavily pretreated with prior TKIs, particularly cabozantinib or lenvatinib. Of the 26 patients evaluated for radiologic response, only 2 achieved a confirmed partial response, with none achieving a complete response, resulting in an objective response rate of approximately 8%. The median progression-free survival was 3.8 months, indicating that deep responses or curative outcomes should not be expected in this setting. However, patients who had been on prior systemic therapy for an extended duration, ranging from 2 to 6 years, were more likely to derive clinical benefit from tivozanib. This suggests a potential correlation between prolonged prior TKI exposure and increased sensitivity to anti-VEGF TKIs, thereby influencing the effectiveness of tivozanib in this subset.

With the partial response and toxicity data in mind, how should your analysis alter the utility of tivozanib in late-line RCC treatment?

Dr. Msaouel: I would like to acknowledge Dr. Andrew Johns, a hematology and oncology fellow at MD Anderson, who led this study and contributed significantly to our understanding of tivozanib’s utility. The contemporary nature of our study provides confidence in its findings, indicating no unexpected outcomes.

It is important to note that tivozanib did not exhibit unusually high response rates or prolonged median progression-free survival, which would have been surprising given the context. The observed cardiovascular toxicity aligns with expectations for a VEGF pathway inhibitor.

This study offers clinicians valuable insights into what to anticipate when using tivozanib in later-line therapy settings. Such information is crucial for making informed treatment decisions, benefiting both clinicians and patients alike.