TiNivo-2: An innovative Phase 3 trial in advanced renal cell carcinoma (aRCC)¹

The Science Behind the Study

While overall survival in aRCC has significantly improved, the need remains for more effective and tolerable treatment options in later-line disease.¹

Current options include vascular endothelial growth factor (VEGFR) inhibitors, which have demonstrated clinical efficacy but may be associated with limiting adverse events, such as tiredness, diarrhea, liver failure, and hand-foot syndrome.^2-4

Further evaluation is needed to inform clinical decisions in relapsed/refractory (R/R) disease.¹ TiNivo-2 is designed to assess the potential synergies of tivozanib—a recently approved oral VEGF tyrosine kinase inhibitor (TKI)—in combination with nivolumab, an immunotherapy.^5,6

It is hypothesized that tivozanib and nivolumab together may provide additional benefits in aRCC, as tivozanib may enhance PD-1 activity through its effects on T-regs.⁵

TiNivo-2 aims to establish a new standard of care for second-line aRCC treatment by evaluating this unique TKI/PD-1 inhibitor combination.

Tivozanib has High Potency and Selectivity⁷

Tivozanib’s Long Half-Life Creates a Unique PK Profile⁷

Tivozanib Significantly Reduces T-Regs⁸

• Cabozantinib and lenvatinib are not shown because absolute oral bioavailabilities are not reported in the literature.
• The plots provide an overall assessment of differences between VEGFR-TKIs; the evaluation is substantially qualitative since threshold values cannot be assessed.

Tivozanib is approved for adults with rrRCC following two or more prior systemic therapies.⁹

Tivozanib was approved for rrRCC based on results from TIVO-3, the first Phase 3 trial to include a predefined population of RCC patients who had received prior immunotherapy.⁹ The Phase 1/2 TiNivo trial aimed to build on these results by examining the combined effects of tivozanib with nivolumab on aRCC.

Nivolumab is a human immunoglobulin G4 (IgG4) that blocks the interaction between PD-1, PD-L1 and PD-L2. The FDA has approved nivolumab for patients with aRCC as a first-line treatment in combination with cabozantinib or with ipilimumab and as a single agent in patients with aRCC who have received prior anti-angiogenic therapy.¹⁰

Preliminary results from 25 patients in the Phase 1/2 TiNivo trial evaluating tivozanib and nivolumab indicated anti-tumor activity in patients who received the combination, regardless of whether they were treatment naïve or had prior exposure to other treatments.¹¹

Find out more about this trial >>

Open access article for TiNivo trial >>

TiNivo-2 Study Design

TiNivo-2 is an open-label, randomized, controlled, multicenter, multinational, parallel-arm Phase 3 trial. The study aims to enroll 326 patients with refractory advanced renal cell carcinoma (aRCC) across 190 clinical sites. Patients will be assigned to treatment groups in a 1:1 ratio; 163 will receive the tivozanib/nivolumab combination and 163 will receive tivozanib alone.⁶

Patients will be given oral tivozanib once daily with a dosing cycle of 3 weeks on and 1 week off. Patients who receive nivolumab will be infused with one treatment at a specified dose on specified days of each cycle.

Primary Outcome⁶

Progression-free survival

• Definition: time from randomization to first documentation of objective tumor progression (progressive disease, radiological) according to Response Evaluation Criteria In Solid Tumors (RECIST), or death due to any reasons, whichever comes first
• Timeframe: until progressive disease

Secondary Outcomes⁶

Overall Survival

• Definition: time from the date of randomization to date of death due to any cause
• Timeframe: from screening (Days -28 to -1) until death

Objective Response Rate

• Definition: proportion of subjects with confirmed complete response or confirmed partial response according to RECIST relative to the total population of randomized subjects
• Timeframe: from screening (Days -28 to -1) until PD or death

Number of subjects with serious and non-serious adverse events

• Definition: assessment of the safety and tolerability
• Timeframe: from screening (Day -28 to Day -1) to follow-up visit (30 days after last dose of study drug ±
• 7 days)

Find out more about the TiNivo-2 study design >>

Eligibility Criteria

Patients with advanced renal cell carcinoma (aRCC) who are 18 years or older are eligible for the TiNivo-2 trial if
they have taken 1 or 2 prior lines of therapy, including an immune checkpoint inhibitor (ICI).

Additional inclusion criteria are as follows:

• Radiographic disease progression during or following at least 6 weeks of treatment with ICI for locally advanced or metastatic RCC with a clear cell component either in first- or second-line treatment
• Recovery from adverse events of a prior therapy or return to baseline
• Histologically or cytologically confirmed RCC with a clear cell component
• Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) criteria Version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Patients are not eligible for the trial if they have:

• Taken more than 2 prior lines of therapy in the advanced or metastatic setting
• A history of life-threatening toxicity related to prior immune therapy
• An active, known, or suspected autoimmune disease
• Uncontrolled hypertension
• Taken more than 1 prior line of therapy with a checkpoint inhibitor in the metastatic setting

If you are a healthcare provider, review the information below to see if your patients may be eligible for the TiNivo-2 study.

Read more about the eligibility criteria for this study >>

TiNivo-2 Trial Sites

These sites are currently open.

Actively recruiting:

The trial is continuing to add clinical sites. Tell colleagues who are interested in enrolling patients that the trial is now open. Contact us to discuss new site opportunities.

AVEO Clinical Development
(857) 400-0101
usmedinfo@aveooncology.com

Check here for trial site updates >>

Enroll your patients in the Phase 3 TiNivo-2 Trial

Let patients and colleagues know about this unique trial for advanced renal cell carcinoma (aRCC).

If you have any patients who are eligible and might be interested in participating or if you have any questions
about the trial, please contact:

AVEO Clinical Development
(857) 400-0101
usmedinfo@aveooncology.com

Participate as an investigator

The trial is continuing to add clinical sites and is looking for additional investigators to participate.

If you or a colleague would like to join as an investigator and have questions about enrolling your institution,
please contact:

AVEO Clinical Development
(857) 400-0101
usmedinfo@aveooncology.com

AVEO Oncology

Passionately pursuing a better life for patients with cancer

AVEO is an oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for cancer patients. We have numerous compounds in clinical testing across different cancer types.

View our clinical trial pipeline here >>

References

1. Zahoor H, Duddalwar V, D’Souza A, Merseburger AS, Quinn DI. What comes after immuno-oncology therapy for kidney cancer? Kidney Cancer. 2019;3(2):93-102.
2. Barata PC, De Liano AG, Mendiratta P, et al. The efficacy of VEGFR TKI therapy after progression on immune combination therapy in metastatic renal cell carcinoma. Br J Cancer. 2018;119(2):160-163.
3. Stukalin I, Dudani S, Wells C, et al. Second-line VEGF TKI after IO combination therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). J Clin Oncol. 2020;38(6):684.
4. Mohamed AF, Hauber AB, Neary MP. Patient benefit-risk preferences for targeted agents in the treatment of renal cell carcinoma. Pharmacoeconomics. 2011;29(11):977-88.
5. Pawlowski N, Hoerzer H, Singh-Jasuja H, Hilf N. Abstract 3971: Impact of various first- and second-generation tyrosine kinase inhibitors on frequency and functionality of immune cells. Cancer Res. 2013;73(8 Suppl):Abstract nr 3971.
6. ClinicalTrials.gov. Study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma. Accessed December 21, 2021. https://clinicaltrials.gov/ct2/show/NCT04987203
7. Fogli S, Porta C, Del Re M, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug- drug interactions of anti-angiogenic drugs. Cancer Treat Rev. 2020;84:101966.
8. Data on file. AVEO Pharmaceuticals, Inc.
9. FOTIVDA (tivozanib) [package insert]. Boston, MA: AVEO Pharmaceuticals, Inc, March 2021.
10. OPDIVO (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, March 2022.
11. Albiges L, Barthélémy P, Gross-Goupil M, Negrier S, Needle MN, Escudier B. TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2021;32(1):97-102.