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ASCO 2021

ASCO 2021: Temporal Characteristics of Treatment-Emergent Adverse Events and Dose Modifications with Tivozanib and Sorafenib in the Phase 3 TIVO-3 Study of Relapsed or Refractory mRCC

(UroToday.com) There have been transformational changes in first-line therapy for patients with advanced renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches. While CheckMate 214 first brought combination therapy with dual checkpoint inhibition (nivolumab and ipilimumab) to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors and tyrosine-kinase inhibitors in the first-line setting. However, the use of combination therapy in the first-line setting has further emphasized the need to identify novel therapeutic targets and further lines of therapy. The randomized phase 3 TIVO-3 study (NCT02627963) met the primary endpoint of improved PFS with tivozanib vs sorafenib in patients with relapsed/refractory mRCC following prior systemic therapy, with fewer dose reductions, interruptions, and discontinuations despite a longer time on therapy. In the Kidney and Bladder Poster session at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting,  Dr. Sumanta Pal presented secondary analyses of the TIVO-3 trial focused on the temporal characteristics of treatment-emergent adverse events (TEAEs) to enable proactive supportive care strategies and improve patient experience.


The TIVO-3 trial enrolled adult patients with metastatic RCC who had previously received at last two lines of systemic therapy (including at least one prior VEGF-R inhibitor) and metastatic disease per RECIST criteria.

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In this analysis, the authors used updated safety data with a data cut-off on August 15, 2019. They examined the time-to-onset (TTO, measured in days) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring for patients receiving tivozanib and sorafenib. Duration of TEAE (median duration and IQ range in days), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm.

The authors examined 173 patients randomized to tivozanib and 170 randomized to sorafenib. Treatment exposure was substantially greater in those receiving tivozanib (11.9 cycles and 336 days of treatment exposure) than those receiving sorafenib (6.7 cycles and 192 days of treatment exposure).

As highlighted below, among TEAE of special interest occurring in at least 20% of patients, rates of hypertension, asthenia, and nausea/vomiting were more common in those receiving tivozanib while rates of diarrhea, rash, and PPE were more common in those receiving sorafenib.

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While tivozanib was associated with less Gr>3 diarrhea, rash, and PPE, and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs.

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Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent among patients receiving tivozanib than those receiving sorafenib, and TTO of first dose reduction (85 vs 45 days), interruption (81 vs 50 days), and discontinuation (114 vs 49 days) was longer for those receiving tivozanib than sorafenib. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent for those receiving tivozanib than sorafenib.

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The authors concluded that this secondary analysis of the TIVO-3 study found that temporal characteristics of TEAEs were similar for those receiving tivozanib and sorafenib, but time to dose modifications was longer with tivozanib. Further, among those with the same TEAEs, unmodified treatment was continued more often with tivozanib.

Presented by: Sumanta Kumar Pal, MD, Associate Professor, Department of Medical Oncology and Therapeutics Research, Co-Director, Kidney Cancer Program, City of Hope

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021