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Should We Be Surprised That in the TiNivo-2 Trial, Tivozanib plus Nivolumab Is Negative When Compared to Tivozanib Monotherapy, After Progression on a Prior Immune Checkpoint Inhibitor?

Tivozanib is a highly selective, oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor that is indicated for the treatment of adults with relapsed or refractory advanced renal cell carcinoma following two or more prior systemic therapies.1 The regulatory approvals through the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) were based on data from the TIVO-3 randomized phase 3 trial of tivozanib 1.34 mg orally daily versus sorafenib, which showed improved progression-free survival at a median of 5.6 versus 3.9 months, respectively.2 This was a third or fourth line patient population as the patients were mandated to have all received at least 2 prior systemic therapies, including at least one previous VEGFR inhibitor.

In attempts to move into earlier lines of therapy, in combination with immune checkpoint inhibitors, the TiNivo trial showed a 56% objective response rate when tivozanib 1.5 mg orally daily was combined with nivolumab 240 mg intravenously every 2 weeks.3 Subsequently, the TiNivo-2 trial was designed to evaluate tivozanib 1.34 mg orally daily for 21 consecutive days followed by 7 days off with or without nivolumab dosed at 480 mg intravenously every 4 weeks.4 This randomized, phase 3 trial design enrolled patients who had advanced renal cell carcinoma who progressed following 1-2 lines of therapy, including a prior immune checkpoint inhibitor.

Unfortunately, a press release just reported out the TiNivo-2 trial was negative for the primary endpoint of progression-free survival.5 Given the efficacy of tivozanib in the third and later line setting, should this result be surprising? There are two areas of concern when I evaluate the design of this trial. The first is that the TiNivo-2 trial administered the tivozanib combination with a different dose and schedule from the accepted single agent dose. This may prove influential on the results, as we know historically that dose intensity generally matters for tyrosine kinase inhibitors.6

The second concern is that the TiNivo-2 trial had tivozanib in both arms and monotherapy with tivozanib was the control. Administering this efficacious tyrosine kinase inhibitor with another immune checkpoint inhibitor soon after progression on a prior immune checkpoint inhibitor may not be an ideal design to capture efficacy in a randomized trial design. If we refer back to phase 1 trials of nivolumab, it was clear that a single dose of nivolumab could sustain PD-1 receptor occupancy on peripheral blood T cells for up to 100 days.7 In the melanoma and Merkel cell carcinoma literature, extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy appears to allow preserved efficacy with cost savings.8 Recently, the CONTACT-03 phase 3 trial showed no benefit to atezolizumab with cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression on a previous immune checkpoint inhibitor.9 Given the long duration of PD-1 receptor occupancy, it is very likely that PD-1 receptors are still fully occupied even many months after cessation of the inhibitor. Therefore, a patient who recently progressed on an immune checkpoint inhibitor is likely still seeing the biological and clinical effects of that immune checkpoint inhibitor for many months after disease progression. We may just be testing novel drug X (fill in the blank) combined with an immune checkpoint inhibitor versus novel drug X with persistent, residual immune checkpoint inhibitor. The result in that situation is rather obvious, and the list of negative trials may continue to pile up if we don’t alter our approach. The lesson to be learned is we should stop trying to continue or switch immune checkpoint inhibitors immediately or soon after progression; we should just completely move on, away from this class of immune checkpoint inhibitors.

My conclusion is that the TiNivo-2 trial should not be viewed as a negative result for tivozanib, rather it is a confirmatory negative result for the trial designs of not only TiNivo-2 but also CONTACT-03, and potentially other future clinical trials. There are other trials actively being designed for renal cell carcinoma, urothelial carcinoma, and many other cancer patients who have recently progressed on an immune checkpoint inhibitor. In those clinical scenarios, it is time to move on from the immune checkpoint inhibitor. That said, there are likely other insights to be gained from the TiNivo-2 trial results, and we eagerly await the presentation(s) and publication(s) from that trial for more complete understanding.

In the meantime, we should still appreciate the efficacy of tivozanib monotherapy in standard clinical practice. We should also continue to accrue to clinical trials that incorporate tivozanib in various patient populations. Below, I highlight a couple of trials using tivozanib that are open to active accrual of patients with genitourinary malignancies.

Select Ongoing Trials with Tivozanib for Patients with Genitourinary Cancers

  • Phase 2 trial of tivozanib and nivolumab in non-clear cell renal cell carcinoma (NCT06053658)
  • Phase 1/2 trial of tivozanib and atezolizumab in immunologically cold tumor types (including metastatic castration-resistant prostate cancer) (NCT05000294)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-fotivda-tivozanib-adult-patients-relapsed-or-refractory#:~:text=On%20March%2010%2C%202021%2C%20the,or%20more%20prior%20systemic%20therapies.
  2. Rini BI, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet 2020; 21:95-104.
  3. Albiges L, et al. TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2021; 32:97-102.
  4. Choueri TK, et al. TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor. J Clin Oncol 40, (No. 6_suppl:TPS405).
  5. https://www.prnewswire.com/news-releases/aveo-oncology-an-lg-chem-company-announces-phase-3-renal-cell-carcinoma-clinical-trial-tinivo-2-results-302199844.html
  6. Motzer RJ, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012; 30:1371-7.
  7. Brahmer JR, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28:3167-75.
  8. Tachiki LML, et al. Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma. Cancer Immunol Immunother 2023; 72:3839-50.
  9. Pal SK, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet 2023; 402:185-95.