Tivozanib Elicits Similar PROs With or Without Nivolumab in Advanced Clear Cell RCC

The addition of tivozanib (Fotivda) to nivolumab (Opdivo) demonstrated comparable patient-reported outcomes (PROs) vs tivozanib monotherapy in patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) following progression on 1 or 2 systemic therapies and at least 1 immune checkpoint inhibitor (ICI), according to results from the phase 3 TiNivo-2 study (NCT04987203).1

Data on PROs, which were presented at the 2025 Genitourinary Cancers Symposium, demonstrated that tivozanib maintained the mean scores for the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease-Related Symptoms (FKSI-DRS) and European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaires.

In the intent-to-treat (ITT) populations from the tivozanib/nivolumab vs tivozanib monotherapy arms, respectively, the mean FKSI-DRS scores at baseline were 28.8 vs 29.3; at week 24, these scores were 29.9 vs 29.4. The mean EORTC QLQ-C30 scores at baseline were 63.4 vs 66.2 in the combination vs monotherapy arms, respectively; at week 24, these mean scores were 68.7 vs 64.8. Patients treated with the combination vs monotherapy in the second line had mean FKSI-DRS scores at baseline of 29.5 vs 29.1; at week 24, these mean scores were 30.1 vs 29.3. Mean EORTC QLQ-C30 scores at baseline in the combination vs monotherapy arms in the second line were 65.0 vs 67.1; these mean scores at week 24 were 68.7 vs 64.6. In the third-line setting, mean FKSI-DRS scores at baseline were 27.6 vs 29.5; these mean scores at week 24 were 29.5 vs 29.6. Mean EORTC QLQ-C30 scores at baseline in the combination vs monotherapy arms in the third were 60.5 vs 64.9, with mean scores at week 24 of 68.6 vs 65.1.

“In the [tivozanib monotherapy] arm, improvement in FKSI-DRS and EORTC QLQ-C30 scores were numerically greater in patients receiving second-line treatment than third-line treatment, while…fewer patients reported deterioration in the second line than in the third line,” lead study author Kathryn Beckermann, MD, PhD, and coauthors wrote in a poster presented at the meeting.

Beckermann is an assistant professor in the Department of Medicine, Division of Hematology and Oncology at Vanderbilt School of Medicine in Nashville, Tennessee.

Tivozanib Background and TiNivo-2 Design

Tivozanib is a potent and highly selective oral vascular TKI designed to optimize VEGF blockade and minimize off-target toxicities. The agent was approved by the FDA in March 2021 for the treatment of patients with relapsed/refractory advanced RCC after 2 or more previous lines of systemic therapy.2 The approval followed efficacy data from the randomized phase 3 TIVO-3 study (NCT02627963).

The TiNivo-2 study compared tivozanib/nivolumab with tivozanib monotherapy in patients with locally advanced or metastatic clear cell RCC following progression on 1 or 2 systemic therapies and at least 1 ICI.3 The trial enrolled patients who had radiographic progression during or after at least 6 weeks of treatment with an ICI in the first or second line; recovered from adverse effects (AEs) of previous therapies to grade 1 or baseline; had histologically or cytologically confirmed clear cell RCC; measurable disease per RECIST 1.1 criteria; and an ECOG performance status of 0 or 1. Stratification factors were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category and prior therapy (ICI as the most recent therapy or not).1

Eligible patients were randomly assigned 1:1 to receive tivozanib/nivolumab or tivozanib monotherapy. Those in the combination arm (n = 171) were treated with oral tivozanib at 0.89 mg on days 1 to 21 and nivolumab at 480 mg intravenously on day 1. Of note, the reduced dose of tivozanib in the combination arm was agreed upon with regulatory authorities because of the potential risk of higher rates of grade 3/4 hypertension. Patients in the tivozanib monotherapy arm (n = 172) were treated with oral tivozanib at 1.34 mg from days 1 to 21. Cycles were 28 days, and treatment was continued until progression or unacceptable toxicity. All patients discontinued nivolumab after 2 years of treatment.

The primary end point was progression-free survival (PFS) by independent radiology review; the key secondary end point was overall survival, and other secondary end points included PFS by investigator review, objective response rate, and duration of response; an exploratory end point was quality of life (QOL). The present analysis was performed to evaluate exploratory PRO data based on FKSI-DRS and EORTC QLQ-C30 questionnaires, which had been provided at baseline, day 1 of each cycle, and at the end of treatment. In the PRO analysis population, the PRO-evaluable set was defined as all randomly assigned patients with a baseline and 1 post-baseline assessment.

Additional PROs and Efficacy Data

Regarding PRO questionnaire completion and compliance rates, FKSI-DRS completion at baseline in the combination vs monotherapy arms, respectively, was 95.3% vs 96.5%; completion at week 24 was 56.4% vs 53.2%. FKSI-DRS compliance at baseline was 95.3% vs 96.5% in the combination vs monotherapy arms, respectively; compliance at 24 weeks was 91.5% vs 92.9%. EORTC QLQ-C30 completion at baseline in the combination vs monotherapy arms, respectively, was 96.5% vs 94.2%; completion at 24 weeks was 53.2% vs 53.8%. EORTC QLQ-C30 compliance at baseline in the combination vs monotherapy arms was 96.5% vs 94.2%; compliance at week 24 was 92.9% vs 93.9%.

The FKSI-DRS and EORTC QLQ-C30 summary scores showed that there was not a significant change in symptom scores over time in the combination and monotherapy arms. Specifically in the second and third line, patients from both arms also demonstrated a similar trend in FKSI-DRS and EORTC QLQ-C30 summary scores, with maintained symptom scores over time.

Regarding QOL scores, FKSI-DRS and EORTC QLQ-C30 questionnaires reported consistent trends and proportions of patients with improved (increases in scores of at least 3 points at any point during the study), stable (a change in score of 3 or fewer points confirmed at the next consecutive visit), or deteriorated symptoms (decrease in score of at least 3 points at any point during the study). Based on the FKSI-DRS questionnaire, patients from the combination vs monotherapy arms, respectively, had improved (28.2% vs 22.9%), stable (47.2% vs 53.5%), and deteriorated symptoms (24.6% vs 23.6%). The EORTC QLQ-C30 questionnaire among patients in the combination vs monotherapy arms, respectively, revealed improved (27.7% vs 21.3%), stable (48.9% vs 53.7%), and deteriorated symptoms (23.4% vs 25.0%).

“Approximately 75% of all patients reported improved or stable kidney cancer and cancer-treatment related symptoms in both treatment arms,” the study authors wrote in the poster.

In patients treated with the combination vs monotherapy in the second line, respectively, FKSI-DRS reflected improved (28.0% vs 27.5%), stable (52.7% vs 53.8%), and deteriorated (19.4% vs 18.7%) health-related QOL (HRQOL) scores. In the third line, patients in the combination vs monotherapy arms, respectively, had improved (28.6% vs 15.1%), stable (36.7% vs 52.8%), and deteriorated (34.7% vs 32.1%) HRQOL scores. Based on EORTC QLQ-C30, patients from the combination vs monotherapy arms, respectively, treated in the second line had improved (27.8% vs 23.0%), stable (52.2% vs 56.3%), and deteriorated (20.0% vs 20.7%) HRQOL scores. Patients treated with the combination vs monotherapy in the third line, respectively, showed improved (27.7% vs 18.4%), stable (42.6% vs 49.0%), and deteriorated (29.8% vs 32.7%) HRQOL scores.

The rate of PFS events that occurred in patients treated in the combination (n = 111) vs monotherapy (n = 105) arms, respectively, in the second line, was 64% vs 61%; median PFS was 7.3 months (95% CI, 5.4-9.3) vs 9.2 months (95% CI, 7.4-10.0 [HR, 1.15; 95% CI, 0.82-1.62; P = .4282]).4 Among patients treated with the combination (n = 60) vs monotherapy (n = 67) in the third line, PFS events occurred in 78% vs 72%, respectively; median PFS was 4.8 months (95% CI, 3.2-7.5) vs 5.5 months (95% CI, 2.9-7.4 [HR, 0.97; 95% CI, 0.65-1.45; P = .8866]).

Safety Data

The type and frequency of safety events in the tivozanib monotherapy arm were consistent with the known safety profile of tivozanib, confirming its tolerability.1

Treatment-emergent AEs (TEAEs) that occurred in 15% or more of patients in the combination vs monotherapy arms, respectively, included hypertension (37% vs 40%), fatigue (29% vs 40%), diarrhea (30% vs 36%), nausea (16% vs 28%), decreased appetite (22% vs 27%), vomiting (12% vs 21%), asthenia (23% vs 21%), proteinuria (10% vs 18%), constipation (10% vs 17%), arthralgia (16% vs 16%), cough (16% vs 15%), hypothyroidism (9% vs 15%), anemia (17% vs 9%), and pruritus (16% vs 6%).

“For certain TEAEs, such as fatigue, nausea, vomiting, proteinuria, and hypothyroidism, the combination group showed lower numerical rates,” the study authors wrote. “However, this was not the case for anemia [or] pruritus, which showed the reverse. The lower dose in the combination [group] potentially explains the lower rate of TEAEs associated with VEGF TKIs.”

References

1. Beckermann K, Choueiri T, Motzer R, et al. Patient-reported outcomes (PROs) for tivozanib (TIVO) + nivolumab (NIVO) vs TIVO monotherapy in patients with renal cell carcinoma (RCC) following an immune checkpoint inhibitor (ICI): results of the phase 3 TiNivo-2 study. J Clin Oncol. 2025;43(suppl 5):459. doi:10.1200/JCO.2025.43.5_suppl.459
2. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. March 10, 2021. Accessed February 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tivozanib-relapsed-or-refractory-advanced-renal-cell-carcinoma
3. Study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma. ClinicalTrials.gov. Updated October 24, 2024. Accessed February 15, 2025. https://clinicaltrials.gov/study/NCT04987203
4. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6