In the TiNivo-2 study, the addition of nivolumab to tivozanib did not result in improved clinical outcomes in patients with metastatic renal cell carcinoma whose disease progressed on or after prior immune checkpoint inhibitor treatment.
To date, immune checkpoint inhibitors (ICIs) are the cornerstone of the first-line treatment of advanced metastatic renal cell carcinoma (mRCC). However, the optimal sequence in patients whose disease progressed after treatment with ICIs is uncertain. Evidence supports the use of VEGFR tyrosine kinase inhibitors, including tivozanib, in patients who were previously treated with ICI-based regimens. Previously, tivozanib was evaluated in combination with nivolumab in the phase I/II TiNivo study, demonstrating anti-tumour efficacy with an expected adverse event profile in patients with mRCC. To further explore retreatment with ICI, the phase III TiNivo-2 study of tivozanib in combination with nivolumab compared with tivozanib monotherapy in patients with mRCC following progression on prior ICI was designed.
TiNivo-2 is an international, randomised, open-label, phase III study that enrolled patients with advanced clear cell RCC after progression on 1 or 2 prior treatments, including treatment with an ICI. Patients were randomised to combination treatment consisting of tivozanib (0.89 mg per day, orally, for three weeks) plus nivolumab (480 mg, IV, once) or monotherapy with tivozanib (1.34 mg per day, orally, for three weeks) in 28-day cycles. The primary endpoint was progression-free survival (PFS) according to an independent radiology review. Key secondary outcomes were overall survival (OS), PFS as assessed by the investigators, the objective response rate (ORR), duration of response (DOR) and safety.
In total, 343 patients were randomised to the combination regimen (N= 171) or monotherapy (N= 172). After a follow-up of 11.8 months in the combination therapy group and 12.5 months in the monotherapy group, the median PFS according to the independent radiology review was 5.7 and 7.4 months, respectively (HR[95%CI]: 1.10[ 0.82-1.43]; p= 0.49). Among participants with an ICI as most recent therapy (N= 244), median PFS was 7.4 months in the combination therapy group and 9.2 months in the monotherapy group (HR[95%CI]: 1.10[0.80-1.52]; p= 0.56). No subgroup was identified that benefited from the addition of nivolumab. Median OS was 17.7 months in the group of patients receiving combination therapy, compared with 22.1 months in the group of patients receiving monotherapy (HR[95%CI]: 1.00[0.68-1.46]; p= 0.99). The ORR was 19.3% in the arm receiving combination therapy and 19.8% in the arm receiving monotherapy, with a median DOR of respectively 15.8 and 9.7 months.
Adverse events (AEs) of grade ≥3 occurred in 61% of patients receiving combination therapy and 60% of patients receiving monotherapy. The most common AE was hypertension, which was reported in 37% of patients in the combination therapy group and 40% in the monotherapy group. In 4% of patients receiving the combination therapy, an AE led to patient death, compared with 3% of patients receiving monotherapy. One of the deaths in the monotherapy group was attributed to the treatment.
The international, randomised, open-label phase III TiNivo-2 study has shown that adding nivolumab to second- or third-line treatment with tivozanib does not lead to better outcomes than monotherapy with tivozanib in patients with advanced clear cell RCC.
Reference
Choueiri TK, et al. Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): results of the phase III TiNivo-2 study. Presented at ESMO 2024; Abstract LBA73.
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