Reviewing Efficacy and Tolerability in TIVO-3 Trial of Tivozanib for RCC

Randy F. Sweis, MD (Moderator)

Assistant Professor of Medicine

Duchossois Center for Advanced Medicine - Hyde Park

UChicago Medicine

Chicago, IL

Targeted Oncology^TM: What clinical trial data supported the approval of tivozanib (Fotivda) as third-line therapy for advanced renal cell carcinoma (RCC)?

RANDY F. SWEIS, MD: The major study that led to its approval was TIVO-3 [NCT02627963]. Eligibility was for patients with advanced RCC who failed 2 or 3 prior regimens including 1 VEGF–tyrosine kinase inhibitor [TKI]. Patients must have had an ECOG performance score of 0 or 1. Of note, the stratification was based on prior regimen and about 27% have had TKI plus immunotherapy (IO), so this study had a decent amount of patients with prior TKI/IO, and then the rest had either TKI/TKI or other combinations.¹

There was a prespecified stratification on those 3 groups, as well as IMDC [International Metastatic RCC Database Consortium] prognostic score. The patients were randomized to tivozanib at 1.5 mg, which translates based on the formulation, to the exact same active drug [dosage] as the 1.34 mg capsule that is on the market. On the trial it was called 1.5 mg with the salt included. It’s [given daily] 3 weeks on, 1 week off, and sorafenib was the comparator arm at a dose of 400 mg twice daily continuously in 4-week cycles, and they were treated until progression or toxicity.

Baseline characteristics were…very well matched, and the 2:1 or 3:1 male predominance was typical for RCC. The median age was in the low 60s, although with a lower end point down into the 30s, which unfortunately I’ve also seen, and 10% were over age 75. Then IMDC score was like a bell curve around intermediate risk, around 20% [each] being favorable risk and poor risk, and the rest being intermediate. The majority had 2 prior therapies [versus 3], but 25% to 27% had an IO plus TKI. The time from initial diagnosis was the same in both arms.

What was the efficacy observed in the TIVO-3 trial?

[At a median follow-up of 19 months,] the progression-free survival [PFS], which was the primary end point, was prolonged with tivozanib versus sorafenib.² The P value was .016, with a hazard ratio of 0.73. The Kaplan-Meier curves split at about month 4 and stayed split. The landmark PFS analyses are 28% versus 11% at 1 year, and 18% versus 5% at 2 years [for tivozanib versus sorafenib, respectively].

At even later follow-up, going out to 4 years, where there were effectively no patients alive without progression on sorafenib at 4 years, and 7.6% were still going without progression on tivozanib.³ Similarly, at 3 years, the PFS rate was 12.3% with tivozanib versus 2.4% with sorafenib.

Looking at PFS based on the prior therapy, the prior IO subgroup was a small subgroup, but it nonetheless favored tivozanib.4 The median PFS was 7.3 months and [19.1%] of patients [had not progressed] at 2 years.

Looking at secondary end points with a prolonged follow-up, 23% or 41 patients had an objective response with tivozanib compared with 11% for sorafenib.^1,3 The disease control rate was 82% with tivozanib versus 69% with sorafenib, and…among the responders in each group, the duration of response was 20.3 months with tivozanib [versus 9.0 months with sorafenib]. [The difference in] overall survival [OS] was not statistically significant. The hazard ratio was less than 1.00, but crossed the interval [HR, 0.91; 95% CI, 0.716-1.165; P = .47​].

The OS in the conditional subset of patients with 12-month PFS, which is a different way to analyze, shows a favorable benefit from those on the tivozanib arm.⁵ There was a hazard ratio of 0.45 with a P value of .02. At different follow-up assessments, all the way from August 2019 through May 2021, the hazard ratio continued to decrease. With longer follow-up, the data continued to mature, and it still looks favorable for tivozanib.

How did tivozanib compare with sorafenib in the trial in terms of safety and adverse events (AEs)?

In terms of safety, hypertension, diarrhea, and fatigue are very common [with tivozanib], mostly low grade.⁶ Palmar-plantar erythrodysesthesia [PPE], which is basically hand-foot syndrome, was rarely high-grade with tivozanib, but approximately 16% in all grades, whereas sorafenib had 10% PPE of grade 3 or higher. Skin rash was also common.

Hypertension was high grade in both arms, perhaps a little bit more with tivozanib. From my experience with tivozanib, I’ve seen some decently high hypertension and it has been manageable with adjustment of medications, but it is a little bit higher than other TKIs. The other AEs are all actually less frequent. High-grade diarrhea, PPE, nausea, vomiting, and rash were more common with sorafenib than with tivozanib.

Overall, I would say these were the typical expected toxicities and there were no major unexpected findings here. Perhaps these toxicities are a little bit better with tivozanib compared with the earlier generation TKIs.

_References

_{1. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(suppl_15):4546. doi:10.1200/JCO.2021.39.15_suppl.4546}

_{2. Pal SK, Escudier BJ, Atkins MB, et al. Final overall survival results from a phase 3 study to compare tivozanib to sorafenib as third- or fourth-line therapy in subjects with metastatic renal cell carcinoma. Eur Urol. 2020;78(6):783-785. doi:10.1016/j.eururo.2020.08.007}

_{3. Atkins MB, Verzoni E, Escudier B, et al. Long-term PFS from TIVO-3: tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC. J Clin Oncol. 2022;40(suppl_6):362. doi:10.1200/JCO.2022.40.6_suppl.362}

_{4. Rini BI, Pal SK, Escudier B, et al. TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). Data presented at: 2019 Genitourinary Cancers Symposium; San Francisco, CA; February 14-16, 2019. Abstract 541.}

_{5. Rini BI, Pal SK, Escudier B, et al. Maturation of overall survival (OS) in TIVO-3 with long-term follow-up. J Clin Oncol. 2022;40(suppl_16):4557. doi:10.1200/JCO.2022.40.16_suppl.4557}

_{6. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1}