Nivolumab/Tivozanib Combo Shows Promise in mRCC

Combining nivolumab with the angiogenesis inhibitor tivozanib led to a high response rate and durable disease control in patients with metastatic renal cell carcinoma, a preliminary open-label study showed.

Philippe Barthelemy, MD

Combining nivolumab (Opdivo) with the angiogenesis inhibitor tivozanib (Fotivda) led to a high response rate and durable disease control in patients with metastatic renal cell carcinoma (mRCC), a preliminary open-label study showed.

A majority of the 25 patients treated with nivolumab and tivozanib attained objective responses. The median progression-free survival (PFS) exceeded 1.5 years. Only 1 patient had progressive disease as best response.

In general, the combination had a favorable adverse-event profile with minimal off-target toxicity, as reported at the 2019 ESMO Congress.1

“The tivozanib/nivolumab combination regimen showed promising antitumor efficacy, with most patients demonstrating disease control for 60 weeks or longer,” Philippe Barthelemy, MD, of CHU Strasbourg-Nouvel Hopital in France, and colleagues concluded in a poster presentation. “The combination regimen was found to be comparable to other VEGFR TKI combinations. Plans are underway for an additional randomized trial.”

The introduction of immunotherapy and antiangiogenic agents has transformed treatment of mRCC in recent years. VEGF inhibitors, in particular, have become standard-of-care treatment for mRCC, and the European Medicines Agency (EMA) approved tivozanib as initial therapy for mRCC, Barthelemy noted.

Because of its highly selective inhibition of VEGFR, tivozanib has minimal off-target toxicity, making it an attractive option for combination therapy with a PD-1 inhibitor. Nivolumab is approved by the FDA and EMA as a second-line therapy for mRCC.

The initial report from the study of tivozanib and nivolumab in combination provided evidence of efficacy.2 Barthelemy and colleagues reported final results from the trial.

Key eligibility criteria for the phase Ib/II trial included any histology of mRCC, measurable disease, and zero or more prior lines of therapy. A total of 28 patients received one of two doses of tivozanib (1.0 or 1.5 mg QD) plus nivolumab 240 mg Q2W. During the phase I portion of the trial, 1.5 mg proved to be the maximum-tolerated dose (MTD) of tivozanib.

The primary objectives were safety, tolerability, and MTD, and antitumor activity was the key secondary objective. Response was assessed by CT or MRI every 8 weeks.

The final analysis included the 25 patients who received the MTD of tivozanib. The patients had a median age of 64, and men accounted for three-fourths of the cohort. Most patients received the tivozanib/nivolumab combination as first-line (48%) or second-line (44%) therapy. All but 1 patient had favorable- or intermediate-risk disease by International Metastatic Renal Cell Carcinoma Database Consortium criteria.

The efficacy analysis showed that 14 (56%) of the 25 patients had objective responses, including 1 complete response. Eight of the 13 partial responses occurred in previously treated patients. An additional 10 patients had stable disease (including 5 previously treated patients), resulting in a disease control rate of 96%.

The median time to best response was 7.9 weeks. Barthelemy reported that 16 (64%) patients had tumor shrinkage of at least 25%. Eight patients remained on treatment as of the ESMO meeting. The entire cohort had a median PFS of 18.9 months, which included 18.9 months in treatment-naïve patients and not yet reached in the previously treated subgroup.

Treatment-related adverse events (TRAEs) occurred frequently but were generally grade 1/2 in severity. The most common grade 3/4 TRAEs were hypertension (52%), laboratory abnormalities (32%, increased amylase, liver enzymes, alkaline phosphatase, gamma-glutamyl transferase, lipase), general disorders (12%, fatigue, systemic inflammatory response syndrome), and skin and related disorders (12%, palmar-plantar erythrodysesthesia, rash).


  1. Barthelemy P, Escudier B, Negrier S, et al. TiNivo: Tivozanib combined with nivolumab results in prolonged progression free survival in patients with metastatic renal cell carcinoma (mRCC): Final results. Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract 947P.
  2. Barthelemy P, Escudier B, Ravaud A, et al. TiNivo: Tivozanib combined with nivolumab: safety and efficacy in patients with metastatic renal cell carcinoma (mRCC). Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 878P.

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