Nivolumab plus tivozanib explored in phase 3 kidney cancer trial

Following the recent FDA approval of tivozanib (Fotivda) in renal cell carcinoma (RCC), the VEGF-TKI is now being explored in combination with the PD-1 inhibitor nivolumab (Opdivo) in the phase 3 TiNivo-2 trial in patients with relapsed/refractory RCC.1

On March 10, 2021, the FDA approved tivozanib for the treatment of adult patients with relapsed or refractory advanced RCC who have received 2 or more prior systemic therapies.2 TiNivo-2 is randomizing patients with RCC who progressed after receiving immunotherapy to either tivozanib alone or in combination with nivolumab.

“With the recent US FDA approval of Fotivda in the relapsed/refractory RCC setting, I look forward to further exploring Fotivda’s immunomodulatory effects and differentiated tolerability profile in combination with Opdivo,” Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology; Director, Kidney Cancer Center; Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, stated in a press release.

“This combination was first explored in the phase 1/2 TiNivo study, where it demonstrated favorable tolerability and prolonged PFS using the combination of Fotivda and Opdivo in both treatment naïve and previously treated patients with advanced RCC. The TiNivo-2 Phase 3 study is expected to further our understanding of the activity and tolerability of this combination following prior immunotherapy,” added Choueiri.

The target enrollment of the open-label TiNivo-2 trial is 326 patients with advanced RCC and disease progression after receiving immunotherapy. The international trial is accruing patients at sites in the United States, Latin America, and Europe. The primary outcome measure is progression-free survival (PFS) and secondary end points include overall survival (OS), overall response rate, duration of response, and safety.

Tivozanib was approved by the FDA based on data from phase 3 TIVO-3 trial. Results from the study presented during the 2020 ASCO Virtual Scientific Program3 showed that the VEGF-TKI tivozanib demonstrated a significant improvement in PFS compared with sorafenib (Nexavar), with similar OS, in patients with highly relapsed/refractory metastatic RCC.

Results showed that the final hazard ratio (HR) for OS was 0.97 (P = .78). Moreover, an updated analysis of the data found that, with a median follow-up of 38 months for tivozanib and 40 months for sorafenib, the median OS was 16.4 months for tivozanib and 19.2 months for sorafenib. A subset analysis showed the greatest benefit was derived by the cohort of patients who previously received a checkpoint inhibitor and VEGF inhibitor, with an HR of 0.55, or 2 VEGF TKIs, with an HR of 0.57.

Prior findings showed an increased median PFS for tivozanib when compared with sorafenib at 5.6 months versus 3.9 months, respectively (HR, 0.73; P = .016).

Nivolumab currently has 3 FDA-approved indications for RCC.

“The advanced RCC treatment landscape has seen significant benefit from the introduction of immunotherapy-VEGF TKI combinations in earlier-line treatment, and we believe that this benefit could extend to the relapsed/refractory setting with an effective, well-tolerated combination,” Michael Bailey, president and chief executive officer of AVEO, stated in the press release.

“On the heels of the recent US FDA approval of Fotivda as monotherapy for the treatment of adult patients with relapsed or refractory advanced RCC following 2 or more prior systemic therapies, we are keenly interested in exploring its full potential in the combination setting. Working with our clinical collaborators and Bristol Myers Squibb, our goal is to advance this trial as expeditiously as possible,” added Bailey.


1. AVEO Oncology Announces Collaboration with Bristol Myers Squibb to Evaluate FOTIVDA® (tivozanib) in Combination with OPDIVO® (nivolumab) in Pivotal Phase 3 TiNivo-2 Trial in IO Relapsed Renal Cell Carcinoma. Posted online March 12, 2021. Accessed March 12, 2021.

2. AVEO Oncology Announces U.S. FDA Approval of FOTIVDA® (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma. Published online March 10, 2021. Accessed March 10, 2021.

3. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). Presented at: 2020 ASCO Virtual Program; May 27, 2020. Abstract 5062.